Malignant Renal Tumors Part One


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Campbell Urology Study Notes

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Malignant Renal Tumors Part One

  1. 1. Malignant Renal Tumors Dr Prashant Bansal
  2. 2. Historical Considerations
  3. 3. Historical Considerations  The first documented nephrectomy was done in 1861 by Wolcott, who operated with the mistaken assumption that the tumor mass was a hepatoma.  In 1867, Spiegelberg removed a kidney incidentally in the course of excising an echinococcus cyst.  1st planned nephrectomy: by Simon in 1869 for persistent ureteral fistula, and this patient survived with cure of fistula  One year later (1870), nephrectomy was successfully accomplished by Gilmore in Mobile, Alabama, for treatment of atrophic pyelonephritis and persistent urinary tract infection  In 1855, Robin examined solid tumors apparently arising in kidney and concluded that renal carcinoma arose from renal tubular epithelium.
  4. 4. Historical Considerations  Theoretical and practical considerations of renal tumors were confused by Grawitz (1883), who contended that such apparent renal tumors arose from adrenal rests within the kidney. He introduced the terminology struma lipomatodes aberrata renis as descriptive nomenclature for the tumors of clear cells that he believed were derived from the adrenal glands.  In 1894, Lubarch endorsed the idea of a suprarenal origin of renal tumors  Term hypernephroid tumors, indicating origin above the kidneys, was advocated by Birch-Hirschfeld  This mistake led to introduction of term hypernephroma  Some clarification of the histopathology of renal tumors was derived from the work of Albarran and Imbert (1903), and the four-volume contribution of Wolff (1883), written between 1883 and 1928, added further historical significance to the understanding of renal tumors
  5. 5. Epidemiology
  6. 6. Epidemiology  Incidence: 12/100,000 per year  M :F = 3 :2  Primarily a disease of elderly  Presentation in 6th and 7th decades of life  Incidence: 10% to 20% higher in African Americans  Mostly: sporadic  Familial: 2% to 3%
  7. 7. RCC in childhood  Uncommon (only 2.3% to 6.6% of all renal tumors in children)  Mean age at presentation = 8 to 9 years  Incidence in Boys = Girls  Although Wilm’s tumor is much more common in younger children, RCC is as common as Wilm’s tumor during 2nd decade of life  More likely to be symptomatic and to exhibit papillary histology, and a predilection for locally advanced, high-grade disease, and unfavorable histologic subtypes  TFE3 protein overexpression  Correlates with presence of ASPL-TFE3 and PRCC-TFE3 gene translocation events (involving Chromosomes X and 1)  Relatively common in children and young adults with RCC and is unique to this population  Clinical significance of TFE3 protein overexpression is not well defined (Preliminary data suggest that these tumors may show differential sensitivity to certain chemotherapeutic agents)
  8. 8. RCC in childhood  Stage for stage, children and young adults with RCC may respond better to surgical therapy  A number of long-term survivors have been reported after radical nephrectomy and lymphadenectomy for LN + disease  An aggressive surgical approach (Radical Nephrectomy + formal lymphadenectomy) has thus been recommended when RCC is suspected in children or young adults
  9. 9. Etiology
  10. 10. Etiology Established Putative  Tobacco exposure  Lead compounds  Obesity   Hypertension Various chemicals (e.g., aromatic hydrocarbons)  Trichloroethylene exposure  Occupational exposure (metal, chemical, rubber, and printing industries)  Asbestos or cadmium exposure  Radiation therapy  Dietary (high fat/protein and low fruits/vegetables)
  11. 11. Tobacco  Most generally accepted environmental risk factor for RCC  Relative risk = modest (1.4 to 2.5)  All forms of tobacco use have been implicated  Risk increases with cumulative dose or pack-years  Relative risk is directly related to duration of smoking and begins to fall after cessation  Accounts for 20% to 30% of cases of RCC in men and 10% to 20% in women
  12. 12. Obesity  Accepted as another major risk factor  Relative risk of 1.07 for each unit of rising body mass index  Increased prevalence of obesity likely contributes to increased incidence of RCC in Western countries  Estimated that > 40% of cases of RCC in US may be causally linked to obesity  Potential mechanisms  Lipid peroxidation leading to DNA adducts  Increased insulin-like growth factor-1 expression  Increased circulating estrogen levels  Increased arterionephrosclerosis and local inflammation
  13. 13. Hypertension  Third major etiologic factor  Proposed mechanisms  hypertension-induced renal injury and inflammation  metabolic or functional changes in the renal tubules that may increase susceptibility to carcinogens
  14. 14. Familial RCC and Molecular Genetics SYNDROME GENETIC ELEMENT MAJOR CLINICAL MANIFESTATIONS von Hippel-Lindau VHL gene Chromosome 3p25-26 Clear cell RCC Hemangioblastomas of CNS Retinal angiomas Pheochromocytoma (PCC) Hereditary papillary RCC c-MET proto-oncogene Chromosome 7q31 Type 1 papillary RCC Familial Leiomyomatosis Fumarate hydratase and RCC Chromosome 1q42 Type 2 papillary RCC Cutaneous leiomyomas Uterine leiomyomas Birt-Hogg-Dubé Chromophobe RCC Oncocytoma Transitional tumors* Occasional clear cell RCC Cutaneous fibrofolliculomas Lung cysts Spontaneous pneumothorax BHD1 gene Chromosome 17p12q11
  15. 15. von Hippel-Lindau Disease  “Familial form of clear cell RCC”  Rare Autosomal dominant disorder  1 per 36,000 population ORGAN SYSTEM LESION INCIDENCE (%) Eye Benign retinal angiomas 49 – 59 Ear Endolymphatic sac tumor 10 CNS Benign Hemangioblastomas 42 – 72 Kidney Clear cell RCC Renal cysts 25 – 70 22 – 59 Adrenal Pheochromocytoma 18 Pancreas Islet cell tumors Malignant islet cell tumor Pancreatic cysts 12 2 21 – 72 Epididymis Cystadenoma 10 – 26
  16. 16. von Hippel-Lindau Disease  All of these tumor types are highly vascular and can lead to substantial morbidity  Increased incidence of neuroendocrine tumors of pancreas  CNS lesions  paralysis or death  Retinal lesions  blindness  RCC in VHL  Develops in about 50%  Early age at onset (3rd, 4th or 5th decade of life)  B/L and multifocal involvement  Due to improved management of CNS complications, RCC is now the major cause of mortality in VHL
  17. 17. von Hippel-Lindau Disease VHL tumor suppressor gene  Located at chromosome 3p25-26  Tumor suppressor gene for both sporadic and familial forms of clear cell RCC  Gene consists of three exons, and it encodes a protein of 213 amino acids.  A large number of common mutations or “hot spots” have been identified  Direct correlation b/w genotype and phenotype has been established in some cases  For instance, missense mutations (type 2 mutations) that result in a full-length but non-functional protein are commonly found in families with VHL that develop pheochromocytomas, whereas deletions leading to a truncated protein (type 1 mutations) are typically found in families that do not develop pheochromocytomas  Both alleles must be mutated/inactivated for development of disease
  18. 18. Incidence of Major Manifestations of VHL by Mutation Status DISEASE TYPE HEMANGIOB LASTOMA RCC PCC GERMLINE MUTATION TYPES 1 High High Low Full gene deletions Partial gene deletions Nonsense mutations Splice acceptor mutations 2A High Low High Missense mutations in specific areas 2B High High High Partial gene deletions Nonsense mutations Missense mutations 2C No No High Missense mutations in other specific areas
  19. 19. von Hippel-Lindau Disease VHL protein  Binds to elongins B and C, CUL-2 and RBX1  forms an E3 ubiquitin ligase complex  This complex modulates degradation of important regulatory proteins  A critically important function of the VHL protein complex is to target the hypoxiainducible factors 1 and 2 (HIF 1 and 2) for ubiquitin-mediated degradation  keeping the levels of HIFs low under normal conditions (HIFs are intracellular proteins that play an important role in regulating cellular responses to hypoxia, starvation, and other stresses)  Inactivation/mutation of VHL gene  dysregulated expression of HIFs  HIF accumulation  several fold upregulation of VEGF expression  pronounced neovascularity  HIFs also upregulate the expression of TGF-α, PDGF, glucose transporter (Glut 1), erythropoietin and carbonic anhydrase IX (CA-IX)
  20. 20. Biologic functions of VHL protein
  21. 21. von Hippel-Lindau Disease  Other genes potentially involved in development of sporadic clear cell RCC  Additional loci on short arm of chromosome 3 (3p)  Loss of heterozygosity (LOH) at 3p12-p14 and 3p21.2- p21.3; particularly common in tumors with wild-type VHL status  Candidate tumor suppressor gene at 3p12 has been described and may contribute to a VHL-independent pathway to RCC  TP53 and PTEN tumor suppressor genes  Increased immunostaining for TP53  in 6% to 40%. Some studies suggest a correlation with tumor grade and stage  Loss of PTEN  constitutive activation of mTOR  promotes tumorigenesis
  22. 22. Familial Papillary RCC  = Familial Type 1 papillary RCC (Type II in HLRCC)  Do not develop tumors in other organ systems  Autosomal dominant  Median age at diagnosis = 45 years  Non–clear cell histotypes  Multifocal and bilateral papillary RCC  Gene for HPRCC = Chromosome 7q31 (Missense mutations of c-MET protooncogene at 7q31)  Inciting event is activation of a proto-oncogene, rather than inactivation of a tumor suppressor gene  Trisomy for chromosomes 7 and 17  Abnormalities on chromosomes 1, 12, 16, 20 and Y  Chromosome 3 and VHL gene abnormalities uncommon
