RCC- Staging and treatment of Renal Cell Carcinoma

In details about staging and treatment regarding renal cell carcinoma

1. Staging and Treatment of Renal Cell Carcinoma Dr. Bikash Chandra Sah. JR General Surgery.

2. Screening RCC remains primarily a surgical disease requiring early diagnosis to optimize the opportunity for cure . P rimary factor that limits the widespread implementation of screening for RCC is the relatively low incidence of RCC in the general population

3. Risk factor for RCC General Male gender , I ncreased age, and H eavy tobacco use . Generalized screening would be difficult to justify because the increase in relative risk associated with each of these factors is at best twofold to threefold.

4. Targeted population risk factor P atients with E nd-stage renal disease ( 5- to 20-fold higher than that in the general population ) A cquired renal cystic disease, T uberous sclerosis, and F amilial RCC ( Molecular screening, C-MET protooncogene mutation like others) R enal transplant recipients remain at high risk for RCC in the native kidneys, with detection in between 1.4% and 2.3% of patients within 3 years of transplantation . Patients suspected of having von Hippel-Lindau disease , or the appropriate relatives of those with documented disease.

5. Investigators at the National Institutes of Health have recommended that such patients be evaluated with Annual physical examination and ophthalmologic evaluation beginning in infancy; Estimation of urinary catecholamines at the age of 2 years and every 1 to 2 years thereafter; MRI of the central nervous system biannually beginning at the age of 11 years ; Ultrasound examination of the abdomen and pelvis annually beginning at the age of 11 years, followed by CT every 6 months if cysts or tumors develop; and P eriodic auditory examination.

6. Staging

7. Staging. Until the 1990s the most commonly used staging system for RCC was Robson’s modification of the system of Flocks and Kadesky . L imitations of this classification scheme are Tumors with lymphatic metastases, a very poor prognostic finding, were combined with those with venous involvement , many of which can be treated and potentially cured with an aggressive surgical approach. T he extent of venous involvement was not delineated in this system, and Tumor size, an important prognostic parameter, was not incorporated.

8. TNM staging classically is defined by the most advanced feature demonstrated by the tumor, yet important prognostic information can be lost in the process   Systemic symptoms such as S ignificant weight loss (>10% of body weight), C achexia , or P oor performance status at presentation all suggest advanced disease, as do physical examination findings of a palpable mass or lymphadenopathy . A non reducing varicocele and lower extremity edema suggest venous involvement .

9. Significant anemia, hypercalcemia , abnormal liver function parameters or sedimentation rate, or elevated serum alkaline phosphatase or lactate dehydrogenase level all point to the probability of advanced disease. R adiographic staging of RCC by high-quality abdominal CT scan and a routine chest radiograph:

10. CT Scan. Enlarged hilar or retroperitoneal lymph nodes (2 cm or more in diameter ), But, this should be confirmed by surgical exploration or percutaneous biopsy if the patient is not a surgical candidate . Many smaller nodes prove to be inflammatory rather than neoplastic and should not preclude surgical therapy.

11. The sensitivities of CT for detection of renal venous tumor thrombus and IVC involvement are 78% and 96%, respectively . CT findings suggestive of venous involvement include V enous enlargement, A brupt change in the caliber of the vein, Filling defects.

12. patients with right-sided tumors produce Most false-negative findings because of short length of the vein and the mass effect from the tumor combine to make detection of the tumor thrombus difficult. Venacavography is now best reserved for patients with equivocal MRI or CT findings or for patients who cannot tolerate or have other contraindications to cross-sectional imaging .

13. Metastatic evaluation in all cases should include Routine chest radiograph, S ystematic review of the abdominal and pelvic CT or MRI, and L iver function tests. Bone scintiscan can be reserved for patients with elevated serum alkaline phosphatase, bone pain, or poor performance status chest CT scan for patients with pulmonary symptoms or an abnormal chest radiograph . Patients with locally advanced disease, enlarged retroperitoneal lymph nodes, or significant comorbid disease may mandate more thorough imaging to rule out metastatic disease and to aid in treatment planning. Positron emission tomography (PET) has also been investigated for patients with high risk of metastatic RCC. Biopsy of the primary tumor and/or potential metastatic sites is also selectively required as part of the staging process.

