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A. Benign Renal Massesnavigator

  1. Angiomyolipoma (renal hamartomas)
    1. Hematuria is major symptom
    2. 90% female
    3. >5cm tumors should be removed because of high potential to rupture
  2. Tuberous Sclerosis with Angiomyolipoma
    1. Paraventricular leukoencephalopathy leads to parenchymal calcifications
    2. Mental Retardation and Seizures
    3. Adenoma, myxoma
    4. Angiomyolipoma
  3. Oncocytoma
    1. Central Stellate scar (though this can occur with adenocarcinoma also)
    2. Highly vascular
  4. Renal Cysts
  5. Nephrogenic Adenomas [3]
    1. Rare, benign tumors
    2. Found within urothelial mucosa of urinary tract
    3. Usually found in bladder
    4. Less commonly in pelvic urothelium, ureter, urethra
    5. Most commonly associated with chronic bladder inflammation
    6. Also occur with previous genitourinary surgery
    7. Particularly frequent in renal-transplant recipients
    8. In transplant recipients, clearly derived from donor renal tubular cells

B. Malignant Tumorsnavigator

  1. Metastatic spread of other primary to kidney more common than primary renal cancer
    1. Lung
    2. Breast
    3. Ovarian
  2. Renal cell carcinoma (adenocarcinoma) - most common primary tumor of kidney (see below)
  3. Transitional Cell Carcinoma [4]
    1. Develops from mesonephric (tubular) duct structures
    2. Increased incidence in patients with recurrent infections, stones
    3. More common in males
    4. Occasionally occurs in renal pelvis (similar to transitional bladder cell carcinoma)
    5. Often low grade, localized tumors which can be cured with surgical resection
    6. Like transitional tumors localized to bladder, can be multifocal
    7. May present as microembolic tumor to lungs [5]
  4. Other Renal Tumors
    1. Squamous cell carcinoma of kidney
    2. Sarcoma
    3. Lymphoma

C. Renal Cell Carcinoma (RCC) [1,2]navigator

  1. Also called hypernephroma, renal adenocarcinoma
  2. Epidemiology
    1. Renal cell carcinoma (RCC) represents ~2% of all cancers
    2. In 2005, ~36,000 new cases in USA, ~12,500 deaths
    3. Worldwide ~100,000 kidney cancer deaths each year
    4. Male to Female is 2 to 1
    5. Usually in adults ages 50-70 years old
    6. About 25% are metastatic at presentation
    7. Screening for hematuria is minimally effective
    8. About 4% of cases are hereditary, related to Von Hippel Lindau (VHL) gene loss
  3. Risk Factors
    1. Von Hippel Lindau Disease >100 fold increased risk
    2. Chronic Hemodialysis >30 fold increased risk
    3. Obesity 3.6 fold risk
    4. Smoking 2.3 fold risk
    5. Arsenic Exposre 1.6 fold risk
    6. Leather Processing
    7. Asbestosis
    8. Polycystic Kidney Diseases
    9. Hypertension (in men) [6]
    10. Obesity (elevated body mass index, in men) [6]
    11. Chinese herb Aristolochia fangchi [7]
    12. Other familial syndromes (paraganglioma, HPRC, HLRCC, BHD syndrome)
  4. Histologic Subtypes
    1. Clear Cell: ~75%
    2. Chromophilic (papillary): ~12%
    3. Chromophobic: 4%
    4. Oncocytic: 4% (many are benign)
    5. Collecting (Bellini's) Duct: <1%
    6. Unclassified ~4%
  5. Pathology
    1. Large ball shape, highly vascular
    2. Majority arise from proximal tubule cells: clear cell (75%), papillary (~15%)
    3. Transitional cell, collecting duct cell, oncocytoma, and others are found
    4. Sarcomatoid changes occur in both clear and papillary cancers; are poor prognostically
    5. Inactivation of p53 tumor suppressor protein correlates with sarcomatoid changes
    6. Differentiation grade, including nuclear grade, is useful prognostically
  6. Pathophysiology [12]
    1. The VHL gene plays a key role in controlling normal proximal tubule proliferation
    2. VHL is a tumor suppressor gene on chromosome 3p25
    3. VHL protein is a normal transcription elongation blocking protein
    4. VHL also plays a role in the hypoxia regulated ubiquitin ligase system and hypoxia inducible factor (HIF) leading to increased growth factor expression
    5. Vascular endothelial growth factor (VEGF), PDGF, TGFalpha all increased in RCC
    6. Over 95% of clear cell cancers have functional loss of both VHL genes
    7. Other genes involved in progression are being evaluated
    8. About 13% of papillary tumors have MET oncogene mutations
    9. Most kidney cancers express the mdr1 (multidrug resistance) genes
    10. Cancers expressing mdr1 are resistant to a number of chemotherapeutic agents
  7. Presentation
    1. Hematuria is most common presentation (may be asymptomatic)
    2. Abdominal Pain (40%) and flank or abdominal mass (35%) are increasingly less common
    3. Presents with classic triad of flank pain, flank mass, hematuria in only ~10% of cases
    4. Systemic symptoms including fever, night sweats, malaise, weight loss can occur
    5. About 1/3 of tumors are found on detection of incidental renal mass (CT or MRI)
    6. Direct invasion of renal vein and/or inferior vena cava is common (with symptoms)
    7. Metastases (20-30% at presentation) to lung, bone, liver or brain
  8. Laboratory Findings
    1. Some tumors produce large amounts of Interleukin 6 (IL6)
    2. IL6 causes fever, malaise, acute phase protein increases
    3. High IL6 levels are associated with erythrocyte sedimentation rates >80mm/hr
    4. About 2% of patients have polycythemia due to erythropoietin production by tumor
    5. Hypercalcemia found in minority of patients and is a poor prognostic factor
  9. Evaluation
    1. CT scans of chest, abdeomen and pelvis in most cases
    2. CT scan of head as needed
    3. Bone scanning as needed
    4. MRI of renal vein and inferior vena cava
    5. Tissue must be obtained to make clear diagnosis and rule out benign disease
    6. Staging is critical

