An overview of Malignant Renal Tumors.pptx

An overview of Malignant Renal Tumors.pptx

1. Malignant Renal Tumors Presenter: Antony Manyanga,MMED1 Facilitator ; Dr. H. Matalu,MD MMED Urology .

2. OUTLINE Historical consideration Classification Radiographic evaluation of renal masses Renal cell carcinoma Other malignant renal tumors References

3. Historical background 1861 ; first nephrectomy by Wolcott , mistakenly for hepatoma . 1869 ; first planned nephrectomy for persistent ureteral fistula by simon . 1855 ; Robin examined solid renal tumors, concluded that renal C a arose from renal tubular epithelium 1867 ; Waldeyer supported this interpretation.

4. The modern era has brought an appreciation that renal cell carcinoma (RCC) includes a number of distinct subtypes derived from the various parts of the nephron, each with a unique genetic basis and tumor biology

5. Classification Can be classified based on ; Pathologic features; malignant, benign, or inflammatory Radiologic features; simple cystic, complex cystic, solid

6. Malignant renal masses ; pathologic features. RENAL CELL CARCINOMA (RCC) • Clear cell RCC • Multilocular cystic clear cell renal cell neoplasm of low malignant potential • Papillary RCC • Chromophobe RCC • Hybrid oncocytic chromophobe tumor • Carcinoma of the collecting ducts of Bellini • Renal medullary carcinoma • MiT family translocation RCCa • Xp11 translocation RCC • t(6;11) RCC • Mucinous tubular and spindle cell carcinoma • Tubulocystic RCC • Acquired cystic disease–associated RCC • Clear cell ( tubulo ) papillary RCC • Hereditary leiomyomatosis RCC syndrome–associated RCC • RCC, unclassified

7. UROTHELIUM-BASED CANCERS • Urothelial carcinoma • Squamous cell carcinoma • Adenocarcinoma SARCOMAS • Leiomyosarcoma • Liposarcoma • Other sarcomas

8. NEPHROBLASTIC TUMORS • Nephrogenic rests • Nephroblastoma ( Wilms tumor) • Cystic partially differentiated nephroblastoma CARCINOMA ASSOCIATED WITH NEUROBLASTOMA Neuroendocrine Tumors • Carcinoid (low-grade neuroendocrine tumor) • Neuroendocrine carcinoma (high-grade neuroendocrine tumor ) • Primitive neuroectodermal tumor • Neuroblastoma • Pheochromocytoma Hematopoietic and Lymphoid Tumors • Lymphoma • Leukemia • Plasmacytoma Germ Cell Tumors • Teratoma • Choriocarcinoma METASTASIS INVASION BY ADJACENT NEOPLASM

9. BENIGN TUMORS CYSTIC LESIONS • Simple cyst • Hemorrhagic cyst SOLID LESIONS • Angiomyolipoma • Oncocytoma • Papillary adenoma (renal adenoma) • Metanephric tumors (adenoma, adenofibroma , stromal tumor) • Congenital mesoblastic nephromaa • Cystic nephroma /mixed epithelial stromal tumor • Reninoma (juxtaglomerular cell tumor) • Renomedullary interstitial tumor • Leiomyoma • Fibroma • Hemangioma • Lymphangioma • Schwannoma • Solitary fibrous tumor

10. VASCULAR LESIONS • Renal artery aneurysm • Arteriovenous malformation PSEUDOTUMOR INFLAMMATORY • Abscess • Focal pyelonephritis • Xanthogranulomatous pyelonephritis • Infected renal cyst • Tuberculosis • Rheumatic granuloma

11. Radiologic evaluation of renal masses Radiographic evaluation of a renal mass remains the strongest predictor of malignancy and metastatic potential

12. The Bosniak classification scheme was developed based on CT imaging criteria to define renal cystic lesions into categories that are distinct from one another in terms of the likelihood of malignancy