  23. 23. Familial Papillary RCC  Protein product of c – MET proto-oncogene  = receptor tyrosine kinase for hepatocyte growth factor (also known as scatter factor)  Activation leads to cellular proliferation and other tumorigenic effects  Most of the mutations in HPRCC have been found in tyrosine kinase domain of c-MET  apparently lead to constitutive activation  Tumors in HPRCC tend to be less aggressive than their sporadic counterparts. But some can metastasize and become lethal  CT is the preferred imaging modality for patients with HPRCC because it has the greatest sensitivity for detecting the small, hypovascular lesions
  24. 24. Hereditary Leiomyomatosis and RCC  = Cutaneous and uterine leiomyomas + type 2 papillary RCC  Autosomal dominant  Renal tumors in this syndrome are different from other familial RCC because  Often solitary and unilateral  More likely to be aggressive than other forms of familial RCC  Collecting duct RCC has also been observed  Histologic hallmark  Large, prominent eosinophilic nuclei and nucleoli with perinucleolar clearing  HLRCC locus  A region on 1q 42-44  = Site of Fumarate hydratase gene (Fumarate hydratase is an essential enzyme in Krebs cycle)  This appears to be a tumor suppressor gene rather than an oncogene
  25. 25. Hereditary Leiomyomatosis and RCC  Penetrance for RCC in HLRCC  Lower than for cutaneous and uterine manifestations  Only 20% develop RCC  In contrast, almost all individuals develop cutaneous leiomyomas and uterine fibroids (if female), manifesting by 20 - 35 yr age.  Prompt surgical management of renal tumors is recommended in this syndrome (tendency toward invasive and aggressive behavior)
  26. 26. Birt-Hogg-Dubé Syndrome  Cutaneous fibrofolliculomas + lung cysts + spontaneous pneumothorax + variety of renal tumors (primarily derived from distal nephron)  Autosomal dominant  The renal tumors typically include chromophobe RCC, oncocytomas and hybrid or transitional tumors that exhibit features of both of these entities.  However, other forms including clear cell RCC have been observed  Overall penetrance for renal tumors is 20% to 40%, but when they occur they are often bilateral and multifocal  Average age at renal tumor diagnosis is approximately 50 years  Most renal tumors have limited biologic aggressiveness  BHD gene   Appears to be a tumor suppressor gene   Chromosome 17p12q11.2 Function is still under investigation Gene product = folliculin
  27. 27. Birt-Hogg-Dubé Syndrome  One hypothesis is that folliculin may interface with the mTOR pathway  Germline mutations in this gene have been found in 88% of kindreds  Genetic testing is now available
  28. 28. Tumour Biology RCC is a prototype of chemorefractory tumors
  29. 29. Tumor Biology and Clinical Implications BIOLOGIC CHARACTERISTIC CLINICAL IMPLICATIONS Expression of multidrug resistance •Contributes to chemorefractory nature of RCC Immunogenic •10%-20% response rate with IFN or IL-2 •3%-5% complete response rate with high-dose IL-2 Angiogenic •Vascular invasion can lead to venous tumor thrombus •20%-40% response rates with agents targeting VEGF (bevacizumab) or the VEGF receptor (sunitinib, sorafenib, etc.) •Prolonged recurrence-free survival and overall survival with some antiangiogenic agents Dependence on mTOR pathway •Agents targeting mTOR prolong survival in patients with poor-risk RCC (temsirolimus) and demonstrate responses in patients failing prior targeted molecular therapies (everolimus)
  30. 30. 1. Resistance to Cytotoxic Therapy  RCC is a prototype of the chemorefractory tumor (limited or modest responses to traditional chemotherapeutics)  Expression of multidrug resistance (MDR) proteins  E.g.: MDR-1 (also known as P-glycoprotein) and MDR-related proteins  Act as energy-dependent efflux pumps for a wide variety of hydrophobic compounds  Contribute to chemorefractory nature of advanced RCC  However there seems to be some redundancy in these resistance mechanisms:  RCC is also resistant to drugs like cisplatin and others (that are not handled by MDR proteins)  Downregulation of MDR-1 in high-grade tumors and metastases
  31. 31. 2. Immunobiology  Evidence demonstrates that RCC is immunogenic  Tumor-infiltrating immune cells can be readily isolated from RCC, including  Cytotoxic T cells with specificity for antigens on tumor cells  Dendritic cells and TH cells: express IL-1 and IL-2 and function as APCs  Clinical observations which support immunogenicity of RCC  Validated responses to immunotherapy  Prolonged disease stabilization  Occasional spontaneous tumor regression  Response of RCC to immunomodulators, such as IL-2, INF and tumorinfiltrating lymphocytes. Infact, high-dose IL-2 is the only treatment with curative potential for metastatic RCC, with durable and complete regression in 3 - 5%  Estimated incidence of spontaneous regression of RCC: 0.3 - 7%  Most spontaneous regressions have been noted in  Pulmonary mets after cytoreductive nephrectomy  Regression of primary RCC has also been reported in absence of any treatment
  32. 32. 2. Immunobiology  CA-IX/Carbonic anhydrase IX/ MN-9 (antigen)  Of the tumor-associated antigens for RCC, CA-IX = most specific  CA- IX is recognized by G250 monoclonal antibody  Expressed almost ubiquitously by clear cell RCC and rarely by other subtypes  IHC analysis of CA-IX expression has been investigated as a diagnostic and a prognostic marker for clear cell RCC  Normally expressed in: gastric mucosa, large bile ducts, and pancreas  Expression in normal renal epithelial cells is suppressed by wild-type VHL protein  CA-IX has also been investigated for RT-PCR detection of circulating RCC cells in peripheral blood  CA-IX based tumor vaccine protocols have been developed  Radioactively labelled G250: shown promise for detection of RCC mets by radionuclide scanning, and more recently by PET  All these potential applications of CA-IX are promising but experimental
  33. 33. 2. Immunobiology  B7 family (cell surface glycoproteins)  A second class of factors that may modulate immunotherapeutic responses  Expressed on various immune and nonimmune cells  B7-H1 is a T-cell coregulatory molecule that is normally expressed by macrophage lineage cells, can be induced on activated T lymphocytes, and is aberrantly expressed by RCC  Tumor-associated B7-H1 impairs antigen-specific T-cell function  Blockade of B7-H1 has been shown to potentiate antitumoral responses in preclinical models  Thompson and associates (2006) have shown that B7-H1 expression by clear cell RCC tumors correlates with aggressive pathologic features and is associated with an increased risk of disease progression
  34. 34. 2. Immunobiology Immune Tolerance  Response rates of immunotherapy for RCC have been disappointing  Range from 15% to 20%  Impaired immune surveillance is seen in RCC  Defective NF-κB (nuclear factor-kappa B) signalling  Defects in transcriptional regulation via NF-κB are present in tumor-infiltrating lymphocytes and dendritic cells in 60% RCC  Impairs lymphocyte function  predisposes lymphocytes to apoptosis  leads to deficient recruitment and activation of dendritic cells  For example, in addition to its antiangiogenic activity, sunitinib also appears to stimulate antitumor immunity by reversing myeloid-derived suppressor cell mediated immunosuppression
  35. 35. 3. Angiogenesis and Targeted Pathways  RCC = one of the most vascular cancers  Primary angiogenesis inducer in clear cell RCC appears to be VEGF  Increased levels of VEGF have been found in serum and urine  Levels correlate with stage and grade  Functional relevance of VEGF:  Increased levels of VEGF transcript in most hypervascular tumors  Hypovascular counterparts exhibit reduced expression of VEGF  Elevated serum basic fibroblast growth factor (bFGF) and other putative angiogenesis inducers also seen
  36. 36. 3. Angiogenesis and Targeted Pathways VEGF (A family consisting of several subtypes)  Bind to 1 or more of corresponding VEGF receptors  Regulated by HIFs and VHL  Suppressed by the wild-type VHL protein normally  Dramatically upregulated during tumor development  Upon binding of ligand (VEGF) to VEGFR, key tyrosine residues along the intracellular portion of VEGFR are phosphorylated  binding of specific intracellular factors  activation of corresponding pathways  Pathways known to be activated by phosphorylation of VEGFRs include  Raf-MEK-Erk pathway  Phosphatidylinositol-3-kinase /Akt /mTOR pathway (promote endothelial cell survival and proliferation)  VEGFR-1 (Flt-1) and VEGFR-2 (KDR/Flk-1) are receptor tyrosine kinases that are the target of several multi–tyrosine kinase inhibitors (TKIs)
  37. 37. 3. Angiogenesis and Targeted Pathways  However, the promiscuity of interactions between the various ligands, receptors, and downstream effectors leads to a host of effects that may be difficult to predict  This promiscuity is likely a major reason that two therapeutic agents that have the “same” mode of action are found to have disparate clinical or off-target effects.  Initial clinical trials identified several antiangiogenic compounds such as TNP-470, roquinimex, and thalidomide with limited activity in patients with advanced RCC.  Thalidomide  Has shown only rare response despite its potent antiangiogenic effects  Toxicity: can be substantial (thrombotic events and neurologic morbidity).  Multiple kinase inhibitors (that target the VEGF pathway)  Substantial activity in advanced RCC  2 agents approved by USFDA – Sunitinib and Sorafenib
  38. 38. 3. Angiogenesis and Targeted Pathways  Bevacizumab (humanized anti VEGF monoclonal antibody)  Monoclonal antibody that binds to VEGF (not to its receptor) and sequesters the ligand so that it cannot interact with VEGFR  More promising initial results were reported  Significant delay in time to progression in met-RCC compared with placebo  Therapy commonly leads to shrinkage in the total tumor burden  Partial responses were uncommon and there were no complete responses  Tumoristatic rather than a tumoricidal mechanism of action.
