Clinica Urologica ed Andrologica Università degli Studi di Chieti-Pescara

1. Kidneycancer: prognosticfactors and newsurgicalapproaches Clinica Urologica ed Andrologica Università degli Studi di Chieti-Pescara Scuola di Specializzazione in Urologia Direttore. Prof. R.Tenaglia Mediterranean School f Oncology ROMA 24 Novembre 2007 Chieti University Department of Medicine and Aging Science

2. What Is Kidney Cancer (Renal Cell Carcinoma)? Kidney cancer is a cancer that starts in the kidneys. In order to understand kidney cancer, it helps to know about the normal structure and function of the kidneys. Renal Cell Carcinoma (RCC) Renal cell carcinoma (also known as renal cell cancer or renal cell adenocarcinoma) is by far the most common type of kidney cancer. It accounts for about 9 out of 10 kidney cancers. Although RCC usually grows as a single mass within the kidney, sometimes tumors are found in more than one part of the kidney or even in both kidneys at the same time. Some renal cell carcinomas are noticed only after they have become quite large, but most are found before they metastasize (spread) to distant organs in the body. Like most cancers, RCC is hard to treat once it has metastasized.

3. There are five subtypes of RCC, based mainly on how the cancer cells look under a microscope Clear Cell Papillary Chromophobe Collecting Duct Unclassified This subtype accounts for about 5% of RCCs. The cells of these cancers are also pale, like the clear cells, but are much larger and have certain other features that can be recognized. This is the most common form of renal cell carcinoma. About 8 out of 10 people with renal cell carcinoma have this kind of cancer. When viewed under a microscope, the cells that make up clear cell RCC appear very pale or clear. This subtype is very rare. The major feature is that the cancer cells can form irregular tubes. The second most common subtype -- about 10% to 15% of people have this kind. These cancers form little finger-like projections (called papillae) in some, if not most, of the tumor. Some doctors call these cancers chromophilicbecause the cells take up certain dyes used in preparing the tissue to be viewed under the microscope, causing them to appear pink. In rare cases, renal cell cancers are labeled as "unclassified" because their appearance doesn't fit into any of the other categories or because there is more than one type of cell present.

4. Other Cancerous Kidney Tumors Less common cancers of the kidney include Transitional cell carcinomas Wilms tumors And Renal Sarcomas

5. RCC - Epidemiology • Approximately 40,000 cases per year • ~12,900 deaths per year • 2% - 3% of all cancers • Average age at diagnosis 50-70 • Nearly 40% of patients with RCC will eventually die from the disease • Associated with inherited syndrome in 2%

6. RCC Age Distribution Source – BAUS 2001

7. Von HippelLindau (VHL) Renal Carcinoma Gene LocalizationStudies: InheritedRenalCancer To identify the disease gene for kidney cancer the familial form of renal cell carcinoma associated with von HippelLindau disease was studied. Von HippelLindau syndrome is an autosomal dominant disease in which affected individuals develop kidney cancers as well as tumors in a number of differentorgans. VHL patients develop multiple, bilateral renal carcinomas and cysts, cerebellar and spinal hemangioblastomas, pheochromocytomas, retinalangiomas, epididymalcystadenomas, pancreaticcystsand islet cell tumors and tumors in the inner ear, endolymphatic sac tumors. ClinicalEvaluation: VHL - MRI of the brain and spine - Abdominal CT and ultrasound - Ophthalmologicevaluation - Audiometric and ENT evaluation - Testicular Ultrasound - Metabolicevaluation

8. It is important that VHL patients undergo a complete screening and metabolic evaluation PRIOR TO A SURGICAL PROCEDURE to rule out such unsuspected manifestations as a CNS hemangioblastomaorpheochromocytoma. The VHL Gene Has Characteristics of a Tumor suppressor Gene.