13. Bosniak 1; lesions are uncomplicated, simple, benign cysts of the kidney that are straightforward to diagnose on ultrasonography, CT, or MRI Bosniak 2; lesions are minimally complex cysts with a low risk of malignancy and include nonenhancing septated cysts , cysts with calcium in the wall or septum, infected cysts, and hyperdense (high-density) cysts

14. Bosniak 2F ; lesions have a 15% risk of radiographic progression to more complex cysts and a 3% to 10% risk of malignancy Bosniak 3; lesions are more complex renal cysts that cannot be confidently distinguished from malignant neoplasms Bosniak 4; lesions have large cystic components; irregular, shaggy margins; and, most important, solid enhancing portions that provide a definitive diagnosis of malignancy

15. A major differentiating factor for complex renal cysts is the presence of unequivocal contrast enhancement, which is not seen in Bosniak 2 and 2F lesions.

16. RENAL CELL CARCINOMA

17. Outline Epidemiology. Etiology/Risk factors. Tumor biology and clinical implications. Classification. Clinical presentation. Staging and grading. Risk assessment. Treatment.

18. Epidemiology. RCC, which accounts for 2% to 3% of all adult malignant neoplasms The most lethal of the common urologic cancers. A male-to-female predominance of 1.9 to 1 . The incidence of RCC has been rising, largely because of incidental detection

19. RCC typically is diagnosed between 55 and 75 years of age and rarely occur in young age Incidence rates are 5 % to 10% higher in African Americans for unknown reasons. The majority of cases of RCC are believed to be sporadic; only 4% to 6% are familial RCC accounts for 80% of all renal tumors in adults .

20. Etiology/Risk factors for RCC. RCCs arise primarily from the proximal convoluted tubules, and this is probably true for the clear cell and papillary variants. However, it is now established that other histologic subtypes of RCC, such as chromophobe and collecting duct RCC, are derived from the more distal components of the nephron.

21. Tobacco exposure Obesity Hypertension other potential causative factors have been identified ; including viruses , lead compounds , and more than 100 chemicals such as aromatic hydrocarbons .

22. NSAIDS, a relative risk of 1.51 Retroperitoneal radiation therapy Eg ; Wilms tumor or testicular cancer. A family history of RCC ; a relative risk of 2.9 with a 1st or 2nd-degree relative with RCC End-stage renal disease and certain familial syndromes such as tuberous sclerosis .

23. Acquired cystic kidney disease from chronic renal failure- 1-3% develop RCC .

24. Genetic risk factors(Familial RCC syndromes) Significant advances have been made in understanding of the molecular genetics of RCC. Novel familial syndromes of RCC have been identified, and the tumor suppressor genes and oncogenes contributing to the development of both sporadic and familial forms of this malignancy have been characterized.

25. Tumor biology and clinical implications Resistance to cytotoxic therapy; limited responses to cytotoxic chemotherapeutic agents, contributing to the traditionally poor prognosis for metastatic disease Study of the tumor biology of RCC has provided insight into its resistance to chemotherapy and, through elucidation of the VEGF, mTOR , and relevant immunomodulatory pathways, has yielded agents with clinical benefit for advanced disease

26. Immunobiology and Immune Tolerance Several lines of evidence demonstrate that RCC is immunogenic, and this has stimulated intensive efforts to harness the immune system to improve outcomes for patients with advanced disease

27. Angiogenesis and Targeted Pathways RCC ; one of the most vascular of cancers The primary angiogenesis inducer in clear cell RCC is VEGF A number of multiple kinase inhibitors that target the VEGF pathway were approved by the US Food and Drug Administration (FDA ) in 2005 and extending into the current era

28. Other Signal Transduction and Cell Cycle Regulation Pathways A ctivation of some signal transduction pathways in RCC , contributes to altered cell cycle kinetics, and these pathways represent excellent targets for therapeutic intervention. One regulatory pathway is the mTOR pathway , which interfaces with Akt (protein kinase B) and the PTEN tumor suppressor gene Inhibition of mTOR with temsirolimus ; shows prolonged survival in patients with poor-risk, metastatic RCC

29. Pathology of rcc

30. Classification of RCC C lear cell ( convetional )RCC. Chromophobe RCC. Papillary RCC Collecting duct carcinoma Renal medullary carcinoma. Unclassified RCC.