D. Stagingnavigator

  1. Two main staging systems: Robson and American Joint Committee on Cancer (AJCC)
  2. Robson System
    1. Stage I: Size variable with no extension through renal capsule
    2. Stage II: Extending through renal capsule but confined to Gerota's Fascia
    3. Stage III: Renal vein, inferior vena cava (IVC), or local nodal involvement
    4. Stage IV: Direct organ invasion and/or distant metastases
  3. AJCC Definitions for Tumor (T) [8]
    1. T1: Tumor <7cm in largest dimension (localized only); T1a <4cm, T1b 4-7cm
    2. T2: Tumor >7cm (localized only)
    3. T3: tumor extens to major veins, adrenal glands, perinephric; not beyond Gerota's fascia
    4. T3a: invasion into adrenals or perinephric tissues
    5. T3b: extension into renal vein(s) or vena cava below diaphragm
    6. T3c: extension into vena cava above diaphragm
    7. T4: tumor extends beyond Gerota's fascia
  4. AJCC Definitions for Lymph Node (LN) Involvement (N)
    1. N0: no metastases to regional LN
    2. N1: metastasis in one LN
    3. N2: metastasis in two or more LN
  5. AJCC Staging
    1. Stage I: T1, N0, M0
    2. Stage II: T2, N0, M0
    3. Stage III: T(1,2,3), N1, M0 or T3, N0, M0
    4. Stage IV: Any N2, M1, or T4