  39. 39. Neovascularity associated with RCC. Renal angiogram shows left renal mass exhibiting markedly increased neovascularity within renal tumor
  40. 40. 4. Signal Transduction, Cell Cycle Regulation, and Other Targeted Molecular Pathways  Aberrant activation of additional signal transduction pathways in RCC may also contribute to altered cell cycle kinetics  mTOR pathway (mammalian target of rapamycin)  Interfaces with Akt (protein kinase B) and the PTEN tumor suppressor gene  Expression of mTOR is upregulated by  Various growth factors  Mutation or loss of PTEN  mTOR pathway  increased expression of HIF-1 and other growth-promoting sequelae  Inhibition of mTOR with Temsirolimus (FDA approved)  prolonged survival in poor-risk, metastatic RCC
  41. 41. 4. Signal Transduction, Cell Cycle Regulation, and Other Targeted Molecular Pathways  Other important growth regulatory elements in RCC  Insulin-like growth factor  Telomerase  BCL2  Insulin-like growth factor receptor expression  Correlates with decreased survival  Increased telomerase activity  Found in 56% to 93% of RCCs  Affects cell cycle by maintaining telomere length  Progressive telomere loss occurs each time a normal cell divides  growth inhibition and cellular senescence  Increased expression of BCL2 (which protects against programmed cell death)  May contribute to tumor viability and treatment failure
  42. 42. 4. Signal Transduction, Cell Cycle Regulation, and Other Targeted Molecular Pathways  Proliferative index  Defined by proliferating cell nuclear antigen (PCNA) or Ki-67 staining  Correlates with pathologic parameters and clinical outcomes  EGFR  Increased expression of TGF-α and its receptor tyrosine kinase (epidermal growth factor receptor - EGFR), have been reported in RCC and may contribute to tumorigenesis through an autocrine mechanism  C225 monoclonal antibody  Neutralizes EGFR and blocks tumor growth and metastasis  Anti EGFR agents  Erlotinib, Gefitinib and ABX-EGF  Phase II clinical trials  lack of substantial activity in advanced RCC  May have a role in cancers that express high levels of EGFR
  43. 43. 4. Signal Transduction, Cell Cycle Regulation, and Other Targeted Molecular Pathways  Hepatocyte Growth Factor and its Receptor (c-MET proto-oncogene)  Normally expressed by proximal tubular cells (PCT)  Normal Function  Branching tubulogenesis of developing kidney  Regeneration after renal injury  In vitro  mitogenic and morphogenic effects on renal epithelial cells  May also contribute to pathogenesis of RCC  Role of activating mutations of c-MET proto-oncogene in HPRCC is well known  Increased levels are seen in most RCCs, independent of histologic subtype  Its activation (by phosphorylation at two sites) is a/w cancer progression  However, constitutive activation of receptor  appears to be primarily limited to familial papillary RCC only
  44. 44. 5. Proteases, Adhesion and ECM      Interactions among cancer cells, adjacent cells and surrounding matrix can strongly influence their pathogenic potential. Altered intracellular processing and secretion of fibronectin and other matrix proteins is found in RCC (one consequence of VHL gene mutation) Proteases (Plasmin and matrix metalloproteinases)  Increased expression correlates with reduced survival  May contribute to aggressive behavior of RCC Adhesion Molecules (E-cadherin and Cadherin-6)  Normally mediate adhesion between cancer cells  Downregulation correlates with poor outcomes α-catenins  Cytoplasmic proteins that bind cadherins  Mediate their effects on the cytoskeleton  Aberrant regulation correlates with compromised survival  Sialyl-Lewis X (endothelial leukocyte adhesion molecule-1) and VLA-4 (vascular cell adhesion molecule-1) interactions regulate this process
  45. 45. Pathology
  46. 46. Pathology  Traditionally thought to arise from PCT (clear cell and papillary variants)  However, other histologic subtypes of RCC, such as chromophobe and collecting duct RCC, are derived from the more distal components of the nephron Gross  Most RCCs are round to ovoid and circumscribed by a pseudocapsule of compressed parenchyma and fibrous tissue rather than a true histologic capsule  Most RCCs are not grossly infiltrative (unlike TCC)  Exception = collecting duct RCC and some sarcomatoid variants  Size ~ 4 - 8 cm  Tumors < 3 cm were previously classified as benign adenomas, but some small tumors have been a/w mets  With exception of oncocytomas and some small (<1 cm) low-grade papillary adenomas, there are no reliable histologic or ultrastructural criteria to differentiate benign from malignant renal epithelial tumors
  47. 47. Pathology  Yellow, tan or brown tumor interspersed with fibrotic, necrotic, or hemorrhagic areas. Very few are uniform in gross appearance.  Cystic degeneration  Found in 10% to 25%  Appears to be a/w better prognosis (compared with purely solid RCC)  Calcification  Stippled or Plaque-like  10% to 20%
  48. 48. HPE  Nuclear features can be highly variable  Grading has been based primarily on nuclear size and shape and the presence or absence of prominent nucleoli  Fuhrman’s system  Most generally adopted  It is an independent prognostic factor for RCC (clear cell RCC particularly) Fuhrman’s Classification System for Nuclear Grade in Renal Cell Carcinoma GRADE NUCLEAR SIZE NUCLEAR OUTLINE NUCLEOLI 1 10 mm Round, uniform Absent or inconspicuous 2 15 mm Slightly Irregular Contours Small Visible at 400 x magnification 3 20 mm Moderate to Markedly Irregular Contours Prominent Visible at 100 x magnification 4 >20 mm Bizarre, often multilobed Large and Prominent Heavy chromatin clumps present
  49. 49. Behaviour      Aggressive local behavior is common  Frank invasion and perforation of renal capsule, renal sinus, or collecting system  ~ 20%  Displacement of these structures is MC Adjacent organs or abdominal wall spread is # by Gerota fascia Venous System Involvement  Unique feature of RCC  Found in 10% of RCCs (MC than any other tumor)  MC manifests as a contiguous tumor thrombus extending into IVC or even RA  Many such tumor thrombi are highly vascularized by arterial blood flow  Directly invasion of wall of renal vein or IVC correlates with compromised prognosis Most sporadic RCCs are unilateral and unifocal Bilateral:  Can be synchronous or asynchronous  2 - 4% of sporadic RCCs. MC in familial RCCs
  50. 50. Behaviour  Multicentricity  10% to 20%  MC with papillary histology and familial RCC  Satellite lesions  are often small and difficult to identify by preoperative imaging, IOUS or visual inspection  main factor contributing to local recurrence after partial nephrectomy  Microsatellite analysis suggests that  There is a clonal origin for multifocal RCC within same kidney  But tumor in C/L kidney is likely to be  An independent growth if it is synchronous  Metastasis if it is asynchronous  Molecular analysis (e.g. - gene expression profiling)  Helps to determine whether an asynchronous tumor is a second primary tumor or a metastasis
  51. 51. Histologic Classification  All RCCs by definition are adenocarcinomas derived from renal tubular epithelial cells  Most RCCs share ultrastructural features with normal PCT cells, such as  Surface microvilli  Complex intracellular junctions  This information applies primarily to clear cell and papillary subtypes.  Other histologic subtypes appear to be derived from more distal elements of nephron
  52. 52. Histologic Classification  Traditionally, RCC was divided into four histologic subtypes  Clear cell  Granular cell  Tubulopapillary  Sarcomatoid  Newer classification scheme was proposed by Kovacs (1993)  In this system 1. Granular cell tumors were reclassified into other categories based on distinct histopathologic features 2. Chromophobe RCC was recognized as a new RCC subtype 3. Sarcomatoid features were categorized as variants of other histologic subtypes rather than a distinct tumor type  Current practice is to identify primary histologic subtype and comment on presence and extent of sarcomatoid differentiation, although the prognostic implications have not changed
  53. 53. Histologic Classification Depending on well-defined histologic and ultrastructural criteria, granular cell tumors were reclassified as papillary RCC, eosinophilic variants of chromophobe RCC, or combined with clear cell RCC  Another important development was the identification of renal medullary carcinoma that is common in young African-Americans with sickle cell trait  With additional advances in ancillary pathologic studies, including EM, IHC, molecular genetics and cytogenetics, several additional unique subtypes of RCC have been identified since 1993.  Based on these findings, an updated classification of malignant epithelial tumors of the kidney was presented by the WHO in 2004 Important changes include  Addition of several RCC subtypes that were previously grouped within “conventional” or unclassified RCC, such as  RCC associated with XP11.2 translocations/TFE3 gene fusions, which has microscopic features of both clear cell and papillary RCC and occurs primarily in children and young adults  indolent mucinous tubular and spindle cell carcinoma 