31. Clinical presentation and diagnosis . more than 60% of RCCs are detected incidentally Symptoms associated with RCC can be due to local tumor growth, hemorrhage, paraneoplastic syndromes , or metastatic disease The classic triad of flank pain, gross hematuria, and palpable abdominal mass is now rarely seen. ………… “too late triad.”

32. Spontaneous renal hemorrhage can occur with RCC or AML( angiomyolipoma ). Paraneoplastic syndromes are seen more commonly with metastatic disease; many resolve once the malignant lesion(s) are surgically removed. Hypercalcemia can also be managed with vigorous hydration and diuresis, or with other medical approaches.

33. Paraneoplastic syndromes are found in 10% to 20% of patients with RCC . the internist’s tumor because of the predominance of systemic rather than local manifestations . the radiologist’s tumor, given the frequency of incidental detection

34. Para neoplastic syndrome associated with RCC K idney produces 1,25-dihydroxycholecalciferol, renin, erythropoietin , and various prostaglandins. RCC may produce these substances in pathologic amounts, and it may also elaborate a variety of other physiologically important factors, such as parathyroid hormone–like peptides , lupus-type anticoagulant , human chorionic gonadotropin , insulin , and various cytokines and inflammatory mediators . These substances are responsible for the development of paraneoplastic syndromes and often contribute to constitutional symptoms and decline of performance status.

35. The most common of these syndromes is elevated ESR , more than 50% of identified paraneoplastic syndromes Hypercalcemia in up to 13% of pts with RCC due to either paraneoplastic phenomena or osteolytic metastatic involvement of the bone ..

36. The signs and symptoms of hypercalcemia are often nonspecific and include nausea, anorexia, fatigue, and decreased deep tendon reflexes . Medical management predominates and includes vigorous hydration followed by diuresis with furosemide and the 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

37. More definite management includes nephrectomy and occasional metastasectomy, depending on the clinical circumstances . Hypercalcemia related to extensive osteolytic metastases is much more difficult to palliate because it is not amenable to surgical approaches, but many such patients may respond to bisphosphonate therapy. Some patients with hypercalcemia related to osteolytic metastases may also benefit from focused radiation therapy if limited sites of involvement can be identified (Gold et al, 1996 ).

38. Hypertension. Hypertension associated with RCC can be secondary to: (i)increased production of renin directly by the tumor. (ii)compression or encasement of the renal artery or its branches, effectively leading to renal artery stenosis; or arteriovenous fistula within the tumor (iii)Less common causes include polycythemia, hypercalcemia, ureteral obstruction, and increased intracranial pressure associated with cerebral metastases

39. Polycythemia . Can be due to increased production of erythropoietin, either directly by the tumor or by the adjacent parenchyma in response to hypoxia induced by tumor growth (Gross et al, 1994; Wiesener et al, 2007 ). Stauffer syndrome nonmetastatic hepatic dysfunction, reported in 3% to 20% of cases. Almost all patients with Stauffer syndrome have an elevated serum alkaline phosphatase level, 67% have elevated prothrombin time or hypoalbuminemia, and 20% to 30% have elevated serum bilirubin or transaminase levels (Sufrin et al, 1989).

40. Other common findings include thrombocytopenia and neutropenia, and typical symptoms include fever and weight loss, which is not surprising given that many patients are found to harbor discrete regions of hepatic necrosis (Sufrin et al, 1989; Gold et al, 1996 ). Hepatic metastases must be excluded . Elevated serum levels of IL-6 have been found in patients with Stauffer syndrome , and it is believed that this and other cytokines may play a pathogenic role (Blay et al, 1997). Hepatic function normalizes after nephrectomy in 60% to 70% of cases

41. A variety of other less common but distinct paraneoplastic syndromes associated with RCC includes Cushing syndrome, hyperglycemia, galactorrhea, neuromyopathy, clotting disorders, and 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.