9. VHL: Surgical Management Surgical management of the renal manifestations of VHL patients involves nephron sparing surgery whenever possible. Patients with small renal tumors, generally under 2.5 cm, are often managed with expectant management. When the tumors reach 3 cm, surgery is often recommended. As it has been estimated that there can be up to 600 tumors per kidney in VHL patients, surgical resection of renal lesions is not considered “curative.” Rather, it is considered that surgical management will hopefully “set back the clock”; i.e. help prevent metastasis. Historically 35 to 45% of VHL patients have died of complications of metastatic renal cell carcinoma. The decision to recommend surgery must balance the risk of metastasis with the morbidity of surgery. When surgery is performed, thorough evaluation of the kidney with intraoperative ultrasound is considered a valuable adjunct to the surgical procedure. This allows the surgeon to localize renal tumors and cysts and to perform as thorough and safe a procedure as possible. Renal Lesions in VHL Patient Microscopic RCC Focus in the Kidney of a VHL Patient

10. Clinical Applications of Cancer • Gene Mutation Detection • 1) Molecular Genetic Classification of Kidney Cancer • The findings have lead to the introduction of a molecular genetic classification of kidney cancer, papillary versus clear, with clear cell renal carcinoma being characterized by mutation of the VHL gene. • Molecular Genetic Classification Of Renal Carcinoma Gene RCC • VHL Clear Cells/Compact Growth • Met Type I Papillary Growth Pattern • BHD Chromophobe renal cell carcinoma, Oncocytoma • FH Type II Papillary Growth Pattern • Somatic VHL Gene Mutation Analysis:

11. Potential Clinical Applications • Detection of VHL gene abnormalities in: • - Formalin fixed tissues • Tissue aspirates • Early Diagnosis • - Circulation Cells • - Urine

12. Renal Carcinoma Associated with Birt Hogg Dube Syndrome (BHDS) We have recently noted an associated of kidney cancer with an inherited familial syndrome known as Birt Hogg Dube Syndrome (BHDS). BHDS is an autosomal dominantly inherited syndrome in which affected individuals are known to be at risk for a cutaneous manifestation, the presence of fibrofolliculomas.

13. Familial Renal Carcinoma (FRC) Recently scientists in Iceland have performed studies suggesting that genetic susceptibility may be a major component in the development of ordinary, “sporadic” renal carcinoma. In their initial study, 68% of individuals in Iceland who had kidney cancer had up to a second degree relative (a second cousin) with kidney cancer. This work suggests that it is important to ask all patients with renal carcinoma whether any other family member also was affected with renal carcinoma. Urologic surgeons at the NCI are currently studying families in which multiple members are affected with kidney cancer (FRC) in order to identify the genetic basis of this form of kidney cancer.

14. Risk Factors for RCC • Smoking • Occupational exposure to toxic compounds • Obesity • Acquired cystic kidney disease • Analgesic abuse nephropathy • Genetic predisposition

15. Risk Factors for RCC • Smoking – • Cigarette smoking doubles the risk • Occupational exposure • cadmium RR 2.0 • asbestos RR 1.4 • gasoline RR 1.6 • increased exposure may be associated with gene mutations such as vHL tumor suppressor gene

16. D i a g n o s i s • CT scan • Ultrasonography • MRI • Renal arteriography • Percutaneous cyst puncture

17. RCC Genetics & Biology • Pathogenesis • VHL • Autosomal dominant • inheritance of one copy of a mutated allele followed by a second somatic gene alteration in the remaining allele leads to various cancers, including RCC • genetic abnormality localized to 3p25 to 3p26

18. RCC Genetics & Biology • Pathogenesis • Sporadic Clear Cell RCC • chromosomal losses often spanning 3p14 to 3p26 • VHL mutations found in up to 80% of sporadic clear cell RCC (Gnarra Nat Genet ’94; 7:85)

19. TNM Staging system Primary Tumor (T) T1 Tumor 7 cm or less in greatest dimension, limited to the kidney T2 Tumor more than 7 cm in greatest dimension limited to the kidney T3 Tumor extends into major veins or invades the adrenal gland or perinephric tissues, but not beyond Gerota’s fascia T3A Tumor invades adrenal gland or perinephric tissue but not beyond Gerota’s fascia T3B Tumor grossly extends into the renal vein (s) or vena cava below the diaphragm T3C Tumor grossly extends into the renal vein (s) or vena cava above the diaphragm T4 Tumor invades beyond Gerota’s fascia

20. Regional Lymph Nodes (N) N0 No regional lymph node metastases N1 Metastases in a single regional lymp h node N2 Metastases in more than one regional lymph node

21. Distant Metastases (M) • M0 No distant metastases • M1 Distant Metastases • The prognostic value of size was further emphasized by introducing an optional division of stage T1 into stage T1a (4 cm or less) and stage T1b (4 to 7 cm). Five-year survival for stage T1a and T1b was 98% and 88%, respectively.