  54. 54. WHO Classification 2004 Histology Clear Cell RCC (70 – 80 %) Familial Forms von Hippel-Lindau disease VHL gene (3p25-26) mutation or hypermethylation Chromosome 3p deletions Also, loss of chromosome 8p, 9p, 14q; gain of chromosome 5q Gross Well-circumscribed, lobulated, golden yellow tumor when bivalved Necrosis and hemorrhage common Venous involvement also common Cystic degeneration HPE Hypervascular tumor Network of delicate vascular sinusoids interspersed b/w Nests/ Sheets/ Acini of clear cells IHC†: low MWCKs,‡ vimentin, EMA, CA-IX Other features Originate from PCT Aggressive behavior more common Tumor shrinkage common with targeted molecular therapy May respond to immunotherapy
  55. 55. Clear Cell Renal Cell Carcinoma      Formerly known as “conventional” RCC Microscopic examination can include  Clear cell, granular cell, or mixed types  Clear cells  Round or polygonal with abundant cytoplasm  Contain glycogen, cholesterol, cholesterol esters, and phospholipids, all of which are readily extracted by the solvents used in routine HPE (Hence  the clear appearance)  Granular cells  Eosinophilic cytoplasm + abundant mitochondria  Sarcomatoid features  2 to 5 % More likely to exhibit venous tumor extension than any other subtype Worse prognosis compared with papillary or chromophobe Most responders in immunotherapy protocols have had clear cell RCC, and these protocols are now being reserved primarily for this population
  56. 56. Clear Cell RCC Clear cell RCC with typical golden yellow color
  57. 57. Clear Cell RCC Clear cell RCC with typical golden yellow color and renal sinus fat invasion
  58. 58. Clear Cell RCC Low-grade clear cell RCC Delicate vascular network interspersed within homogeneous nests of cells with clear cytoplasm Low-power view
  59. 59. Clear cell RCC Deletion of 3p as the only karyotype change
  60. 60. WHO Classification 2004 Histology Papillary RCC (10%-15%) Familial Forms Type 1: HPRCC Type 2: HLRCC Activation of c-MET oncogene (7q31-34) by mutation common in HPRCC but uncommon (~10%) in sporadic cases Trisomy of chromosome 7 and 17; loss of Y Gross Fleshy tumor with fibrous pseudocapsule Necrosis and hemorrhage are common HPE Hypovascular tumor Papillary structures with single layer of cells around fibrovascular cores Type 1: basophilic cells with low-grade nuclei Type 2: eosinophilic cells with high-grade nuclei IHC: LMWCKs, CK7 (type 1 > type 2), AMACR Other features Originate from PCT Commonly multicentric Common in ARCD Type 1: good prognosis Type 2: worse prognosis
  61. 61. Papillary Renal Cell Carcinoma  These 2 subtypes appear to represent distinct entities  Subclassification into type 1 and type 2 is not routinely practiced Type 1 papillary RCC Type 2 papillary RCC MC Less Common Basophilic cells with scant cytoplasm Eosinophilic cells and abundant cytoplasm Potentially more aggressive variants A/w HPRCC syndrome A/w HLRCC syndrome Better Survival as compared to HLRCC Sporadic Type I comparison with Sporadic Type II is NA Poor Survival as compared to HPRCC Sporadic Type I comparison with Sporadic Type II is NA granular
  62. 62. Papillary Renal Cell Carcinoma  Aka chromophilic RCC  2nd most common histologic subtype  10% to 15% of all RCCs  More commonly found in patients with ESRD and acquired renal cystic disease  On microscopic examination  Basophilic or eosinophilic cells arranged in papillary or tubular configuration  Previously, > 50 - 75% of tumor had to exhibit such architectural features to qualify as a papillary RCC  One unique feature of papillary RCC is its tendency toward multicentricity, (~ 40%)
  63. 63. Papillary Renal Cell Carcinoma  Cytogenetic abnormalities  Trisomy of chromosomes 7 and 17  Loss of the Y chromosome  Gain of chromosomes 12, 16, and 20 and loss of heterozygosity on chr 14  VHL mutations are rare  More likely to be hypovascular (lack of VHL mutations)  Activating mutations of the c-MET proto-oncogene (chromosome 7) which encodes the receptor for hepatocyte growth factor  These mutations have been detected in only ~ 10% of sporadic papillary RCCs
  64. 64. Papillary Renal Cell Carcinoma  Prognosis: Controversial  Tendency towards low-grade disease  80% are confined to kidney  Recent studies: increased proportion of high-grade and advanced tumors  Although venous tumor thrombus is less common than clear cell RCC, outcomes in this subgroup are compromised.  Conversely, although lymph node involvement is more common than clear cell RCC, patients have higher cancer-specific survival at 5 years (65% vs. 19%, P = .03)  At present, most authors believe that papillary RCC, and type 1 papillary RCC in particular, carry a better prognosis than clear cell RCC when compared grade for grade and stage for stage
  65. 65. Papillary Renal Cell Carcinoma Papillary adenomas  Small (≤5 mm) tumors that resemble papillary RCC  Commonly found at autopsy  Possess many of the same genetic alterations as papillary RCCs  Benign neoplasms
  66. 66. Papillary RCC Multiple Small Mildly enhancing renal tumors
  67. 67. Type 1 Papillary RCC Basophilic cells with scant cytoplasm Low-grade nuclei Microscopic appearance
  68. 68. Type 2 Papillary RCC Eosinophilic cells with abundant granular cytoplasm High-grade nuclei Microscopic appearance
  69. 69. Trisomy 7, 12, 13, 16, 17 and 20 and deletion of 21 and Y
  70. 70. WHO Classification 2004 Histology Chromophobe RCC (3%-5%) Familial Forms Birt-Hogg-Dubé syndrome Fumarate hydratase gene (1q42-43) mutation Loss of multiple chromosomes (1, 2, 6, 10, 13, 17, 21) Gross Well-circumscribed, homogeneous Tan or light brown cut surface HPE “Plant cells” with pale cytoplasm Perinuclear clearing or “halo” Nuclear “raisins” Prominent cell borders Positive Hale colloidal iron staining IHC: diffuse CK7 Other features Originate from intercalated cells of collecting duct Generally good prognosis Sarcomatoid variant associated with poor prognosis
  71. 71. Chromophobe Renal Cell Carcinoma  First described by Theones and colleagues in 1985  appears to be derived from the cortical portion of collecting duct  3% to 5% of all RCCs  The tumor cells typically exhibit a relatively transparent cytoplasm with a fine reticular pattern that has been described as a “plant cell” appearance  The chromophobic nature of this classic variant is responsible for the name of this histologic subtyp  However, eosinophilic variants of chromophobic RCC have also been described and constitute about 30% of cases  In either case, a perinuclear clearing or “halo” is typically found and electron microscopic findings consist of numerous 150- to 300-nm microvesicles, which are the single most distinctive and defining feature of chromophobe cell carcinoma  These microvesicles characteristically stain positive for Hale colloidal iron, indicating the presence of a mucopolysaccharide unique to chromophobe RCC
  72. 72. Chromophobe Renal Cell Carcinoma  IHC  Stain positive for various cytokeratins  Negative for Vimentin  Genetic analysis  Multiple chromosomal losses  MC = whole chromosomes 1, 2, 6, 10, 13, 17, and 21  Flow cytometric analysis: hypodiploid DNA content in most cases  An increased incidence of TP53 mutations  Upregulated expression of the c-KIT oncogene  Commonly seen in Birt-Hogg-Dubé syndrome, but most cases are sporadic
  73. 73. Chromophobe Renal Cell Carcinoma  Behaviour  Generally presents at an earlier stage  > 90% of patients remain cancer free for 5 or more years after treatment  Tendency to remain localized despite growth to large size  Predominance of low-grade disease  Better prognosis for localized chromophobe RCC than clear cell RCC  Poor outcome in patients with sarcomatoid features or metastatic disease  In High Grade Disease:  LN and distant metastases are common  Systemic disease is poorly responsive to IL-2  Temsirolimus may have some activity against metastatic chromophobe RCC (Initial data for Metastatic Non Clear Cell RCC)
  74. 74. Chromophobe RCC Well-circumscribed Homogeneous Tan tumor
  75. 75. Chromophobe RCC Mixture of classic (chromophobic) and eosinophilic cells Characteristic features: Distinct cytoplasmic borders Perinuclear halos Nuclear “raisins” The classic variant is notable for its “plant cell” appearance
  76. 76. Chromophobe RCC Stains positive for Hale colloidal iron Demonstrates multiple microvesicles on electron microscopy