14. Five year survival rate of Renal Cell Cancer.

15. Other factor like Patient-related factors such as: A ge , CKD , and Other comorbidities have a significant impact on overall survival and should be a primary consideration during treatment planning for patients with localized RCC C ompromised prognosis in patients with presumed localized RCC include systemic symptomatic

16. P athologic staging Pathologic stage has proved to be the single most important prognostic factor for RCC. Renal sinus involvement is classified along with perinephric fat invasion as T3a are higher risk of metastasis because of access to the venous system . Collecting system invasion has also been shown to confer poorer prognosis in otherwise organ-confined RCC.

17. Several studies demonstrate 5-year survival rates of 70% to 90% for organ-confined disease and document a 15% to 20% reduction in survival associated with invasion of the perinephric fat . Patients with direct or metastatic ipsilateral adrenal involvement, F ound in 1% to 2% of cases, Suggesting a hematogenous route of dissemination or a highly invasive phenotype. Eventually succumb to systemic disease progression with poor prognosis.

18. Venous involvement Once thought to be a very poor prognostic finding for RCC , S everal reports demonstrate that many patients with tumor thrombi can be salvaged with an aggressive surgical approach. These studies document 45% to 69% 5-year survival rates for patients with venous tumor thrombi as long as the tumor is otherwise confined to the kidney.

19. Patients with venous tumor thrombi and concomitant lymph node or systemic metastases have markedly decreased survival , and those with tumor extending into the perinephric fat have intermediate survival. Direct invasion of the wall of the vein appears to be a more important prognostic factor than level of tumor thrombus and is now classified as pT3c independent of the level of tumor thrombus

20. The major drop in prognosis comes in patients whose tumor extends beyond the Gerota fascia to involve contiguous organs (stage T4) and in patients with lymph node or systemic metastases Lymph node involvement has long been recognized as a dire prognostic sign because it is associated with 5- and 10-year survival rates of 5% to 30% and 0% to 5%, Systemic metastases also portend a particularly poor prognosis for RCC, traditionally with 1-year survival of less than 50%, 5-year survival of 5% to 30%, and 10-year survival of 0% to 5 %. Patients presenting with synchronous metastases fare worse.

21. Tumor size A n independent prognostic factor for both organ-confined and invasive RCC. Larger tumors are more likely to exhibit clear cell histology and high nuclear grade, and both of these factors correlate with a compromised prognosis.

22. Nuclear grade and histologic subtype RCC have been proposed on the basis of nuclear size and morphology and presence or absence of nucleoli. N uclear grade has proved in most cases to be an independent prognostic factor   Histologic subtype also carries prognostic significance. The presence of sarcomatoid differentiation or collecting duct, renal medullary, or unclassified histologic subtype denotes a poor prognosis.

23. The SSIGN score can be used to estimate cancer-specific survival based on TNM stage, tumor size, nuclear grade, and presence of tumor necrosis (Frank et al, 2002). The SSIGN score has been validated in multiple data sets , B ut the inclusion of histologic necrosis as a predictor limits its clinical usefulness .

24. N utshell RCC prognosis depends on clinical presentation, TNM staging, Histologic grading and other factor like age, stages of CKD, other comorbidities. Pathologic stage has proved to be the single most important prognostic factor for RCC organ confined RCC have better prognosis in comparison to involvement to adrenal gland, perinephric fat and collecting system involvement . If Venous thrombus or IVC involved thrombus level and invasion of wall determine prognosis

25. Lymph node invasion, systemic metastasis , synchronous metastasis have worst long term prognosis. Tumor size show independent prognostic factor. Nuclear grading in multivariate studies have proved to be independent of prognostic value nevertheless, Histologic sub variants have prognostic role.

26. Treatment.

27. TREATMENT OF LOCALIZED RENAL CELL CARCINOMA After recognizing great heterogeneity in the tumor biology of these lesions, and multiple management strategies are now available, including Radical Nephrectomy (RN), partial nephrectomy (PN), T hermal ablation (TA), A ctive surveillance (AS)

28. Renal Function after Surgery for Localized Renal Cell S urgery remains the mainstay for curative treatment of this disease. The objective of surgical therapy is to excise all tumor with an adequate surgical margin . RN when Robson and colleagues (1969 ) established this procedure as the gold standard curative operation for localized RCC.

29. RN is still a preferred option for Many patients with localized RCC, such as those with very large tumors (most clinical T2 tumors ). T he relatively limited subgroup of patients with clinical T1 tumors that are not amenable to nephron-sparing approaches . The main concern with RN is that it predisposes to CKD , which is potentially associated with morbid cardiovascular events and increased mortality rates.