22. Staging - Prognoses Predictors of Response • Historically, clinical factors alone were used as prognostic markers for RCC: • 1999 MSKCC (Motzer et al, J Clin Oncol)* • PS • LDH • Hgb • Corrected serum Ca++ • Nephrectomy status (*0 favorable risk, 1-2 intermediate risk, >3 poor risk) • Median Survival • favorable 20 months • intermediate 10 months • poor 5 months

23. Staging - Prognoses Predictors of Response International Kidney Cancer Working Group – currently creating a comprehensive data base of >4,000 patients with metastatic RCC to provide and validate a single model that can be used to predict survival. • Biomarkers being evaluated for their potential as prognostic factors: • tumor proliferation • tumor growth • angiogenesis • loss of cell adhesion • CA-IX is highly expressed in RCC, may be a useful prognostic and predictive marker.

24. Promising Therapies Target Specific mTOR, VEGF, EGFR, PDGF, RAF, KIT, proteosome Antibody Therapy VEGF +/– EGFR TKI EGFR CAIX  Renal CA cell Dendritic cell Vaccine gp 96 HSP CAIX/GM-CSF T cell Systemic cytokines (IL-2, IFN) Allogeneic stem cell transplant T Cell

25. Treatment • Surgery is the standard treatment for contained kidney cancer. • Various surgical options may be available to you, depending on tumor size and location within the kidney capsule. Such surgery is performed by a urologic surgeon. • Radiation and chemotherapy are not very effective in treating kidney cancer. Biologic therapies are used more frequently.

26. Treatment Options Surgery is best option Radical nephrectomy is the established therapy for localized renal carcinoma

27. Surgical Treatment Radical nephrectomy has been the standard of care for localized renal cell carcinoma since the description by Robson. Partial nephrectomy has been used to avoid dialysis in patients with a solitary kidney, compromised renal function, or bilateral multifocal (hereditary) tumors. However, performed in patients with small renal tumors (less than 4 cm) has been associated with survival similar to that found after radical nephrectomy.

28. Treatment Options Other treatments include: • Radiation therapy for renal cell carcinoma • Chemotherapy – not effective • Treatment with interleukin II and interferon can be used and at times renal cell carcinoma will respond • Interleukin II has resulted in 14% remission rate, 5% complete response and 9% partial response – approved by FDA

29. Five- year survival for localized renal cancers is related to size 100% (< 2.5 cm) 83% (2.5- 4.9cm) 61% (5.0- 7.4 cm) 51% (7.5- 10.0 cm) 27 % (greater than 10.0 cm) These and other observations led to a change in the TMN classification of stage T1 renal tumors from 2.5 cm in diameterto 7.0 cm in diameter.

30. Partial Nephrectomy Sporadic renal cancer A solitary small renal tumor is ideally suited for partial nephrectomy with an adequate margin. Surface cooling for 10 minutes with ice slush will then provide up to 3 hours safe ischemia. Excision of the renal tumor with a 1 cm margin is performed by the appropriate technique, including wedge resection, transverse or amputation, or segmental renal artery occlusion with resection of the appropriate renal segment. Small polar tumors may be exc ised with local pressure in the absence of renal artery occlusion. Extracorporeal partial nephrectomy with renal autotransplantation is seldom performed now except in the setting of the Jehovah’s witness with multiple or complex tumors. Five- year cancer specific survival after partial nephrectomy has been reported to be 87 to 90%, with a local recurrence in 4 to 6%.

31. Hereditary renal cancer Hereditary renal cancer syndromes are characterized by the presence of bilateral, multiple renal tumors, often presenting in the third and fourth decade of life. Examples of hereditary renal cancer syndromes include Von Hippel-Lindau disease (VHL) Hereditary Papillary Renal Cancer (HPRC) Hereditary Renal Oncocytoma (HRO) Burt-Hogg-Dubé. Examination of normal renal tissue from patients with renal cancer and VHL has shown microscopic renal tumors are frequently present. Extrapolations based on these studies predict as many as 600 clear cell renal cancers and 1100 clear cell cysts per kidney. These cysts are found only in VHL patients, and are microscopically and genetically similar to clear cell renal cancer. .

