THE MANAGEMENT OF RENAL CELL CARCINOMA (RCC).pptx

This PowerPoint is aimed enhancing relevant knowledge on renal cell carcinoma and its management. Its suitable for the scholars in urology and medical students who would wish to pursue urology later in their career. The slides are designed to lay a good foundation for understanding of renal cell carcinoma.

1. RENAL CELL CARCINOMA (RCC) Dr. Chipili B . Bsc.HB, MBChB, FZCMS (Urology)

2. Incidence RCC accounts for 2% to 3% of all adult malignant neoplasms The incidence has now increased due to more prevalent use of imaging for nonspecific abdominal complaints It is the most lethal of all common urological cancers The typical presentation is between 55 and 75 years of age It has a male to female ratio of 3 : 2 The majority of RCC are sporadic and only 4% to 6% are familial

3. Etiology RCC is thought to arise from the nephron Different histological subtypes arise from different parts of the nephron The most generally accepted environmental risk factors for RCC are; Tobacco exposure Obesity Hypertension Other risk factors include end-stage renal failure on dialysis and acquired renal cystic disease

4. Familial RCC and molecular genetics This is the form of RCC in which one mutant allele is transmitted during birth predisposing all cells in various organs at risk of malignancy This accounts for the multifocality and early onset nature of familial RCC RCC is generally believed to follow a two-hit theory of carcinogenesis Both familial and sporadic forms are associated with tumor suppressor genes and oncogenes Familial RCC is associated with various clinical syndromes

5. Syndromes associated with familial RCC Von Hippel-Lindau disease Hereditary papillary renal cell carcinoma syndrome Hereditary Leiomyomatosis and Renal cell carcinoma Birt-Hogg-Dube Syndrome Cowden Syndrome Tuberous Sclerosis Complex Succinate Dehydrogenase Renal Cell Carcinoma Microphthalmia-Associated Transcription Factor–Associated Cancer Syndrome

6. von Hippel-Lindau Disease and VHL gene Characterized by RCC, pheochromocytoma, retinal angiomas and hemangioblastomas of the brainstem, cerebellum and spinal cord Histological subtype of RCC in von Hippel-Lindau (VHL) disease is clear cell Other common manifestations include renal and pancreatic cysts, neuroendocrine tumors of the pancreas, inner ear tumors and papillary cystadenoma of the epididymis RCC develops in about 50% of VHL disease

7. von Hippel-Lindau Disease and VHL gene RCC has early age at onset (3 rd to 5 th decade), usually bilateral and multifocal The is syndrome results from a mutation in the VHL tumor suppressor gene on chromosome 3 VHL protein complexes with hypoxic inducible factors 1 ά and 2 ά (HIF-1 ά and HIF 2- ά ) resulting in their ubiquitin mediated degradation This keeps the HIFs low under normal circumstances Inactivation or mutation of the VHL gene leads to accumulation of HIFs and most notably HIF-2 ά

8. von Hippel-Lindau Disease and VHL gene Accumulation of HIF-2 ά leads to upregulation of the expression of vascular endothelial growth factor (VEGF) VEGF is the primary angiogenic growth factor which contributes to pronounced neovascularity associated with clear cell RCC HIF-2 ά also upregulates the expression of other growth factors that promotes tumorigenesis These growth factors include transforming growth factor- ά , platelet growth factor, glucose transporter 1, erythropoietin and carbonic anhydrase 1

9. Hereditary Papillary Renal Carcinoma Syndrome This syndrome presents with multifocal and bilateral papillary RCC Unlike VHL disease HPRC does not present with tumors in other organs It is associated with type 1 papillary RCC Papillary RCC is characterized by trisomy for chromosomes 7 and 17 and abnormalities on chromosomes 1, 12, 16, 20, and Y Most mutations in HPRC are in the c-MET gene a proto-oncogene These mutations lead to a constitutive activation of the hepatocyte growth factor

10. Hereditary papillary renal carcinoma syndrome Activation of the hepatocyte growth factor results in cellular proliferation and other potential tumorigenic effects Like any other familial syndrome of RCC it has an autosomal dominant mode of transmission