  77. 77. WHO Classification 2004 Histology Multilocular cystic clear cell RCC (uncommon) Familial Forms Identical to clear cell RCC Gross Well-circumscribed mass of small and large cysts HPE Cysts lined by single layer of grade 1 clear cells No expansive nodules of tumor cells Other features Almost uniformly benign clinical behavior Histology Collecting duct carcinoma (<1%) Familial Forms Unknown Multiple chromosomal losses Gross Firm, centrally located tumor with infiltrative borders Light gray to tan-white HPE Complex, highly infiltrative cords within inflamed (desmoplastic) stroma High-grade nuclei, mitoses Other features Originate from collecting duct Poor prognosis May respond to chemotherapy
  78. 78. Collecting Duct Carcinoma  Carcinoma of the collecting ducts of Bellini  Rare (less than 1% of all RCCs)  Younger patients; often in 3rd, 4th or 5th decades of life  Most patients are symptomatic at presentation  Up to 50% have metastatic disease at the time of detection  Ulex europaeus agglutinin 1 reactivity and positivity for E-cadherin and c-KIT help to distinguish this entity from aggressive papillary RCC, but this staining profile can also be present in urothelial carcinoma  Expression of high-molecular-weight cytokeratin (HMWCK) was initially believed to support a collecting duct origin, but more recent studies suggest that this is not a reliable marker  Small collecting duct carcinomas can arise in a medullary pyramid, but most are large, infiltrative masses and extension into the cortex is common
  79. 79. Collecting Duct Carcinoma  On microscopic examination  Mixture of dilated tubules and papillary structures typically lined by a single layer of cuboidal cells, often creating a cobblestone appearance  Genetics  Deletion on chromosome 1q  Monosomy of chromosomes 6, 8, 11, 18, 21, and Y  Most cases: high grade, advanced stage and unresponsive to conventional therapies  Reflecting the fact that collecting duct RCC may share features in common with TCC, some patients with advanced collecting duct RCC have responded to cisplatin- or gemcitabine -based chemotherapy
  80. 80. WHO Classification 2004 Histology Renal medullary carcinoma (rare) Familial Forms Associated with sickle cell trait Gross Infiltrative, gray-white Extensive hemorrhage and necrosis HPE Poorly differentiated cells with lacelike appearance Inflammatory infiltrate Other features Originate from collecting duct Dismal prognosis Histology Unclassified RCC (1 - 3%) Familial Forms Unknown Gross Varied HPE Varied Other features Origin not defined Generally poor prognosis
  81. 81. Renal Medullary Carcinoma  Occurs almost exclusively in association with the sickle cell trait.  Diagnosed in young African- Americans  Often in 3rd decade of life  Many cases are both locally-advanced and metastatic at the time of diagnosis  Most patients do not respond to therapy and succumb to their disease in a few to several months  Mean survival ~ only 15 weeks  Histology  Shares many histologic features with collecting duct carcinoma  Some consider it a subtype of collecting duct carcinoma  Thought to arise from calyceal epithelium near renal papillae but is often highly infiltrative  The site of origin (renal papillae) and association with sickle cell trait suggest that a relatively hypoxic environment may contribute to tumorigenesis
  82. 82. Unclassified Renal Cell Carcinoma  <3%  Presumed RCC with indeterminate features even after careful analysis  Poorly differentiated  Highly aggressive biologic behavior  Particularly poor prognosis  Included within this “catch-all” category are RCCs with extensive sarcomatoid differentiation and no discernible epithelial component.
  83. 83. WHO Classification 2004 Histology RCC associated with Xp11.2 translocations/TFE3 gene fusions (rare) Familial Forms Various mutations involving chromosome Xp11.2 resulting in TFE3 gene fusion Gross Well-circumscribed, tan-yellow tumor HPE Variable; often clear cells with papillary architecture IHC: nuclear TFE3 Other features Occur in children and young adults 40% of pediatric RCC t(X;17) present with advanced stage and follow indolent course t(X;1) can recur with late lymph node metastases
  84. 84. Xp11 translocation carcinomas
  85. 85. WHO Classification 2004 Histology Post-Neuroblastoma RCC (rare) Familial Forms Unknown Gross Well circumscribed HPE Oncocytic or clear cells with solid and papillary architecture Other features Occurs exclusively in children with prior Neuroblastoma Histology Mucinous tubular and spindle cell carcinoma (rare) Familial Forms Unknown Gross Well-circumscribed, tan-white-pink tumors centered in medulla HPE Mixture of tubules and spindle-shaped epithelial cells; mucin background Other features Favorable prognosis
  86. 86. Sarcomatoid Differentiation        Sarcomatoid differentiation is found in 1% to 5% of RCCs Most commonly in a/w clear cell RCC or chromophobe RCC Represent poorly differentiated regions of other histologic subtypes of RCC rather than independently derived tumors A thorough search for epithelial-derived malignant components is almost always fruitful; it is rare to find a truly pure sarcomatoid renal mass. For this reason, it is no longer recognized as a distinct histologic subtype of RCC. Characterized by  Spindle cell histology  Positive staining for vimentin  Infiltrative growth pattern  Aggressive local and metastatic behavior  Poor prognosis Invasion of adjacent organs is common, and median survival is < 1 year Multimodal approaches should be considered if performance status allows  Extremely poor prognosis with surgery alone  Modestly improved response rates in patients receiving IL-2–based immunotherapy, chemotherapy or targeted molecular therapy after surgery
  87. 87. Clear Cell RCC with Sarcomatoid Differentiation Normal tissue Clear cell RCC with sarcomatoid differentiation Tumor Demonstrating extension into the perinephric fat extension into perinephric fat
  88. 88. Clear Cell RCC with Sarcomatoid Differentiation High-grade RCC with typical spindle-cell appearance on the left indicating a component of sarcomatoid differentiation
  89. 89. Clinical Presentation
  90. 90. Clinical Presentation  Many renal masses remain asymptomatic and nonpalpable until they are advanced  More than 50% of RCCs are now detected incidentally on routine radiology imaging
  91. 91. Presentation Modes Incidental Obstruction of IVC Local Tumor Growth  Bilateral lower extremity edema Nonreducing or right-sided varicocele  Hematuria   Flank pain Paraneoplastic Syndromes  Abdominal mass  Hypercalcemia  Perirenal hematoma  Hypertension  Polycythemia  Stauffer’s syndrome Metastases  Persistent cough  Bone pain  Cervical lymphadenopathy  Constitutional symptoms  Weight loss/fever/malaise
  92. 92. Paraneoplastic Syndromes   Classic triad of flank pain, gross hematuria and palpable abdominal mass is now rarely found Paraneoplastic syndromes       Found in 20% RCC was previously referred to as the internist’s tumor because of the predominance of systemic rather than local manifestations Now, a more appropriate name would be the radiologist’s tumor, given the frequency of incidental detection Under normal circumstances, the kidney produces 1,25-dihydroxycholecalciferol, renin, erythropoietin, and various prostaglandins, all of which are tightly regulated to maintain homeostasis RCC may produce these substances in pathologic amounts, and it may also elaborate a variety of other physiologically important factors, such as PTRrP, Lupustype anticoagulant, hCG, insulin, and various cytokines and inflammatory mediators These substances are believed to be responsible for the development of constitutional symptoms such as weight loss, fever, and anemia as well as some of the distinct paraneoplastic syndromes observed with this malignancy
  93. 93. Paraneoplastic Syndromes Incidence of Systemic Syndromes Associated with RCC SYNDROME % Elevated erythrocyte sedimentation rate 55.6 Hypertension 37.5 Anemia 36.3 Cachexia, weight loss 34.5 Pyrexia 17.2 Abnormal liver function 14.4 Hypercalcemia 4.9 Polycythemia 3.5 Neuromyopathy 3.2 Amyloidosis 2.0
  94. 94. Paraneoplastic Syndromes Hypercalcemia  Upto 13% of patients with RCC  Can be due to either paraneoplastic phenomena or osteolytic mets  Etiology  MC = Production of PTHrP  Others = Tumor derived 1,25-dihydroxycholecalciferol and prostaglandins  Expression of PTHrP is suppressed by wildtype VHL protein,  These peptides may act as potent growth factors for RCC  Patients with RCC who present with hypercalcemia have a compromised prognosis, with a relative risk of death from cancer progression of 1.78 compared with patients with normal serum calcium levels  The signs and symptoms of hypercalcemia are often nonspecific and include nausea, anorexia, fatigue, and decreased deep tendon reflexes.