30. Though Partial Nephrectomy ( PN) is not a stronger oncologic intervention than RN, and the only reasonable way to explain an advantage for PN . Significant results in favor of PN in mangment for T1 mass : A 61% risk reduction for the development of severe CKD, A 19% risk reduction in overall mortality, and A 29% risk reduction in cancer-specific mortality.

31. Radical Nephrectomy

32. Radical Nephrectomy: The prototypical concept of RN encompasses the basic principles of Early ligation of the renal artery and vein , R emoval of the kidney with primary dissection external to the Gerota fascia, E xcision of the ipsilateral adrenal gland, and P erformance of an extended lymphadenectomy from the crus of the diaphragm to the aortic bifurcation.

33. Performance of a perifascial nephrectomy is of during RN to prevent postoperative local tumor recurrence as approx 25% of clinical T1b/T2 RCCs manifest perinephric fat involvement . Tumor located in the upper portion of the kidney immediately adjacent to the adrenal gland is another relative indication for adrenalectomy

34. RCC metastasizes through the bloodstream independent of the lymphatic system in many patients, involved lymph nodes in many of these patients would be removed by conventional RN, which incorporates the renal hilar and immediately adjacent paracaval or paraaortic lymph nodes.

35. Approach The operation is usually performed through T ransperitoneal incision to allow abdominal exploration for metastatic disease and early access to the renal vessels. E xtended subcostal incision for most patients undergoing open RN. M idline incision is a reasonable alternative, and the T horacoabdominal approach can be useful for very large and potentially invasive tumors involving the upper portion of the kidney. E xtraperitoneal flank incision may be appropriate in E lderly patients or patients of poor surgical risk, but Limited exposure, particularly for large tumors or those with contentious hilar anatomy.

36. Laparoscopic RN is now established as a less morbid alternative to open surgery in the management of Low - to moderate volume (10 to 12 cm or smaller), L ocalized RCCs with no local invasion, L imited or no venous involvement, and M anageable lymphadenopathy. Robotic assisted surgery .

37. Follow up protocol

38. Partial Nephrectomy Nephron-sparing surgery

39. PN for the treatment of a renal tumor F irst described by Czerny in 1890 Nephron-sparing surgery entails complete local resection of the tumor while leaving the largest possible amount of normal functioning parenchyma in the involved kidney . Margin width appears to be immaterial as long as the final margins are negative ; T his is particularly relevant when the tumor is located within the hilum and preservation of renal function is at a premium. Gold standard management of small renal masses (clinical T1a ) in the presence of a normal contralateral kidney, presuming that the mass is amenable to this approach.

40. Indication PN Pt. with bilateral RCC or RCC involving a solitary functioning kidney . A solitary functioning kidney may be the result of unilateral renal agenesis, prior removal of the contralateral kidney, or irreversible impairment of contralateral renal function by a benign disorder . Relative indication for PN was represented by patients with unilateral RCC and a functioning opposite kidney affected by a condition that might threaten its future function , S uch as renal artery stenosis, hydronephrosis , chronic pyelonephritis, ureteral reflux, calculus disease, or systemic diseases such as diabetes and nephrosclerosis .

41. A functioning renal remnant of at least 20% to 30% of one kidney is necessary to avoid end-stage renal failure , although this presumes good functional status of the remaining parenchyma. So, pt must be advised about the potential need for temporary or permanent dialysis postoperatively. Local recurrence after PN for imperative indications traditionally ranged from 3% to 5 %, mainly when tumor is located in hilar region.

42. The RENAL scoring Radius , Endophytic vs. exophytic , Nearness to collecting system, Anterior/posterior , Location relative to polar lines O ther nephrometry scoring systems allow for assessment of the complexity of the tumor and have facilitated comparison of evolving surgical techniques for PN in this era .

43. Follow up protocol.

44. Long term complication Pt. increased risk for development of proteinuria, focal segmental glomerulosclerosis , and progressive renal failure due to Patients who undergo nephron-sparing surgery for RCC may be left with a relatively small amount of renal tissue and are at risk for development of long-term renal functional impairment from hyperfiltration renal injury.

45. Patients with bilateral RCC and von Hippel-Lindau disease require Surgery is the mainstay of treatment. B ilateral nephrectomy and renal replacement therapy or N ephron-sparing approaches such as PN For PN, an enucleative approach is often preferred rather than wide resection or TA to avoid end-stage renal disease. Local recurrence rates for patients treated with PN were 100% and 81%, respectively. Survival free of local recurrence after PN was 71% at 5 years but only 15% at 10 years.