11. Hereditary Leiomyomatosis and Renal Cell Carcinoma This syndrome presents with cutaneous and uterine leiomyomas in addition to RCC Associated with type 2 papillary RCC Renal tumor in this syndrome are unusual for familial RCC as it is often solitary, unilateral and aggressive The associated gene mutation in this syndrome is fumarase hydratase on chromosome 1 The RCC in this syndrome requires prompt surgical management

12. Birt-Hogg-Dube Syndrome This syndrome is associated with a variety of renal tumors derived from distal nephron These tumors include chromophobe RCC, oncocytomas and a hybrid of these two entities It is also associated with cutaneous fibrofolliculomas, lung cysts and spontaneous pneumothoraces BHD gene a tumor suppressor gene on chromosome 17 is responsible for this syndrome BHD gene codes for folliculin which forms a complex of proteins that interferes with mammalian target of rapamycin (mTOR)

13. Birt-Hogg-Dube Syndrome Loss of folliculin leads to activation of mTOR signaling complexes 1 and 2 (mTORC1 and mTORC2) This leads to increased transcriptional activities and nuclear translocation of TFE3 This eventually results in the upregulation of several growth factors

14. Cowden syndrome It is one of the several syndromes resulting from germline mutations of the phosphate and tensin ( PTEN ) tumor suppressor gene Syndromes with this germline mutation are collectively referred to as PTEN hamartoma tumor syndrome Cowden syndrome carries a 50% risk of breast cancer, 34% risk of RCC and 10% risk of epithelial thyroid cancer RCC in this syndrome is mostly papillary type

15. Tuberous sclerosis complex Tuberous sclerosis complex (TSC) is an autosomal dominant disorder that manifests with characteristic tumors in multiple organs These tumors include AML, cortical tubers, subepidermal nodules or subepidermal giant cell astrocytomas (SEGA), pulmonary lymphangioleiomyomatosis (LAM), cardiac rhabdomyomas and facial angiofibromas The major clinical manifestations include adenoma sebaceous, epilepsy, mental retardation and renal cysts and AMLs

16. Tuberous sclerosis complex Germline mutations in either TSC1 gene on chromosome 9 or TSC2 gene on chromosome 16 are responsible for TSC The TSC1/TSC2 complex normally downregulates the mTOR pathway Renal AML are typically multifocal, bilateral and often large They may require angioembolization or partial nephrectomy to treat or prevent bleeding from larger (>5cm) tumors

17. Tumor biology and clinical implications RCC demonstrates limited response to cytotoxic chemotherapy and this contributes to poor prognosis of metastatic disease RCC expresses multi-drug-resistant proteins (MDR-1) on its surface (also known as glycoprotein P) These molecules act as energy dependent efflux pumps for a wide variety of hydrocarbon cytotoxic compounds This contributes to the chemorefractory nature of advanced RCC Resistance to cisplatin and other agents not extruded by MDR proteins suggests redundancy in chemotherapy resistance mechanism

18. Immunology and Immune Tolerance RCC is an immunogenic tumor but suppresses the immune system T lymphocytes have cytotoxic T lymphocyte antigen-4 (CTLA-4) and programed death-1 (PD-1) cell surface receptors Under normal circumstances these receptors participate in immune system regulation They serve an inhibitory role and prevent autoimmune disease RCC expresses PD-L1 which causes increased activation of the PD-1 and CTLA-4 resulting in downregulation of the T lymphocytes This forms the basis of immune checkpoint inhibitors

19. Angiogenesis and Targeted pathways RCC has long been recognized as one of the most vascular cancers The primary angiogenic factor in clear cell RCC is vascular endothelial growth factor (VEGF) VEGF is normally suppressed by the wild type VHL protein and upregulated during tumor development VEGF receptors (VEGFR) are tyrosine kinases that are a target of multiple tyrosine kinase receptor blockers (TKIs)

20. Other signal transduction and cell regulation pathways Altered cell circle kinetics in RCC is affected by other signal transduction pathways These pathways become excellent targets for therapeutic intervention One of such pathways is the mTOR pathway The expression of mTOR is upregulated by various growth factors or mutation of PTEN This upregulation leads to increased expression of HIFs and other growth promoting and potentially tumorigenic sequalae mTOR is also another target for therapeutic intervention