42. Physical examination. Physical examination has a limited role in diagnosing RCC, but may be valuable in detection of signs of advanced disease such as a palpable abdominal mass, lymphadenopathy, nonreducing varicocele or bilateral lower extremity edema . Blood pressure: Hypertension can be caused by paraneoplastic syndrome from RCC. Diagnosis. (II)Imaging. Most cases of RCC are strongly suspected by imaging. Diagnosis is usually suggested by US and further investigated by CT scan, which allows for assessment of local invasiveness, lymph node involvement, or distant metastases. Magnetic resonance imaging (MRI) may provide additional information in investigating local advancement and venous involvement by tumour thrombus.

43. For accurate staging of RCC, contrast-enhanced chest, abdominal, and pelvic CT is mandatory. In case of an allergy to CT contrast medium , adequate staging should include a high-resolution CT scan of the chest without contrast medium, together with an abdominal MRI . Routine metastatic evaluation S hould include liver function tests, abdominal/pelvic CT and chest radiography Bone scan should be obtained for patients with elevated serum alkaline phosphatase , bone pain or decline in performance status, and chest CT should be obtained for patients with pulmonary symptomatology or an abnormal chest radiograph. Most brain and bone metastases are symptomatic at time of diagnosis, and therefore, routine imaging of these sites is generally not indicated.

44. Laboratory studies in the evaluation of RCC should include a workup for paraneoplastic syndromes . Initial studies are as follows: Urine analysis CBC count with differential Electrolytes e.g. calcium Renal profile Liver function tests (AST and ALT ) Erythrocyte sedimentation rate Prothrombin time Activated partial thromboplastin time Other tests indicated by presenting symptoms

45. Role of Renal Mass Biopsy. A positive biopsy is reliable with high specificity (96%) and positive predictive value (99.8%). It is recommended before treatment with ablative therapies, as well as in patients with metastatic disease before starting systemic treatment. RMB is safe with relatively low rates of hematoma (4.9%), clinically significant pain (1.2%), gross hematuria (1.0%), pneumothorax (0.6%), and hemorrhage requiring transfusion (0.4 %).

46. RMB should be considered when a mass is suspected to be hematologic, metastatic, inflammatory , or infectious . Multiple core biopsies are preferred over FNA.

47. Screening and Clinical Associations RCC remains primarily a surgical disease requiring early diagnosis to optimize the opportunity for cure Due to poor prognosis for advanced d/se ; early/incidental findings shows advantage. Low incidence of d/se in general population accounts for limited widespread screening. (approx. 16 cases per 100,000 poln per year)

48. Staging Until the 1990s the most commonly used staging system for RCC was Robson’s modification of the system of Flocks and Kadesky ( Robson , 1963; Robson et al, 1969 ). L imitations of this classification scheme includes: (i)The primary problem can be found in stage III, where tumors with lymphatic metastases, a very poor prognostic finding, were combined with those with venous involvement. (ii)extent of venous involvement was not delineated in this system, and tumor size, an important prognostic parameter, was not incorporated .

49. The tumor, nodes, and metastasis (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. 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 .

50. TNM STAGING

51. Grading High grade implies worse prognosis. Chromophobe, collecting duct, renal medullar and unclassified RCC are designated as low or high grade. Fuhrman grade is not appropriate. For papillary RCC-Fuhrman may be used, but histological subtypes(type I and II) should also be reported. For clear cell RCC-Fuhrman grading should be utilized.

52. Fuhrman nuclear grade is used for clear and papillary RCC. Based on nuclear characteristics(size, contour and nucleoli) Mitotic activity is not considered. The tumor is assigned the highest identified grade. If spindle shaped( sarcomatoid ) cells are present, nuclear grade IV is assigned

53. Risk assessment. The natural clinical course varies in RCC, which has led to the development of different prognostic models for the assessment of the patient’s individual risk. Extent of disease, histology, grading and clinical factors have been recognized as having prognostic value in RCC and may be used in localised or metastatic disease.