32. Treatment options Bilateral nephrectomy Included observation,or renal parenchymal sparing surgery to remove renal tumors while sparing normal tissue. Before the widespread use of computerized tomography, VHL renal tumors were not well imaged, and 35 to 45% of VHL patients died of metastatic renal cancer. Median age at death was 44 years and the youngest reported patient died at age 23 years. These data represent the best available estimate of the natural history of untreated VHL. HP RC is a recently described hereditary cancer syndrome inherited in an autosomal dominant fashion.

33. The treatment strategy of bilateral nephrectomy and renal replacement removes all tissue at risk of developing renal cancer and metastases. The one-year survival in 30 to 40 year old, white,nondiabetic renal failure patients (characteristics similar to those of VHL patients detected by screening) is 78% with dialysis. Two- year survival with a living related or cadaver transplant is 96% and 78%, respectively. Similarly, a 65% 5-year survival of VHL patients has been reported after bilateral nephrectomy and renal replacement.

34. The treatment strategy In order to delay surgeries and improve quality of life, a strategy consisting of observing patients with hereditary renal cancer until the largest tumor was 3 cm in diameter before recommending surgery, regardless of the recurrence pattern or number of tumors was implemented. Fifty-two VHL patients had renal tumors less than 3 cm in diameter (group 1), and were followed a median of 5 years. No metastases were observed in these patients

36. 1. The renal capsule is first incised sharply. 2. The tumor is gradually dissected out. 3. The defect is packed with thrombin soaked gelfoam.

37. Nephrectomy in Metastatic RCC • Nephrectomy in pts with metastatic RCC • palliation of symptoms • therapeutic • Metastatic disease: Resection of solitary mets – 5-yr. survival of 35-50% • (Kavolius J Clin Oncol ’99; 16:2261)

38. Nephrectomy in Metastatic RCC • α-IFN +/- Nephrectomy in Metastatic Dz • SWOG 8949 (246 pts) • Survival (months) • No • Nephrectomy Nephrectomy • All Pts 8.1 12.5 • PS 0 12.8 17.4 • 1 4.8 6.9

39. Radiofrequency Ablation Tissue radiofrequency ablation (RFA) takes advantage of the same technology present in the surgical Bovie we use every day, when tissue is cauterized or cut. Fourteen to eighteen gauge needles, some with deployable arrays, are inserted in the tumor using ultrasound or CT guidance. Power output has increased from 50 watts in early models to 250 watt generators that will soon be available, allowing increases heat delivery to tissues. The ablation process is monitored using temperature feedback from thermocouples located in the tips of the catheter prongs or by changes in impedance during treatment. At least two 10-minute treatments per tumor are performed. The needle tract is cauterized to avoid bleeding and prevent tumor seeding. Energy delivered to tissues resulting in heating tissues to 60- 70o C, causing cell death. Currently, tumors up to 5- 6 cm in diameter may be treated with a single needle insertion. Three companies have commercially available radiofrequency ablation generators and needles; Radionics, Radiotherapeutics, and RITA Medical Systems.

40. The greatest experience with RFA has been in the treatment of normal and malignant liver tissue. RITA was the first device available for soft tissue treatment. The lesions induced by RITA are well demarcated and well seen as early as one day after treatment. Gross examination of treated porcine liver tissue has shown a central firm core of cooked tissue, with a surrounding 1-2 mm hemorrhagic, well demarcated perimeter. Microscopic examination demonstrates microvascular thrombosis and coagulative necrosis. In the porcine model, 3.5 to 4 cm lesions could be reproducibly generated, and larger lesions in humans have undergone treatment. The greatest human experience with this system is in the treatment of liver metastases. Few complications have been reported in treating liver tumors, except for mild discomfort at the skin site, when percutaneous RITA is performed. A similar, although limited, experience has been observed in radiofrequency ablation of renal cancers.