21. Other signal transduction and cell regulation pathways Mutations in c-MET proto-oncogene and upregulation of the hepatocyte growth factor most commonly result in papillary RCC It may also occur in other histological subtypes of RCC Under normal circumstances hepatocyte growth factor is expressed by proximal tubular cells It is important in branching tubulogenesis in the developing kidney and regeneration after kidney injury c-MET is a potential therapeutic target for papillary RCC

22. Pathology Most RCC are round to ovoid and are circumscribed by a pseudocapsule of compressed parenchyma and fibrous tissue Most tumors are not grossly infiltrative except for collecting duct carcinoma and sarcomatoid variants Most sporadic RCCs are usually solitary and unifocal Bilateral involvement can be synchronous or asynchronous and is found in 2% to 4% of sporadic RCC Bilateral tumors are more common in familial forms of RCC RCC has a predilection venous system involvement

23. Pathology All RCCs are adenocarcinomas by definition derived from the renal tubular epithelial cells Nuclear features are highly variable and are independent prognostic factors for RCC generally (clear cell and papillary in particular)

24. Histological classification of RCC Clear cell Papillary Chromophobe Collecting duct Renal medullary carcinoma Sarcomatoid Unclassified

25. Clear cell RCC It’s the most come histological subtype and accounts for 70% to 80% of all RCCs Typically, yellowish in appearance of the cut surface and highly vascular On microscopic examinations they contain clear cells, granular or eosinophilic cells or mixed types Has worse prognosis compared to papillary type 1 and chromophobe Chromosome 3 alterations occur in more than 90% of clear cell RCC This leads to mutation or inactivation of the VHL gene

26. Clear cell RCC

27. Papillary RCC It’s the second most common histological subtype and makes up 10% - 15% of all RCCs Has a unique feature of multicentricity which approaches about 40% Type 1 papillary RCC is more common form and consist of basophilic cells with scanty cytoplasm Type 2 is a more aggressive variant with eosinophilic cells and abundant granular cytoplasm Type 1 papillary RCC has a better prognosis than clear cell while type 2 is similar or worse

28. Chromophobe RCC Represents 3% to 5% of all RCCs and is derived from the distal convoluted tubules Commonly seen in BHD syndrome but most cases are sporadic Has a characteristic perinuclear clearing referred to as “halo” Electron microscopy shows numerous 150- to 300nm macrovesicles which are single most and distinctive feature of chromophobe RCC It has a better prognosis than ccRCC when localized but poor outcome when consist sarcomatoid features or metastatic

29. Collecting duct carcinoma Carcinoma of the collecting ducts of bellini is rare subtype of RCC It has poor prognosis Most reported cases of this subtype are high grade, high stage and unresponsive to conventional therapies The characteristic immunophenotype of these tumors is the coexpression of low and high molecular weight cytokeratins and Ulex europaeus agglutinin-1 reactivity

30. Renal medullary carcinoma This is uncommon subtype of RCC that occurs almost exclusively in sickle cell It is typically diagnosed in young African-Americans in the 3 rd decade of life Many cases are locally advanced or metastatic at the time of diagnosis Most do not respond to therapy and usually result in mortality within few months

31. Sarcomatoid Sarcomatoid differentiation is found in 1% to 5% of RCCs most commonly in association with clear cell or chromophobe RCC Rarely found in pure form but in association with other histological subtypes No longer considered as a distinct histological subtype of RCC It is characterized by infiltrative growth pattern, aggressive local and metastatic behavior The prognosis is poor

32. Unclassified RCC Unclassified RCC represents a minority of cases (1% to 5%) of RCC with indeterminate features Many are poorly differentiated and are associated with highly aggressive biologic behavior Prognosis is usually poor

33. Clinical presentation Asymptomatic Symptomatic Hemorrhage Locally advanced Paraneoplastic syndrome Metastatic

34. Asymptomatic Most renal masses are asymptomatic and nonpalpable due to the sequestered location of the kidneys in the retroperitoneum More than 60% of RCC is discovered incidentally This is attributed to the increased usage of imaging for a variety of nonspecific abdominal symptoms Most tumors discovered incidentally are confined to the kidneys and have a good prognosis