54. ( a)localised disease . Different pre- or postoperative scores have been applied to assess prognosis in RCC, which are used for risk-adapted follow-up strategies. These models are composed of histological and clinical factors . The most recent modifications of the stage, size, grade and necrosis ( SSIGN) score and the University of California Los Angeles Integrated Staging System (UISS ) score are frequently used.

55. (b)Advanced disease. The Memorial Sloane Kettering Cancer Centre (MSKCC) was the gold standard for the risk assessment during cytokine treatment in metastatic ( m)RCC. Further refinement was introduced with the International Metastatic RCC Database Consortium (IMDC) score, which extended the previous factors to a total number of 6 to increase concordance. Karnofsky performance status (PS) <80 %, Haemoglobin <lower limit of normal,Time from diagnosis to treatment of <1 year, Corrected calcium above the upper limit of normal, Platelets greater than the upper limit of normal, Neutrophils greater than the upper limit of normal.

56. Surgical approaches Determined: by tumor location and size, body habitus, prior surgical history, and surgeon preference. Anterior Approach. A transperitoneal anterior midline, anterior subcostal, or chevron incision is made. The abdomen is systematically examined for metastatic disease . Also thoracoabdominal approach can be used..

57. Ipsilateral Adrenalectomy Contrary to the classic description of radical nephrectomy, removal of the ipsilateral adrenal gland is not routinely necessary unless the tumor either extensively involves the kidney or is located in the upper portion of the kidney (Sagalowsky et al, 1994 ). Regional Lymphadenectomy removal of lymphatic tissue from the crus of the diaphragm to the aortic bifurcation. removed en bloc with the kidney and adrenal gland or separately after completing the nephrectomy . Although lymphadenectomy is a recognized component of pathologic staging, the impact of lymphadenectomy on progression-free and overall survival is controversial

58. Venous Extension and Tumor Thrombectomy. Classification of Venous Tumor Thrombus Extension LEVEL DISTAL EXTENT OF THROMBUS I Limited to renal vein II Infrahepatic inferior vena cava III Retrohepatic inferior vena cava in proximity to renal veins IV Supradiaphragmatic inferior vena cava or right atrium

59. Surgical techniques for management of IVC thrombi according to level. Level I IVC thrombus Level II IVC thrombus

60. Level III IVC thrombus

61. (b) M anagement of metastatic disease. (i) R ole of surgery and local therapy . C ytoreductive nephrectomy is recommended in patients with good PS and large primary tumours with limited volumes of metastatic disease and for patients with a symptomatic primary lesion. Cytoreductive nephrectomy is not recommended in patients with poor PS. Metastasectomy and other local treatment strategies including whole brain radiotherapy (WBRT), conventional radiotherapy, stereotactic radiosurgery (SRS), stereotactic body radiotherapy (SBRT ), cyberknife radiotherapy and hypofractionated radiotherapy can be considered and carried out for selected patients after multidisciplinary review .

62. No systemic treatment is recommended after metastasectomy .

63. (b)Systemic treatment . The landscape in RCC has been radically changed by the introduction of five agents tested in phase III clinical trials that have been designed to target tumour-related angiogenesis and signal transduction. These are the multitargeted, oral, receptor tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib . T he inhibitors of the mammalian target of rapamycin ( mTOR ) pathway temsirolimus and everolimus; A nd the anti- angiogenic monoclonal antibody bevacizumab , given in combination with interferon (IFN)

64. Recommendations mainly relate to clear cell histology, since most of the pivotal trials have been done in this common histological subtype. In addition, recommendations will differ according to risk stratification. The time to start systemic therapy is not well defined. Because some RCCs have a very indolent course, a period of observation before starting treatment should be considered, especially in patients with limited tumour burden and few symptoms .