41. Histologic exam of treated tumors is very limited. We have recently excised tumors from previously treated patients that responded or did not respond to RFA. Tumors with a “halo” sign consisted of a fibrous capsule containing necrotic fluid and tumor. Enhancing tumors had focal areas of residual tumor. Necrotic tumor 1 year after ablation Foci of viable tumor 1 year after RFA

42. Laparoscopic Radical Nephrectomy Localized Renal Cancer Laparoscopic radical nephrectomy was first performed by Clayman in 1990, and a growing worldwide experience has shown laparoscopic surgery is safe and associated with similar survival as open surgery. Patients eligible for laparoscopic radical nephrectomy have similar characteristics as those undergoing open nephrectomy, with the exception of a vena caval thrombus. While local invasion of tumor, large tumors, metastatic disease, and extensive retroperitoneal lymphadenopathy add significantly to the degree of difficulty, they are not absolute contraindications to laparoscopic radical nephrectomy. Hand assisted laparoscopic surgery and retroperitoneal or transperitoneal approaches can be used at the surgeons preference. Small localized tumors are best suited to gain experience with this approach.

43. Laparoscopic Radical Nephrectomy Several hundred laparoscopic nephrectomies have been reported for cancer. Laparoscopic radical nephrectomy has been associated with a decrease in blood loss, postoperative analgesic requirements, hospital stay, and time to return to normal activities, compared to open radical nephrectomy. Two-year follow-up has shown an over 95% cure rate, similar to open nephrectomy. The nephrectomy specimen may be removed through a small incision, or fragmented and removed in pieces through a 10 mm port. Placement of the kidney in an impermeable sac prior to morcellation is performed to prevent tumor spillage. Tumor morcellation has been performed with ring forceps or a high-speed electrical tissue morcellator. Pathologic evaluation of morcellated tissue can be performed, although very small tumors may not be identified. Staging information is lost during morcellation.

44. Metastatic Renal Cancer 1 Tumor bleeding and pain can often adversely affect the ability to treat patients with metastatic renal cancer. At the NIH, over 200 patients with metastatic renal cancer underwent cytoreductive nephrectomy as preparation for systemic treatment with Interleukin-2, chemotherapy based regimens, or anti-angiogenic based regimens. These were bulky tumors usually required a chevron incision. 23% of patients required an additional resection, most commonly a regional lymph node dissectio n or vena caval thrombus extraction. While there was similar morbidity to surgery performed in patients with localized renal cancer, 38% were not eligible for high dose Interleukin-2, usually because of progression of disease during the 6-week recovery time prior to treatment. We looked at laparoscopic surgery as a way to decrease morbidity and shorten time to treatment. The benefit of laparoscopic nephrectomy in terms of time to recovery and completeness of resection has been demonstrated in patients with small renal tumors and no local invasion or metastases, but has not been reported in patients with metastatic disease. Tumor morcellation further reduces surgical trauma, since tumor dissemination is not a primary concern in patients with metastatic cancer. Laparoscopic techniques thus offer the possibility of lower morbidity, faster recovery, and more rapid patient availability for systemic treatment

45. Others strategy From January, 1995 to November, 1997, 44 patients with metastatic renal cell carcinoma and renal primary in place underwent cytoreductive surgery prior to systemic treatment with Interleukin-2. Patients undergoing open cytoreductive nephrectomy served as historical controls. • Schmidt, L et al. Germline and somatic mutations in the tyrosine kinase domain of the MET proto-oncogene in papillary renal carcinomas. Nat.Gen., 16: 68-73,1997. • Schmidt, L. et al .Novel mutations of the MET proto-oncogene in papillary renal carcinomas. Oncogene, 18: 2343- 2350, 1999. • Latif, F et al. Identification of the von Hippel-Lindau disease tumor suppressor gene. Science, 260: 1317-1320, 1993.