35. Symptomatic Flank pain is due to hemorrhage and clot obstruction but can also be due to locally advanced disease The classic triad of flank pain, gross hematuria and palpable mass is rare (10% to 12%) Almost always denotes advanced disease Other indicators of advanced disease include constitutional symptoms such as weight loss, fever and night sweats Minority of RCC presents with symptoms of metastatic disease such as bone pain and persistent cough

36. Paraneoplastic syndrome This phenomenon found in about 10% to 20% of RCC More common in metastatic disease and almost nonexistent in small incidental renal masses Results from the excessive release of various molecular substances by the tumor which affect the physiological processes The most common paraneoplastic syndromes are Hypertension Hypercalcemia Non metastatic hepatic dysfunction (Stauffer syndrome) Polycythemia

37. Paraneoplastic syndrome Hypertension is due to excessive production of renin directly from the tumor It may also arise from compression of the renal artery or its branches leading to arterial stenosis and stimulation of renin production Polycythemia is due to increased production of erythropoietin from the tumor or adjacent parenchyma in response to hypoxia induced tumor growth Non metastatic hepatic dysfunction is due to excessive production of IL6 and other cytokines from the tumor Characterized by elevated alkaline phosphatase, prothrombin time, bilirubin and transaminase levels and hypoalbuminemia

38. Paraneoplastic syndrome Stauffer syndrome may present with fever and weight loss Hypercalcemia is due to paraneoplastic syndrome or osteolytic metastatic bone involvement In paraneoplastic syndrome it results from production of parathyroid like related peptides by the tumor Clinical manifestations of hypercalcemia are often nonspecific and include nausea, anorexia, fatigue and decrease deep tendon reflexes Medical management is the first line treatment for hypercalcemia of paraneoplastic syndrome

39. Paraneoplastic syndrome Medical management of hypercalcemia involves; Vigorous hydration, diuretics with furosemide and selective use of bisphosphonates or calcitonin Bisphosphonate therapy is a standard of care of hypercalcemia of malignancy provided renal function is adequate Zoledronic acid 4mg IV every 4 weeks Should be withheld renal function is insufficient If refractory to bisphosphonates denosumab therapy is considered Definitive management includes nephrectomy and occasional metastasectomy

40. Paraneoplastic syndrome Other less common paraneoplastic syndromes include Cushing syndrome, hyperglycemia, galactorrhea, neuropathy, clotting disorders and cerebella ataxia Generally, the treatment for paraneoplastic syndrome associated with RCC requires surgical excision or systemic antineoplastic therapy to reduce the burden of the disease Except for hypercalcemia medical therapy is not useful for the management of paraneoplastic syndromes

41. Screening of RCC Screening of RCC in the general population is discouraged by very low incidence of disease It's recommended in very well-defined target populations End stage renal disease Acquired renal cystic disease Tuberous sclerosis Familial disease

42. Diagnosis of RCC The gold standard for the clinical diagnosis of RCC is contrast enhanced CT scan MRI scan can be used as an alternative diagnostic imagining in those allergic to iodinated contrast media It can also be used in assessment of suspected venous involvement where CT is equivocal Histological diagnosis is confirmed by histopathological examination of the tumor after surgery Renal biopsy is only done is special circumstances

43. Imaging CT scan without and with administration of contrast during the nephrogenic phases verifies the clinical diagnosis of RCC CT scan also assess the extent of tumor including venous or collecting system involvement, extrarenal spread, enlargement of lymph nodes and adrenals It also provides information about function and morphology of the contralateral kidney Chest CT is the most accurate for chest staging and is recommended in primary workup of RCC

44. Indications for renal mass biopsy Radiologically indeterminate renal masses Small renal masses for active surveillance Small renal masses selected for ablative surgery Suspected metastatic disease from other sources