65. (c)Role of radiotherapy and bisphosphonates. The spectrum of radiosensitivity in RCC is wide, but it is not a radioresistant disease. Radiotherapy has been shown to provide good symptom palliation and local control in RCC depending on the dose that can be delivered. There is a developing rationale with emerging data suggesting that the apparent radioresistance of RCC can be overcome through the ceramide pathway with the use of higher dose per fraction treatments usually delivered by new high-precision radiotherapy methods such as SBRT. This can be exploited and used in many different clinical situations particularly for unresectable local recurrences or oligometastatic disease

66. There is no current evidence for the use of radiotherapy in the neoadjuvant or adjuvant setting. Radiotherapy can be used in the following settings: (i)Radiotherapy can be used to treat unresectable local or recurrent disease with the aim of improving local control . (ii) For patients in whom surgery cannot be carried out due to poor PS or unsuitable clinical condition, radiotherapy can be an alternative if other local therapies such as radioablation are not appropriate

67. (iii)Radiotherapy is an effective treatment for palliation of local and symptomatic mRCC disease or to prevent the progression of metastatic disease in critical sites: bones, brain. (iv) For the management of spinal cord compression, an ambulatory status at diagnosis and limited metastatic disease are favourable prognostic factors in those patients able to undergo surgery .

68. (d)Role of chemotherapy Numerous chemotherapeutic agents including 5-FU, platinum compounds, gemcitabine, vinblastine, and bleomycin have been evaluated as single agents in this disease but have failed to demonstrate clinically meaningful activity; a wide array of combination chemotherapy regimens have fared little better. Comprehensive meta-analyses of chemotherapy trials in RCC indicate the overall response rate is 5.5% to 6.0 %. Cytotoxic chemotherapy has no role in the current management of most patients with clear cell RCC .

69. (e)Role of hormonal therapy. Hormonal therapy had been the subject of trials in RCC in the 1970s and 1980s, preceding the advent of cytokines. Hormonal agents such as medroxyprogesterone have been noted to induce tumor regressions in a small minority of patients, but overall response rates are too low (approximately 2%) to have meaningful clinical impact in most patients. Progestational and other hormonal agents have no role in the current management of renal cell cancer .

70. Follow up. Overall, there is no evidence that any particular follow-up protocol influences the outcome in early RCC . No standard recommendation can be given for the follow-up in advanced RCC either .

71. (a)Localized RCC following surgery. The follow-up scheme for localised RCC following surgery should depend on the therapeutic possibilities upon recurrence. CT scans of thorax and abdomen are routinely carried out, with time intervals depending on risk factors . It is recommended to perform CT scans every 3–6 months in high-risk patients for the first 2 years, while a yearly CT scan is probably sufficient in low-risk patients. Long-term follow-up is proposed in some institutions, due to the possibility of late relapse, but its benefit has never been demonstrated.

72. (b)systemic therapy. During systemic therapy in mRCC patients, 2- to 4-month follow-up schemes with CT scan should be advised to determine response and resistance . Although not perfect, RECIST (Response Evaluation Criteria in Solid Tumours) criteria remain the most frequently used method to assess drug efficacy.

73. References. Renal cell carcinoma: esmo clinical practice guidelines for diagnosis, treatment and follow-up. Annals of oncology 27 (supplement 5): v58–v68, 2016. AUA guideline for management of the clinical stage 1 renal mass,j,uro , vol. 182, 1271-1279, october 2009. Guideline of guidelines: follow-up after nephrectomy for renal cell carcinoma; bju int 2016; 117: 555–562. Canadian guidelines for the management of small renal masses( srm ); can urol assoc j 2015;9(5-6):160-3. The medical management of metastatic renal cell carcinoma: integrating new guidelines and recommendations ; b j u i n t2009 ;1 0 3 :5 7 2 – 5 7 7. Wein : campbell-walsh urology, 12th ed.