  95. 95. Paraneoplastic Syndromes  Medical management  Vigorous hydration followed by diuresis with furosemide  Selective use of bisphosphonates, corticosteroids or calcitonin  Bisphosphonate therapy  is now established as standard of care for patients with hypercalcemia of malignancy, as long as renal function is adequate  Zoledronic acid, 4 mg intravenously every 4 weeks  Indomethacin has also proved useful in a minority of cases  More definite management includes nephrectomy and occasional metastasectomy,.  Systemic therapy to reduce the burden of disease is also desirable but difficult Osteolytic Mets  Hypercalcemia related to extensive osteolytic mets is much more difficult to palliate because it is not amenable to surgical approaches, but many such patients may respond to bisphosphonate therapy
  96. 96. Paraneoplastic Syndromes  Some patients benefit from focused radiation therapy if limited sites of involvement can be identified Hypertension  Etiology  Increased production of renin directly by the tumor  Compression or encasement of renal artery or its branches, effectively leading to renal artery stenosis;  Arteriovenous fistula within tumor  Less common = polycythemia, hypercalcemia, ureteral obstruction, and increased intracranial pressure associated with cerebral metastases Polycythemia  Due to increased production of erythropoietin  directly by tumor or by adjacent parenchyma in response to hypoxia induced by tumor growth
  97. 97. Paraneoplastic Syndromes Stauffer Syndrome  Nonmetastatic hepatic dysfunction  3% to 20% of cases  elevated serum alkaline phosphatase ~ 100 %  67% have elevated prothrombin time or hypoalbuminemia  20% to 30% have elevated serum bilirubin or transaminase levels  Other common findings = thrombocytopenia and neutropenia  S/S = fever and weight loss  Many patients have discrete regions of hepatic necrosis  Hepatic mets must be excluded  Biopsy, when indicated, often demonstrates nonspecific hepatitis associated with a prominent lymphocytic infiltrate  Elevated serum IL-6  Hepatic function normalizes after nephrectomy in 60% to 70%  Persistence or recurrence of hepatic dysfunction is almost always indicative of the presence of viable tumor and thus represents a poor prognostic finding
  98. 98. Paraneoplastic Syndromes  Other less common paraneoplastic syndromes  Cushing syndrome  Hyperglycemia  Galactorrhea  Neuromyopathy,  Clotting disorders  Cerebellar ataxia  In general, treatment of paraneoplastic syndromes associated with RCC has required surgical excision or systemic therapy and, except for hypercalcemia, medical therapies have not proved helpful
  99. 99. Screening and Clinical Associations
  100. 100. Why it is not done?  The primary factor that limits widespread screening for RCC is relatively low incidence of RCC in the general population (~ 12/100,000 population/year)  In this setting a screening test must be almost 100% specific to avoid an unacceptably high false-positive rate  Even if test were 100% sensitive and specific, the yield from screening would be so low that it would not be cost effective  Even with established risk factors for RCC, such as male sex, increased age, and heavy 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  Another confounding factor  substantial prevalence of clinically insignificant tumors such as renal adenomas, which are found at autopsy in 10% to 20%  Studies on use of dipstick analysis for hematuria and USG/CT for screening supports these conclusions
  101. 101. Urine Screening  Urinalysis is simple and inexpensive, but the yield is exceedingly low  Because small RCCs are often not associated with hematuria (gross or microscopic) because this is a parenchymal rather than urothelium-based  The incidence of RCC in ultrasound or CT screening studies has ranged from 23 to 300 per 100,000 population  Although the yield of RCC has been higher than expected, it is still relatively low; and it is unlikely that such efforts would be considered cost effective  Novel molecular assays to detect rcc-related biomarkers in the urine or serum  Microsatellite alterations in the DNA  VHL gene mutations or hypermethylation  Expression of rcc-specific proteins such as CA-9  Upregulation of angiogenic factors, including VEGF  Proteomic profiling of urine to detect rcc-specific markers also holds much promise
  102. 102. Target Populations  Examples: ESRD and acquired renal cystic disease,TS and familial RCC ESRD  80% of patients with ESRD  develop acquired renal cystic disease (ACKD)  1-2% of this ACKD subgroup develop RCC  Overall, RR of RCC ~ 5-20 fold higher than general population  15% of RCC in the setting of ESRD have mets at presentation and many die of malignant progression  Problems associated with screening this population  Concerns about short life expectancy  Increased incidence of adenomas (20-40% vs. 10-20% in general population)  Complexity of imaging (given the altered architecture a/w ACKD)  Inevitable cost-related issues  Elevated serum levels of VEGF in dialysis patients with RCC (potential biomarker)  Renal transplant recipients remain at high risk for RCC in the native kidneys  Recommended: continued periodic radiologic screening even after transplantation
  103. 103. Target Population Patients with ESRD •Screen only patients with long life expectancy and minimal major comorbidities. •Perform periodic ultrasound examination or CT scan beginning during third year on dialysis Patients with Known VHL Syndrome •Obtain biannual abdominal CT or ultrasound study beginning at age 15 to 20 years. •Perform periodic clinical and radiographic screening for nonrenal manifestations. Relatives of Patients with VHL •Obtain genetic analysis. •If positive, follow screening recommendations for patients with known von Hippel-Lindau syndrome. •If negative, less stringent follow-up is required Relatives of Patients with Familial RCC •Obtain periodic ultrasound or CT study and consider genetic Analysis Patients with Tuberous Sclerosis •Perform periodic screening with ultrasound examination or CT scan Patients with ADPKD •Routine screening is not justified
  104. 104. Target Population Tuberous Sclerosis  Autosomal dominant  Epilepsy + Mental Retardation + Adenoma Sebaceum +AML + renal cysts  Increased incidence of RCC  RCC in TS: early onset and multifocal  Gene for TS in humans = TSC2 (Tumor Suppressor gene) (action is analogous to VHL protein)  Develop RCC at high frequency  Eker rat (mutant for rodent homologue of TSC2 gene)  TSC2- deficient knockout mice  Increased incidence of TSC2 mutations has been found in human RCC  Loss of TSC2  mTOR and HIF-2α–mediated mechanisms  upregulated expression of VEGF  A reasonable conclusion is that periodic renal imaging should be pursued in TS
  105. 105. Target Population ADPKD  previously recommended, not now  More recent studies suggest no significantly increased risk  imaging is extremely difficult in this population  Increased incidence of adenomas VHL  This syndrome should be considered in any patient with early-onset or multifocal RCC or RCC in combination with any of the following: a history of visual or neurologic disorders; a family history of blindness, central nervous system tumors, or renal cancer; or coexistent pancreatic cysts, epididymal lesions, or inner ear tumors  Patients suspected of VHL, or appropriate relatives of those with documented disease, should strongly consider genetic evaluation  Patients with germline mutations can be identified and offered clinical and radiographic screening  identify major manifestations at a presymptomatic phase  decreasing associated potential morbidity
  106. 106. Target Population  National Institutes of Health recommendations: 1. Annual physical examination and ophthalmologic evaluation beginning in infancy 2. Urinary catecholamines at age of 2 years and every 1 to 2 years thereafter 3. MRI of CNS biannually beginning at age of 11 years 4. USG abdomen and pelvis annually beginning at the age of 11 years, followed by CT every 6 months if cysts or tumors develop 5. Periodic auditory examinations  Individuals who are found to be wild type for both alleles of VHL also benefit because they can be spared much of the expense and anxiety a/w such intensive surveillance protocols.