45. TNM staging of RCC

46. WHO/ISUP Grading

47. Principals of management Treatment depends on the staging and size of the tumor Considers whether the disease is organ confined or metastatic Surgery is the mainstay curative treatment for organ confined disease The treatment options for localized disease include radical nephrectomy, partial nephrectomy, thermal ablation or active surveillance Treatment of metastatic disease involves the use of systemic therapy which includes targeted therapy or immune checkpoint inhibitors

48. Risk stratification for renal masses Not all organ confined renal tumors are malignant About 20% of solid enhancing clinical T1 renal masses are benign (most often oncocytomas or atypical AMLs) An important determinant of benign pathology is tumor size Tumor size also correlates strongly with biologic aggressiveness for clinical T1 renal masses Current algorithms incorporating clinical and radiographic factors to predict tumor aggressiveness for small renal tumors are very limited in accuracy

49. Treatment of localized RCC Localized RCCs are best managed with partial nephrectomy rather than radical nephrectomy Partial nephrectomy may be unsuitable some localized RCC due to; Locally advanced tumor growth Unfavorable tumor location Significant health deterioration Lymphadenectomy is restricted to staging as the survival benefit of extended lymph node dissection is unclear in localized disease Before routine nephrectomy tumor embolization has no benefit

50. Radical nephrectomy The basic principles of prototypical radical nephrectomy includes; Early ligation of the renal artery and vein Removal of the kidney with primary dissection external to the Gerota's fascia Excision of the ipsilateral adrenal gland Performance of extended lymph node dissection Removal of ipsilateral adrenal gland is not routinely necessary Extended lymph node dissection is also not performed routinely especially localized disease with clinically negative nodes Surgical approach is determined by size and location of tumor as well as body habitus

51. Criteria for radical nephrectomy All tumors demonstrating features of increased oncologic potential (tumor size, aggressive histology on RMB or infiltrative appearance on imaging) should be considered for radical nephrectomy High tumor complexity and partial nephrectomy would be challenging even in experienced hands No pre-existing CKD or proteinuria Normal contralateral kidney and new baseline GFR will likely be > 45 ml/min/1.73m² If all these criteria are not met partial nephrectomy should be considered if feasible

52. Disadvantages of Radical nephrectomy Radical nephrectomy once the gold standard for all enhancing renal masses are has fallen out of favor for small renal tumors It predisposes to chronic kidney disease which is associated with morbid cardiovascular events and increased mortality rates The need for optimization of renal function underscores nephron sparing as an important principle in the management of clinical T1 renal masses

53. Partial nephrectomy Nephron sparing surgery entails complete resection of the tumor while optimally preserving normal functioning parenchyma Accepted indications for partial nephrectomy included situations in which radical nephrectomy would lead to; anephric ultimate need for dialysis This comprised bilateral RCC or RCC in a solitary functioning kidney When partial nephrectomy was not feasible despite absolute indications radical nephrectomy coupled with dialysis would be considered

54. Partial nephrectomy Partial nephrectomy is now considered the standard of care for small renal masses (clinical T1) The oncological outcome for partial nephrectomy in this group is equivalent to radical nephrectomy The remnant kidney after partial nephrectomy maybe at risk of long-term functional impairment from hyperfiltration If proteinuria or progressive decline in GFR is noted a nephrology consultation is necessary Management involves use of ACE inhibitors along with low protein diet

55. Tumor Enucleation Tumor enucleation is well established in familial kidney cancer Its role in sporadic RCC is controversial Tumor enucleation entails blunt dissection along the pseudocapsule thereby reducing amount of normal parenchyma removed with tumor The main concern of tumor enucleation is high rate of tumor recurrence 40% to 50% of localized RCC infiltrate into or beyond the pseudocapsule

56. Active surveillance Active surveillance is the preferred management option for elderly and those with significant comorbidities It also applies to tumors with low malignant potential such as those with diameter < 2 cm Many small renal masses grow slowly at the rate of 0.09 to 0.34 cm/year with relative low rate of metastasis Active surveillance is followed up with active treatment if the tumor shows signs of progression If comorbidities are too significant for active treatment watchful waiting is considered