46. L Local recurrence, which was defined as any persistent or recurrent disease present in the treated kidney or ipsilateral renal fossa after initial treatment

47. Thermal Ablative Therapies Includes Renal cryosurgery and R adiofrequency ablation (RFA ). High Intensity Focused Ultrasound ( HIFU) Both can be administered percutaneously or through laparoscopic .

48. Ideal candidates for TA procedures patients with advanced age or S ignificant comorbidities who prefer a proactive approach but are not optimal candidates for conventional surgery, patients with local recurrence after previous nephronsparing surgery . patients with hereditary renal cancer who present with multifocal lesions for which multiple PNs might be cumbersome. Patient preference must also be considered, and some patients not fitting these criteria may also select TA, a decision that can be supported as long as balanced counseling about the current status of these modalities has been provided Tumor size <4 cm.

49. R enal cryosurgery P rerequisites for successful cryosurgery include rapid freezing, gradual thawing, and a repetition of the freeze-thaw cycle. The mechanism underlying tissue cryodestruction is I nvolve immediate membrane and cellular damage followed by microcirculatory failure . Intracellular ice irreversibly disrupts cell organelles and the cell membrane, a lethal event. Delayed microcirculatory failure occurs during the slow thaw phase of the freeze-thaw cycle, leading to circulation arrest and cellular anoxia. Cells that survive the initial cryogenic assault are destroyed by this secondary insult of ischemia. Repetition of the rapid freeze–slow thaw cycle potentiates the damage.

50. Campbell and coworkers (1998) confirmed that the target lethal temperature of −20°C was achieved at a distance of 3.1 mm inside the leading edge of the iceball as visualized by real-time ultrasonography. In practice, we routinely extend the iceball approximately 1 cm beyond the edge of the tumor Encouraging outcomes for smaller tumors, particularly those less than 3.0 cm in diameter.

51. Complications associated with cryoablation I nclude R enal fracture, H emorrhage , A djacent organ injury , I leus , and W ound infection , I ncidence of treatment. Local recurrences (may require repetitive ablation or conventional surgery)

52. Radio F requency Ablation Application of high-frequency electrical current by RFA induces excitation of ions, frictional forces, and heat, which in turn cause denaturation of intracellular proteins and melting of cellular membranes, a lethal sequence of events. These effects are observed at tissue temperatures above 41°C but increase directly with increasing temperature and duration of treatment. Temperatures in excess of 100°C are typically obtained at the tips of the probes, and thermosensors can be used to monitor progress during active treatment.

53. Complications from RFA A re uncommon but have included A cute renal failure, S tricture of the ureteropelvic junction, Necrotizing pancreatitis, and L umbar radiculopathy. R elatively low rates of local recurrence, although some patients require repeat treatments to achieve local control, which is an infrequent event with cryoablation .

54. Other exciting new technologies Such as High-Intensity f ocused U ltrasound (HIFU) and F rameless , image-guided radiosurgical treatments ( CyberKnife ), These are also under development and may allow extracorporeal treatment of small renal tumors in the future . However, at present cell kill with these modalities is not sufficiently reliable and they are best considered developmental .

55. Active Surveillance Indication : The incidental discovery of many small RCCs in Small, solid, enhancing, well- marginated , homogeneous renal lesions ; Tumor < 3.5cm. Asymptomatic elderly patients orThose of poor surgical risk Patients who are unable or unwilling to undergo surgery. Those tumors grew at slow and variable rates of up to 1.1 cm per year, with a median growth rate of 0.36 cm per year . It can safely be managed with observation and serial renal imaging at 6-month or 1-year intervals .

56. AS is not appropriate for patients with L arger (>3 to 4 cm), poorly marginated , or nonhomogeneous solid renal lesions, when biopsy indicates a potentially aggressive RCC, Exception in patients with limited life expectancy .

57. TREATMENT OF LOCALLY ADVANCED RENAL CELL CARCINOMA

58. Inferior Vena Caval Involvement RCC has frequent pattern of growth intra- luminally into the renal venous circulation, also known as venous tumor thrombus . 4-10% of RCC involves IVC 45% to 70 % of patients with RCC and IVC thrombus can be cured with an aggressive surgical approach including RN and IVC thrombectomy .

59. IVC tumor thrombus It should be suspected in patients with a renal tumor who also have L ower extremity edema , Isolated right-sided varicocele or one that does not collapse with recumbency , D ilated superficial abdominal veins, P roteinuria , P ulmonary embolism, R ight atrial mass, or nonfunction of the involved kidney.