E. Treatment of RCC [1,2,8,9,31]navigator

  1. Well documented spontaneous remissions of metastatic disease in <3% of cases
    1. May occur with or without primary tumor surgical resection
    2. May be related to host immune response to tumor
  2. Surgical Resection (debulking) [22]
    1. Radical nephrectomy is mainstay of therapy for localized tumors
    2. Radical nephrectomy added to systemic therapy prolongs survival in metastatic RCC [31]
    3. Nephron sparing (partial) and laparoscopic nephrectomies have also been used
    4. Nephrectomy also used in locally advanced disease with LN dissection
    5. Large margins are generally not recommended
    6. About 20% of patients with localized tumors relapse after radical nephrectomy
    7. If the inferior vena cava (T3b or higher) is involved, radical nephrectomy not recommended [31]
    8. Partial nephrectomy is probably equivalent to total nephrectomy for <4cm tumors [8]
    9. Radical nephrectomy followed by interferon alpha (IFNa) prolongs time to progression and increases complete response rate and survival in metastatic disease [9,11]
    10. Laparoscopic nephrectomy for smaller renal masses possible with reduced hospitalization
    11. Addition of adjuvant autologous renal tumor vaccine in patients with pT2-3bN0-3M0 (>2.5cm) RCC prolongs time to progression, progression free survival [10]
    12. Angioembolism, where the main renal artery is embolized, may be an alternative to nephrectomy
  3. Cryotherapy and radiofrequency ablation are being investigated for <4cm tumors [8]
  4. Poor Response to Chemoradiotherapy
    1. 5-FU infusions are often tried and have ~15% response rate
    2. Cisplatin, carboplatin, gemcitabine based regimens without survival benefit
    3. Sunitinib and sorafenib have shown good responses in cytokine-refractory RCC [17]
    4. Most tumors express mdr1 and other resistance genes
    5. Carboplatin + paclitaxel being evaluated in collecting duct form of RCC
  5. Radiotherapy
    1. Not used alone
    2. May help control local disease following surgery if local invasion is present
    3. May be used for painful bone lesions or metastatic brain foci
    4. Can be used in patients who cannot undergo surgery [22]
    5. Radiation nephritis is a common side effect
  6. Vascular Endothelial Growth Factor (VEGF) Blockade
    1. VEGF is a vascular growth factor implicated in tumor angiogenesis
    2. VEGF expression is high in renal cancer, particularly with defective VHL function
    3. Several receptors for VEGF (VEGF-R) exist and these have tyrosine kinase activity
    4. Blockade of VEGF-R tyrosine kinase activities are FDA approved oral therapies
    5. Blockade of VEGF-R itself is often used, typically in combination with interferon alpha (IFNa)
    6. Oral sunitinib or sorafenib are usually first line until progression
    7. Combination bevacizumab + IFNa, or termsirolimus alone, are reasonable second line
  7. Sunitinib (Sutent®) [17,21,25]
    1. Multikinase inhibitor (oral) - inhibits VEGF and PDGF receptor kinases, other kinases
    2. Blocks both tumor cell and vasculature targets
    3. Approved for renal cell (clear cell) carcinoma based on objective resopnse rates
    4. Overall 34% response and 8.3 month progression free survival in cytokine refractory RCC
    5. Superior progression free survival (11 months) versus IFNa (5 months), better quality of life, with 31% response rate versus 6% for IFNa in first-line metastatic RCC [17]
    6. Cycles of 50mg po qd x 4 weeks, then 2 weeks off
    7. Fatigue most common side effect
    8. Nausea, mucositis, stomatitis, skin discoloration, hypothyroidism, hepatitis
    9. Other side effects inlcude hypertension, LV dysfunction, CHF (usually reversible) [28]
    10. Grade 3 neutropenia in ~10% of patients
    11. Sunitinib is now standard first line therapy for metastatic RCC
  8. Sorafenib (Nexavar®) [23,26]
    1. Multikinase inhibitor (oral), blocks VEGF, PGDF, and other tyrosine kinase receptors
    2. Blocks both tumor cell and vasculature targets
    3. Progression free survival improved (5.5 months) versus placebo (2.8 months), and reduced overall risk of death in advanced RCC
    4. Dose is 200mg po qd up to 400mg po bid
    5. Fatigue and diarrhea most common
    6. Rash and hand-foot syndrome in ~40% of patients (may require dose reduction)
    7. Hypertension, nausea, hypophosphatemia, weight loss, neuropathy (pain)
  9. Temsirolimus (Torisel®) [27,30]
    1. Inhibitor of mammalian target of rapamycin (mTOR) kinase
    2. Binds to FKBP-12, forming complex that inhibits mTOR signaling
    3. This leads to suppression of proteins that mediate progression through cell cycle and HIF
    4. Temsirolimus 25mg IV weekly superior to IFNa or temsirolimus+IFNa in untreated poor prognosis metastatic RCC with overall survival 10.9, 7.3, 8.4 months respectively [27]
    5. Side effects: rash, asthenia, peripheral edema, hyperglycemia, hyperlipidemia
    6. Neutropenia and thrombcytopenia also occur
  10. Bevacizumab (Avastin®) [12,24]
    1. Humanized anti-VEGF IgG1 monoclonal antibody
    2. Bevacizumab given 10mg/kg q2 weeks for metastatic renal cancer
    3. In second line therapy (after IFNa or IL2, or both), progression free survival (PFS) was 4.8 months with bevacizumab versus 2.4 months with placebo [16]
    4. Second line bevacizumab showed 10% partial response rate
    5. In first line therapy for metastatic RCC, bevacizumab+IFNa gave (PFS) of 10.2 months versus 5.4 months for IFNa alone [29]
    6. Main side effects: hypertension, malaise, hematuria, epistaxis, proteinuria, hyponatremia
  11. Interferon alpha (IFNa)
    1. IFNa response rate 14% with median duration of response of 6 months
    2. IFNa had 28% reduction in mortality compared with medroxyprogesterone (MPA) [13]
    3. IFNa had overall 2.5 month increase in average survival compared with MPA [13]
    4. IFNa appears to be less potent alone than IL2 alone
    5. IFNa is clearly less effective than sunitinib in first-line metastatic renal cell ca [17]
    6. Erythropoietin producing tumors may be responsive to IFNa + IL2
  12. Interleukin 2 (IL2) Cytokine Therapy [1]
    1. IL2 high dose bolus IV with best overall response rates (and highest toxicity)
    2. Overall responses in 21% with high dose versus 13% with low dose IL2
    3. Median response duration of 54 months with high dose IL2
    4. Complete remission ~5-6%; most of these patients appear to be cured
    5. Partial remission in additional ~10-15% with overall time to progression >54 months
    6. Combined IL2 + IFNa had 19% response rates (versus 8% for IL2 alone)
    7. IL2 has moderate side effects but capillary leak syndrome may curtail therapy
    8. Activated lymphocytes added to IL2 in humans increases toxicity without benefit
    9. Patients with good or intermediate prognosis metastatic clear-cell RCC are most likely to benefit from high dose IL2; poor prognosis patients should not be offered this regimen [31]
  13. Vaccination
    1. Autologous RCC vaccine following nephrectomy in >2.5cm tumors improves outcomes [10]
    2. Autologous heat-shock protein (gp96) following nephrectomy in patients at high risk of recurrence did not improve outcomes [32]
  14. Allogeneic Peripheral Blood Cell Transplantation [15]
    1. Tested in patients with refractory renal adenocarcinoma
    2. Patients treated with nonmyeloablative chemotherapy to permit transplantation
    3. Allogeneic donor stem cell infusions from HLA-similar sibling
    4. Cyclosporine given to prevent graft-versus-host disease
    5. Ten of 19 patients had tumor regression (7 partial, 3 complete)
    6. Donor T cells were detected in all patients with regression
    7. The 3 complete responders remained in remission 16, 25, and 27 months after transplant