57. Thermal ablation Thermal ablation include renal cryosurgery and radiofrequency ablation Can be administered percutaneously Long-term efficacy is not well established compared to surgery and has higher local recurrence rate Thermal ablation is offered to elderly and those with comorbidities who show signs of disease progression on active surveillance Other candidates for thermal ablation include disease recurrence after renal sparing surgery and familial RCC not feasible for partial nephrectomy

58. Treatment of locally advanced RCC Surgery is the only potentially curative treatment for RCC Treatment of locally advanced requires radical nephrectomy with en bloc resection of affected adjacent organs Venous tumor thrombus in the absence of metastasis requires thrombectomy in addition to radical nephrectomy Lymphadenectomy is accurate for staging purposes but its therapeutic benefits remain controversial It is only performed in clinically positive lymph nodes Tumor debulking is rarely indicated as 1 year survival is 10% to 20%

59. Prognostic factors for metastatic RCC Generally metastatic RCC has poor prognosis The long-term survival of metastatic RCC in the cytokine therapy era was less than 5% This is unlikely to change significantly with targeted therapy It is hoped that newer immunotherapeutic strategies may be associated with higher complete or durable responses Longer follow ups are required to quantify the long-term benefits Several clinical and laboratory parameters have been associated with the outcome on systemic treatment

60. Adverse prognostic factors based on chemotherapy or immunotherapy therapy at Memorial Sloan Kettering Cancer Center

61. Risk stratification based on the Memorial Sloan Kettering Cancer Center prognostic factors (MSKCC)

62. International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) prognostic factors

63. Risk stratification based on the IMDC prognostic factors

64. Surgical management of metastatic RCC Nephrectomy as a sole therapeutic treatment in metastatic disease is unlikely to alter the outcome Tumor nephrectomy is curative only if all tumor deposits are excised This includes the primary tumor and single or oligometastatic resectable disease For most metastatic disease cytoreductive nephrectomy is palliative and systemic therapy is necessary Patients with MSKCC or IMDC poor risk do not benefit from cytoreductive nephrectomy

65. Palliative surgery in metastatic RCC Cytoreductive nephrectomy can be performed with palliative intent It can be performed to alleviate; Interactable pain Hematuria constitutional symptoms Paraneoplastic manifestations Resection of the primary renal tumor does not always result in clinical benefit Cytoreductive nephrectomy with palliative intent is therefore performed relatively infrequent but may be appropriate

66. Systemic therapy for metastatic RCC Conventional cytotoxic chemotherapy has no role in the current management of clear cell renal cell carcinoma Renal cell carcinoma is both chemo- and radio-resistant The current management of metastatic ccRCC involves the use of targeted therapy and immune check point inhibitors They are used as combination or single agent therapies The selection of these agents is dependent on the IMDC risk stratification

67. Treatment of metastatic clear cell RCC The first line treatment for metastatic clear cell renal cell carcinoma with favorable IMDC risk involves the use the following; Single agent tyrosine kinase inhibitors (Sunitinib or pazopanib) or Combination therapy of tyrosine kinase inhibitors with immune checkpoint inhibitors (Nivolumab/ Cabozantinib , Pembrolizumab/ Axitinib , Pembrolizumab/Lenvatinib) Intermediate or poor IMDC risk is preferentially treated with combination therapy of immune checkpoint inhibitors and targeted therapy Metastatic ccRCC with sarcomatoid features is treated with immune checkpoint combination therapy

68. R ecommendations for the first-line treatment of cc- mRCC

69. Recommendations for later-line therapy

70. Treatment of non clear cell RCC VEGFR inhibitors which are active in clear cell RCC have only modest efficacy in papillary RCC There is no standard approach of proven efficacy for most non clear cell RCC Cabozantinib a multityrosine kinase inhibitor is recommended for papillary RCC based on some randomized controlled trials The evidence for systemic therapy of non clear cell RCC other than papillary RCC is weak Enrollment in suitable trials should be considered for all non clear cell RCC

71. References Lous R. Kavoussi , Andrew C. Novick, Alan W. Partin, Craig A. Peters, CAMPBELL-WALSH Urology , 12 th Edition, Chapters 97 and 162, Elsevier Saunders, USA. European Association of Urology, 2024 updated guidelines, limited edition.