  107. 107. Target Population Familial RCC  Molecular screening  Individuals at risk =  presence of mutations of the c-MET proto-oncogene or other relevant genetic alterations  those with suggestive clinical or family histories  Abdominal USG/CT at periodic intervals.  Further testing according to syndrome/system involved
  108. 108. Staging
  109. 109. Staging  Until the 1990s, most commonly used staging system was Robson’s modification of Flocks and Kadesky system.  Limitations of this classification scheme  In stage III, tumors with lymphatic mets (very poor prognostic finding) were combined with those with venous involvement (treated and potentially cured with an aggressive surgical approach)  Extent of venous involvement was not delineated  Tumor size, an important prognostic parameter, was not incorporated  The net effect was that the prognostic significance of the various stages was blunted, with some studies reporting equivalent survival for patients with stage II and stage III tumors
  110. 110. Staging  The TNM system proposed by the Union International Contre le Cancer (UICC) represented a major improvement because it separated tumors with venous involvement from those with lymphatic invasion and defined the anatomic extent of disease more explicitly  Another advantage of the TNM system is that it has facilitated comparison of clinical and pathologic data from various centers across the globe  In 2009 the American Joint Committee on Cancer (AJCC) proposed a revision of the TNM system that is now the recommended staging system for RCC  In 1997 the previous division of stages T1 and T2 at tumor size of 2.5 cm was abandoned because several studies showed no prognostic significance at this level.
  111. 111. Staging  SEER demonstrated survival differences associated with 5, 7.5 and 10-cm cut points  7-cm cut point between stages T1 and T2 was adopted because it reflected the mean tumor size in the database  In the 2002 version stage T1 was subdivided:  T1a represents tumor size of 4 cm or less  T1b represents tumor size between 4 and 7 cm  Excellent outcomes for patients with small (≤4 cm), unilateral, confined tumors managed by either partial or radical nephrectomy  The most recent change for organ-confined tumors is a subdivision of T2 tumors:  T2a tumor represents tumors between 7 and 10 cm  T2b represents tumors greater than 10 cm
  112. 112. Staging  Other major revisions in 2009 included a reclassification of tumors with adrenal metastasis, venous thrombi, and lymphatic involvement  Poor prognosis of adrenal involvement is well documented  Contiguous extension of tumor into ipsilateral adrenal gland is now T4  Metastatic involvement of either adrenal as M1  The favorable prognosis of isolated renal venous thrombi prompted a downgrading  From stage T3b to stage T3a in 2009 version  Finally, lymphatic extension  Previously subdivided based on number of involved nodes  Now been compressed to simplify this aspect  Because prognostic relevance of previous version was not observed
  113. 113. Staging  TNM staging classically is defined by the most advanced feature demonstrated by the tumor  Important prognostic information can be lost in the process  Many tumors exhibit multiple adverse findings, such as high-level tumor thrombus along with ipsilateral adrenal involvement  Clinical staging disease begins with a thorough history, physical examination, and judicious use of laboratory tests  Presentation with systemic symptoms such as significant weight loss (>10% of body weight), cachexia, or poor performance status 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.  Abnormal liver function test results, elevated serum alkaline phosphatase or lactate dehydrogenase level or sedimentation rate, hypercalcemia, and significant anemia point to the probability of advanced disease
  114. 114. Staging T: Primary Tumor  TX Primary tumor cannot be assessed   T0 No evidence of primary tumor  T1 Tumor ≤7.0 cm and confined to the kidney  T1a Tumor ≤4.0 cm and confined to the kidney  T1b Tumor >4.0 cm and ≤7.0 cm and confined to the kidney  T2 Tumor >7.0 cm and confined to the kidney  T2a Tumor >7.0 cm and ≤10.0 cm and confined to the kidney  T2b Tumor >10.0 cm and confined to the kidney  T3 Tumor extends into major veins or perinephric tissues but not into the ipsilateral adrenal gland and not beyond the Gerota fascia  T3a Tumor grossly extends into the renal vein or its segmental (muscle containing) branches or tumor invades perirenal and/or renal sinus fat but not beyond the Gerota fascia  T3b Tumor grossly extends into the vena cava below the diaphragm  T3c Tumor grossly extends into the vena cava above the diaphragm or invades the wall of the vena cava T4 Tumor invades beyond the Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)
  115. 115. Staging N: Regional Lymph Nodes  NX: Regional lymph nodes cannot be assessed  N0: No regional lymph nodes metastasis  N1: Metastasis in regional lymph node(s) M: Distant Metastases  MX Distant metastasis cannot be assessed  M0 No distant metastasis  M1 Distant metastasis present
  116. 116. Radiographic staging of RCC  Radiographic staging of RCC  High-quality abdominal CT  Routine chest radiograph  Selective use of MRI  Other studies as indicated  MRI: For patients with locally advanced malignant disease, equivocal venous involvement, or allergy to intravenous contrast
  117. 117. Radiographic staging of RCC Perinephric Fat  CT findings suggestive of extension into perinephric fat  Perinephric stranding (nonspecific)  Distinct soft tissue density within perinephric space (definitive but uncommon)  Overall accuracy of CT/MRI for detection of involvement of perinephric fat is low, reflecting the fact that extracapsular spread often occurs microscopically  Many of these potentially locally advanced cases are managed with radical nephrectomy, so the clinical relevance of this imprecision in staging is blunted.
  118. 118. Radiographic staging of RCC Adrenal involvement  Ipsilateral adrenal involvement can be assessed with reasonable accuracy through a combination of preoperative CT and intraoperative inspection  Patients at risk for ipsilateral adrenal involvement 1. Enlarged or indistinct adrenal gland on CT 2. Extensive malignant replacement of kidney 3. Palpably abnormal adrenal gland  Should be managed accordingly
  119. 119. Radiographic staging of RCC Lymph nodes and adjacent organs  Enlarged hilar or retroperitoneal lymph nodes 2 cm or more in diameter on CT almost always harbour malignant change  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  MRI:  Adds specificity to evaluation of retroperitoneal nodes by distinguishing vascular structures from lymphatic ones  Still the premier study for evaluation of invasion into adjacent structures and surgical planning  Obliteration of fat plane between tumor and adjacent organs (e.g., the liver) can be a misleading finding on CT and should prompt further imaging with MRI  Surgical exploration is often required to make an absolute differentiation.
  120. 120. Radiographic staging of RCC Venous tumor thrombus  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  Venous enlargement, abrupt change in the caliber of the vein, and intraluminal areas of decreased density or filling defects  The diagnosis is strengthened by demonstration of collateral vessels  Most false-negative findings occur in patients with right-sided tumors in whom the short length of the vein and the mass effect from the tumor combine to make detection of the tumor thrombus difficult  MRI is well established as the premier study for the evaluation and staging of IVC tumor thrombus  MRI and multiplanar CT are equivalent  MRI and multiplanar CT are noninvasive methods that provide reliable information about both the cephalad and caudal extent of the thrombus and can often distinguish bland from tumor thrombus
  121. 121. Radiographic staging of RCC Venous tumor thrombus  Venacavography  For patients with equivocal MRI or CT findings  Who cannot tolerate or have other contraindications to cross-sectional imaging  Transesophageal echocardiography also appears to be accurate for establishing the cephalad extent of the tumor thrombus, but it is invasive and provides no distinct advantages over MRI or CT  Doppler ultrasonography is operator dependent and does not provide the anatomic resolution available with MRI or multiplanar CT
  122. 122. Radiographic staging of RCC Metastatic evaluation  Should include a routine chest radiograph, careful and systematic review of the abdominal and pelvic CT or MRI findings, and liver function tests  Bone scintiscan: for patients with elevated alkaline phosphatase/bone pain  Chest CT: for patients with pulmonary symptoms/abnormal chest radiograph  However, 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  Performance status is a powerful predictor of bone metastasis  Patients with good performance status (Eastern Cooperative Oncology Group performance status score of 0), no evidence of extraosseous metastases, and no bone pain were at extremely low risk and did not benefit from bone Scintigraphy.  They recommended a bone scintiscan for all other patients, and the incidence of bone metastasis in this group was above 15%.