F. Prognosis [1,2]navigator

  1. Poor prognosis in general
  2. Stage IV
    1. Overall <10% 5 year survival rates [8,10]
    2. Median survival rates after diagnosis of Stage 4 disease are 13-16 months [31]
    3. Stage T4 with no evidence of metastatic disease ~20% 5 year survival
    4. Combination IFN alpha and IL2 increase response rates slightly
    5. Up to 20% of patients have 1 year event free given combined IFNa/IL2 therapy
  3. Stage I or II 5 year survival
    1. Stage T1 95%
    2. Stage T2 88%
  4. Stage T3 20-60% survival

G. Wilms Tumor (Nephroblastoma) [18] navigator

  1. Familial and Sporadic Cases, ~1/10,000 children
  2. Most common cause of abdominal mass in newborn / young children
  3. Several different loci on chromosome 11 linked to gene
    1. Gene on 11p13 codes for 345 residue zinc finger protein; probable tumor suppressor
    2. The 11p13 gene expressed in kidney and urogenital precursors (WAGR)
    3. WT2 gene found on chrom 11p15, associated with Beckwith-Wiedemann Syndrome
    4. This syndrome has macroglossia, organomegaly, hyperinsulinemic hypoglycemia
    5. Loss of imprinting on insulin like growth factor 2 (IGF-2) on chrom 11p15 [19]
  4. Developmental Syndrome with Wilms' Tumors Common
    1. Called "WAGR"
    2. Wilms' tumor with aniridia, genitourinary malformations and retardation
    3. Aniridia gene Pax6 in close proximity with Wilms' Suppressor gene WT1
  5. Treatment
    1. Surgical resection of tumor (uusually includes entire kidney) in 2 stages
    2. Preoperative radiotherapy reduces tumor rupture during surgery
    3. Standard chemotherapy is preoperatively for 4 weeks with vincristine and dactinomycin
    4. Postoperative chemotherapy is usually given for 14 weeks
    5. For Stage I intermediate-risk and anaplastic tumors who have received preoperative chemotherapy, no further chemotherapy has same outcome as 14 additional weeks [20]