60. Imaging MRI: N oninvasive and accurate modality D emonstrates both the presence and the cephalad extent of vena caval involvement and T he preferred diagnostic . G adolinium contrast MRI: Enhance the tumor thrombus which differentiate from bland thrombus as it does not enhances

61. Renal vein thromus level Staging of the level of IVC thrombus is as follows: Level I: Adjacent to the ostium of the renal vein; Level II: extending up to the lower aspect of the liver ; Level III :involving the intrahepatic portion of the IVC but below the diaphragm; and Level IV: extending above the diaphragm.

62. Transesophageal echocardiography I s an invasive study U nnecessary before surgery, I mportant intraoperative diagnostic modality for evaluation of T hrombus extension, M onitoring for embolic phenomena, Recognition of residual tumor during and after resection, and A ssessment of preload/cardiac function during IVC clamping.

63. Treatment The surgical approach is tailored to the level of IVC thrombus, In general it uniformly begins with careful mobilization of the kidney and early ligation of the arterial blood supply . level I thrombi are isolated by a Satinsky clamp and are thus readily addressed. Level II thrombi require sequential clamping of the caudal IVC, contralateral renal vasculature, and cephalad IVC along with mobilization of the relevant segment of the IVC and occlusion of lumbar veins . The renal ostium is then opened and the thrombus is removed, all in a bloodless field.

64. Vascular control for level III and level IV IVC thrombi requires more extensive dissection, venovenous bypass, or cardiopulmonary bypass and hypothermic circulatory arrest. For level III thrombi , mobilization of the liver and exposure of the intrahepatic IVC will often allow the thrombus to be mobilized caudad to the hepatic veins, and venous isolation can then proceed as for a level II thrombus.

65. Locally Invasive Renal Cell Carcinoma Patients with pathologic stage T4 disease have represented less than 2% of surgical series. Patients with locally advanced RCC usually present with pain , generally from invasion of the posterior abdominal wall, nerve roots, or paraspinous muscles . Large tumors may indent and compress adjacent liver parenchyma.

66. S urgical therapy : T he only potentially curative management for RCC. E xtended operations with en bloc resection of adjacent organs are occasionally indicated . The aim of therapy is Complete excision of the tumor, including resection of the involved bowel, spleen, or abdominal wall muscles. Incomplete excision of a large primary tumor, or debulking , is rarely indicated as survival estimates are only 10% to 20% at 12 months.

67. Lymph Node Dissection for Renal Cell Carcinoma The need for extensive lymphadenectomy in patients undergoing RN remains controversial , as a randomized trial of lymphadenectomy at nephrectomy failed to show a distinct advantage.

68. Adjuvant Therapy for Renal Cell Carcinoma Unfortunately , recurrence develops in a significant proportion of patients thought to be rendered disease free after surgical resection, primarily due to occult micrometastatic disease. Distant metastases develop in 20% to 35% and L ocal recurrence in 2% to 5% of patients .

69. A strong rationale for systemic adjuvant therapy exists in high-risk patients. However , none of the adjuvant studies in this field have been convincingly positive thus far, and the standard of care remains observation if the patient will not consider an adjuvant trial.

70. Metastatic Tumors Metastatic tumors are the most common malignant neoplasms in the kidney , outnumbering primary renal tumors by a wide margin. The profuse vascularity of the kidney makes it a fertile soil for the deposition and growth of cancer cells. Autopsy studies have shown that 12% of patients dying of cancer have renal metastases. The most frequent sources of renal metastases include L ung , B reast , and G astrointestinal cancers, M alignant melanoma, and H ematologic malignant neoplasms .

71. Most renal metastases are M ultifocal , and A lmost all are associated with widespread nonrenal metastases The typical pattern of renal metastases consists of Multiple small nodules that are often clinically silent, A lthough they can lead to hematuria or flank pain in exceptional circumstances . CT typically demonstrates isodense masses that enhance only moderately (5 to 30 HU ) after administration of intravenous contrast material .

72. Renal metastases should be suspected in any patient with Multiple renal lesions and widespread systemic metastases or H istory of nonrenal primary cancer. If there is any uncertainty about the diagnosis, percutaneous renal biopsy usually provides pathologic confirmation

73. Management Most patients with renal metastases are managed with S ystemic therapy or P laced on a palliative care pathway, D epending on the clinical circumstances. Nephrectomy is almost never required except in extenuating circumstances, such as renal hemorrhage that is refractory to embolization.

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