  123. 123. Radiographic staging of RCC Positron emission tomography (PET)  For patients with high risk of metastatic RCC  Good specificity but suboptimal sensitivity  At present its best role is for patients with equivocal findings on conventional imaging  In this setting an abnormal PET scan may indicate metastatic disease and could strongly influence further evaluation and management  PET/CT combined with radiolabeled monoclonal antibody to CA-9 is also being explored in this population for molecular imaging of clear cell RCC  Biopsy of the primary tumor and/or potential metastatic sites is also selectively required as part of the staging process
  124. 124. Prognosis  Important prognostic factors for cancer-specific survival in patients with localized RCC include  specific clinical signs or symptoms  tumor-related factors  various laboratory findings  Overall, tumor-related factors such as pathologic stage, tumor size, nuclear grade, and histologic subtype = independent  Patient-related factors, such as age, CKD, and co-morbidity, have a significant impact on overall survival  Clinical findings s/o compromised prognosis in presumed localized RCC:  Symptomatic presentation  Weight loss of more than 10% of body weight  Poor performance status
  125. 125. Prognostic factors in RCC
  126. 126. Prognostic factors in RCC
  127. 127. Prognostic factors in RCC  Anemia, thrombocytosis, hypercalcemia, albuminuria, elevated serum alkaline phosphatase, C-reactive protein, lactate dehydrogenase, or erythrocyte sedimentation rate, and other paraneoplastic signs or symptoms have also correlated with poor outcomes  Abnormal values are more common in patients with advanced RCC  Independent predictors of cancer-specific mortality in localized clear cell RCC  Hypercalcemia  Anemia  Elevated erythrocyte sedimentation rate  Pathologic stage  Single most important prognostic factor  5-year survival rates  70% to 90% for organ-confined disease  15% to 20% reduction in survival associated with invasion of perinephric fat
  128. 128. Prognostic factors in RCC  Pathologic stage (contd)  Renal sinus involvement is classified along with perinephric fat invasion as T3a  These patients may be at even higher risk for metastasis related to increased access to the venous system  Collecting system invasion has also been shown to confer poorer prognosis in otherwise organ-confined RCC  Most patients with direct or metastatic ipsilateral adrenal involvement, which is found in 1% to 2% of cases, eventually succumb to systemic disease progression, suggesting a hematogenous route of dissemination or a highly invasive phenotype  The most recent staging system now reclassifies tumor as T4 if there is direct invasion of the adrenal gland or otherwise as M1, to reflect this poor prognosis  Venous involvement was once thought to be a very poor prognostic finding. Many patients can be salvaged with an aggressive surgical approach.  45% to 69% 5-year survival rates for patients with venous tumor thrombi as long as the tumor is otherwise confined to the kidney  84% 5-year survival in tumor thrombus limited to the main renal vein and tumor otherwise confined to the kidney
  129. 129. Prognostic factors in RCC  Pathologic stage (contd)  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  The prognostic significance of the cephalad extent of tumor thrombus has been controversial  Incidence of advanced locoregional or systemic disease increased with the cephalad extent of the tumor thrombus, accounting for the reduced survival associated with tumor thrombus extending into or above the level of the hepatic veins  Cephalad extent of tumor thrombus is not of prognostic significance as long as the tumor is otherwise confined  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
  130. 130. Prognostic factors in RCC  Pathologic stage (contd)  The major drop in prognosis when tumor extends beyond Gerota fascia to involve contiguous organs (stage T4)  Rarely associated with 5-year survival  Lymph node involvement (Poor sign)  5 yr SR = 5 - 30%  10 yr SR = 0 – 5%  Systemic metastases (poor prognosis)  1-year survival of less than 50%  5-year survival of 5% to 30%  10-year survival of 0% to 5%,  Synchronous metastases = worse. Patients die of disease progression in a year  In patients with asynchronous metastases, mets-free interval = useful prognosticator because it reflects the tempo of disease progression
  131. 131. Prognostic factors in RCC  Other important prognostic factors for systemic mets  Performance status, number and sites of metastases, anemia, hypercalcemia, elevated alkaline phosphatase or lactate dehydrogenase levels, thrombocytosis, and sarcomatoid histology  The presence of bone, brain, and/or liver metastases, and multiple metastatic sites  further compromise in prognosis  These factors have been used to effectively categorize patients with metastatic RCC as low, intermediate, and poor risk, with corresponding differences in median survival  These risk groups provide important information for determining the likelihood of benefit a patient may expect to receive after cytoreductive nephrectomy and/or resection of other metastatic disease.
  132. 132. Prognostic factors in RCC  Tumor Size  Another significant prognostic factor  independent prognostic factor for both organ-confined and invasive RCC  5-year survival rates  84% for patients with tumor diameter less than 5 cm  50% for tumors between 5 and 10 cm  0% for tumors more than 10 cm in diameter.  Larger tumors  more likely to exhibit clear cell histology + high nuclear grade  Favorable prognosis for unilateral pT1a tumors  Such tumors are associated with > 95% 5-year cancer-specific survival rates, whether they were managed with nephron-sparing surgery or radical nephrectomy
  133. 133. Prognostic factors in RCC  Nuclear grade, histologic subtype and symptomatic presentation  Several grading systems  Interobserver variability is common  No ideal classification system  Nuclear grade has proved in most cases to be an independent prognostic factor  Fuhrman’s classification system (MC adopted system)  5-year survival rates for grades 1 to 4 = 64%, 34%, 31%, and 10%, respectively  Nuclear grade = most significant prognostic factor for organ-confined tumors  Subsequent reports have demonstrated correlations between Fuhrman’s nuclear grade and tumor stage, tumor size, venous tumor thrombi, and lymph node and systemic metastases
  134. 134. Prognostic factors in RCC  Histologic subtype  Also carries prognostic significance  The presence of sarcomatoid differentiation or collecting duct, renal medullary, or unclassified histologic subtype denotes a poor prognosis  Several studies now suggest that clear cell RCC may have a worse prognosis on average compared with papillary or chromophobe RCC  Several subtypes of RCC are predictably indolent, including multiloculated cystic clear cell RCC and mucinous tubular and spindle cell carcinoma.
  135. 135. Prognostic factors in RCC  For patients with clinically localized disease, mode of presentation (incidental vs. symptomatic) can be combined with other predictive elements to better stratify patients after primary surgical management  In addition, patients with systemic symptoms suggestive of metastatic spread have significantly poorer outcomes than those with only local symptoms, such as hematuria or flank pain  Dozens of genes that may have prognostic or therapeutic significance for patients with RCC have been identified  Gene expression profiling (cDNA microarrays) can quantify the levels of thousands of individual messenger RNA transcripts within an individual tumor sample.  Alterations in gene expression can then be correlated with the amount and location of specific gene products (proteins) using immunohistochemical staining of cancer specimens  Construction of tissue microarrays can facilitate the screening of hundreds of tumors, but interpretation of results can be challenging due to tumor heterogeneity and the selection of only a small amount of tissue for analysis
  136. 136. Prognostic factors in RCC  Molecular markers  Independent prognostic factors for RCC  CA-IX, which is regulated by the VHL gene and overexpressed in most clear cell RCCs  Although initial studies indicated that decreased expression of CA-IX is independently associated with poorer survival in patients with metastatic RCC  this association does not appear to apply for patients with localized disease  CA-IX also may serve as a marker for response to systemic therapy  B7-H1 a strong independent predictor of disease progression for RCC  Increased proliferative index as assessed by Ki-67 has also been correlated with reduced survival in clear cell RCC  Although initial data indicated that Ki-67 expression was a surrogate for histologic necrosis, more recent studies have found Ki-67 to be an independent predictor and have incorporated it into predictive algorithms
  137. 137. Prognostic factors in RCC  Molecular markers (contd.)  Other factors that appear to be useful include  Cell cycle regulators, such as the tumor suppressor TP53  Growth factors and their receptors, including members of the VEGF family adhesion molecules  Survivin
  138. 138. Prognostic factors in RCC  Nomograms  Tools that combine various prognostic factors and predict survival  Kattans Nomogram  Kattan and colleagues (2001) have combined  Manner of presentation (incidental vs. local or systemic symptoms),  Tumor histology  Tumor size  Pathologic stage  Predicts cancer-free survival after nephrectomy  Tumor grade was not included (role for non– clear cell RCC not clearly defined)  Subsequent analysis focused only on patients with clear cell RCC  incorporated tumor grade, assessment of tumor necrosis, and vascular invasion to further improve prognostication  Several predictive algorithms incorporate histologic necrosis but the utility of this predictor has been called into question
  139. 139. Prognostic factors in RCC    Pantuck and colleagues (2001a)  Integrated analysis of prognostic factors for all stages of RCC  revealed three independent prognostic factors that were most robust for predicting outcomes  TNM stage,  Performance status  Tumor grade UCLA integrated staging system (UISS) was subsequently modified to identify patients with localized or metastatic disease at low, intermediate, and high risk of disease progression and has been validated internally and externally Molecular factors such as TP53, Ki-67, VEGF family members, and CA-IX have also been incorporated into UISS-based algorithms to predict outcomes for patients with localized or metastatic RCC
  140. 140. Prognostic factors in RCC  SSIGN Score  Another predominant model that provides individualized information for patients with clear cell RCC is the SSIGN score, which incorporates 1997 TNM stage, tumor size, nuclear grade, and presence of tumor necrosis to predict recurrence and survival after radical nephrectomy  BioScore  Most recently, the group at Mayo Clinic has developed a sequential approach in which the predicted outcomes for patients at various risk of recurrence according to clinical and pathologic factors can be further stratified based on molecular data incorporated into a BioScore  The expression of B7-H1, survivin and Ki-67 each added independent predictive ability after accounting for either the UISS or SSIGN score, especially for patients at intermediate or high risk of recurrence