References navigator

  1. Cohen HT and McGovern FJ. 2005. NEJM. 353923):2477
  2. Curti BD. 2004. JAMA. 292(1):97 abstract
  3. Mazal PR, Schaufler R, Altenhuber-Muller R, et al. 2002. NEJM. 347(9):653 abstract
  4. Dahl DM, Mueller PR, Young RH. 2004. NEJM. 351(20):2102 (Case Record) abstract
  5. Markowitz DH and Mark EJ. 2002. NEJM. 346(17):1309 abstract
  6. Chow WH, Gridley G, Fraumeni JF Jr, Jarvholm B. 2000. NEJM. 343(18):1305 abstract
  7. Nortier JL, Martinez MCM, Schmeiser HH, et al. 2000. NEJM. 342(23):1686 abstract
  8. Reddan DN, Raj GV, Polascik TJ. 2001. Am J Med. 110(7):558 abstract
  9. Mickisch GHJ, Garin A, van Poppel H, et al. 2001. Lancet. 358(9286):966 abstract
  10. Jocham D, Richter A, Hoffmann L, et al. 2004. Lancet. 363(9409):594
  11. Flanigan RC, Salmon SE, Blumenstein BA, et al. 2001. NEJM. 345(23):1655 abstract
  12. Brugarolas J. 2007. NEJM. 356(2):185 abstract
  13. Medical Research Council Renal Cancer Collaborators. 1999. Lancet. 352(9146):14
  14. Motzer RJ and Basch E. 2007. Lancet. 370(9605):2073
  15. Childs R, Chernoff A, Contentin N, et al. 2000. NEJM. 343(11):750 abstract
  16. Yang JC, Haworth L, Sherry RM, et al. 2003. NEJM. 349(5):427 abstract
  17. Motzer RJ, Hutson TE, Tomczak P, et al. 2007. NEJM. 356(2):115 abstract
  18. Gommersall LM, Arya M, Mushtaq I, Duffy P. 2005. Nat Clin Pract Oncol. 2(6):298 abstract
  19. Fukuzawa R, Breslow NE, Morison IM, et al. 2004. Lancet. 363(9407):446 abstract
  20. De Kraker J, Graf N, van Tinteren H, et al. 2004. Lancet. 364(9441):1229 abstract
  21. Motzer RJ, Rini BI, Bukowski RM, et al. 2006. JAMA. 295(21):2516 abstract
  22. McDougal WS, Tolkoff-Rubin NE, Michaelson MD, et al. 2006. NEJM. 355(11):1161 (Case Record) abstract
  23. Escudier B, Eisen T, Stadler WM, et al. 2007. NEJM. 356(2):125 abstract
  24. Bevacizumab. 2004. Med Let. 46(1184):47 abstract
  25. Sunitinib. 2007. Med Let. 49(1255):18
  26. Sorafenib. 2007. Med Let. 49(1255):19
  27. Hudes G, Carducci M, Tomczak P, et al. 2007. NEJM. 356(22):2271 abstract
  28. Chu TF, Rupnick MA, Kerkela R, et al. 2007. Lancet. 370(9604):2011 abstract
  29. Escudier B, Pluzanska A, Koralewski P, et al. 2007. Lancet. 370(9605):2073
  30. Temsirolimus. 2007. Med Let. 49(1276):103 abstract
  31. Michaelson MD, Illiopoulos O, McDermott DF, et al. 2008. NEJM. 358(22):2389 (Case Record) abstract
  32. Wood C, Srivastava P, Bukowski R, et al. 2008. Lancet. 372(9633):145 abstract