46. Large renal tumors Could not be lifted and placed into the 8 by 10 inch "lapsac" surgical tissue pouch used for morcellation. Instead, with the patient in the Trendelenburg position, one or two additional ports were used to facilitate opening the morcellation sac, allowing the specimen to slide in. The mouth of the sac was draped with towels and an occlusive adhesive barrier. A COOK Tissue MorcellatorTM (COOK, Spencer, IN) was used to extract the tumor from the "lapsac". The use of twelve- inch tissue forceps alternating with the morcellator greatly facilitated tissue removal. Contaminated drapes, gloves, gowns and instruments were removed after tumor morcellation. Patients undergoing laparoscopic surgery had their tumor removed without an incision using morcellation, or through a small incision. Patients undergoing radical nephrectomy by an open, laparoscopic, or laparoscopic assisted technique had similar gender, age, performance status, tumor size, and number of metastatic sites. Six patients had laparoscopic ports placed and the tumor specimen removed with morcellation. Five additional patients did not undergo morcellation and had their tumors removed intact.

47. Laparoscopic Radical Nephrectomy The year 1990 ushered in the minimally invasive management of renal malignancy. Clayman and colleagues reported the first laparoscopic radical nephrectomy for suspected renal cell carcinoma. Over the last decade, we have seen a rapid movement toward minimally invasive surgery of the kidney. The decreased perioperative morbidity, less pain, and shorter hospitalization and convalescence have primarily been responsible for this movement. As surgeons seek to expand their surgical armamentarium, we have seen the development of Hand Assisted Laparoscopic techniques. Indications for miminally invasive surgery have also expanded to other indications such as nephron sparing surgery. The mo st recent direction of the minimally invasive movement has been toward incorporating ablative technologies such as cryoablation and Radiafrequency thermal ablation into laparoscopic and even percutaneous treatment of small renal lesions.

48. Laparoscopic Radical Nephrectomy The gold standard for surgical management of T1 –T3N0M0 RCC is the removal of the kidney and surrounding tissues as originally described by Robson in the 1960’s. Clayman and collegues applied laparoscopic techniques to perform a laparoscopic radical nephrectomy for suspected RCC in 1990. The initial reports were met with some skepticism, but now multiple institutions have adopted the minimally invasive approach for the treatment of RCC. There is a growing body of evidence that demonstrates the safety and efficacy of laparoscopic radical nephrectomy.

49. In 2001, Chan et al reported on 67 laparoscopic nephrectomies performed for renal cell carcinoma. The authors reported a 5 year disease free survival of 95% for this series, despite at least some degree of understaging in the laparoscopic cases done with specimen morcellization. This was consistent with earlier results from Ono (1999) and Cadeddu (1998) demonstrating 97.5% and 91% 5 year disease free survival rates. Portis et al reported a multicenter experience with 64 patients undergoing laparoscopic radical nephrectomy, comparing these cases to a series of 69 comparable open radical nephrectomy patients. The authors noted excellent oncologic results noting no positive margins in the laparoscopic group, no port site or local recurrence. The disease free survival overall was 92% in the laparoscopic group (91% in the open cohort) and cancer specific survival was 98% (laparoscopic) vs. 92% (open). The laparoscopic group has slightly smaller tumors but analysis of survival by tumor size (> or < 7cm) demonstrated comparable results in the open and laparoscopic cohorts. All of these series continue to demonstrate the acceptable morbidity, shorter hospitalization, faster convalescence and less pain associated with the laparoscopic vs. open radical nephrectomy. With the emergence of 5 year data demonstating excellent oncologic results, the move toward minimally invasive surgery of the kidney as first line therapy for T1 – T2 renal cell carcinoma appears justified.

50. Partial Nephrectomy Nephron sparing surgery (NSS) is an accepted method of treatment for selected renal masses. Long term results for properly selected masses reveal oncologic control comparable to the golden standard, radical nephrectomy. Laparoscopic partial nephrectomy (LPN), has been shown to be technically feasible by several authors including Janetschek, McDougall, Gill, Rassweiler, and others. The goal of LPN is to maintain the principles of open NSS in order to maintain the excellent oncologic control associated with NSS. The challenge with LPN is attainment of suitable hemostasis. The indications for LPN are fairly straightforward. The patient must be able to tolerate a laparoscopic procedure. The properly selected renal lesion should be less than 4cm in size and peripheral in nature. Polar lesions are preferable, especially early in the laparoscopic surgeon’s experience with this technique. Renal masses abutting the hilar vessels and central collecting system can be safely resected by the experienced surgeon. Patients with prior renal surgery or history of anyinflammatory conditions of the operative kidney should be avoided.