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2 DEPARTMENT OF SURGERY MYSORE MEDICAL COLLEGE AND RESEARCH INSTITUTE,MYSORE SUBJECT SEMINAR ON RENAL CELL CARCINOMA Moderator Presenter Prof. Dr. B.K. Ramu Dr. Raviprakasha A. Professor and Unit Chief Post Graduate in Surgery Surgery ‘E’ Unit MMC&RI, Mysore Department of Surgery MMC&RI, Mysore

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3 CONTENTS 1. History and Introduction 2. Anatomy, Physiology and Embryology 3. Clinical Anatomy of Kidneys 4. Etiology and Pathology and Clinical Features 5. Staging of RCC 6. Managements of RCC 7. Nephrectomy 8. Conclusion 9. References

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4 HISTORY AND INTRODUCTION Renal cell carcinoma (RCC) has been described as one of the great mimics in medicine because it tends to produce a diversity of systemic symptoms not related to the kidney.8 Renal cell carcinoma is the most common malignancy of kidney and accounts for 2-3% of all adult neoplasms. Majority of cases are sporadic, only 4% are familial. The RCC is primarily a disease of elderly, the typical presentation is 6th to 7th decade. 8-9 cases for 1,00,000 population. Male and female ratio is 3:2. Renal cell carcinomas which originates in cortex is responsible for 80-85% of all primary renal neoplasms. It is called by different names such as Adenocarcinoma, Nephrocellular carcinoma, Gravitz tumour, hypernephroma, Clear cell carcinoma, Golden tumour, Internist’s tumour, now called as radiologist’s tumour. RCC in childhood represent only 2.3% to 6.6% of all tumours in children.

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5 Transitional cell carcinoma of renal pelvis accounts for 8% of all renal tumours. Other rare renal tumours are oncocytomas, sarcomas (Leiomyosarcoma is most common), metastatic tumours (lung, breast, GIT, melanoma, hematological malignancies, carcinoid tumours). Wilm’s tumour: 3% of all Wilm’s tumours are seen in adults (Campbell). Renal cell carcinoma was first described by Konig in 1826. In 1855, Robin concluded that renal tubular epithelium was the most probable tissue of origin which was confirmed by Waldeyer in 1867. In 1883, Gravitz introduced the term stroma lipomatodes aberrata renis for clear cell carcinoma. They are called as adenocarcinomas because they originate from renal tubular epithelium. In 1984, Birsch Hirschfield field introduced the term hypernephroma because of their yellow colour and resemblance of the tumour cells to clear cells of adrenal cortex. Renal cancers with vHL gene deletion, all of the tumour cells express high levels of HIF-1 and VEGF induced angiogenesis leads to high microvascular density. Hence the term Hypernephroma (Harrison).

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6 Peculiarities of RCC One of the many peculiarities of RCC is its occasional regression in the absence of treatment which is also found in gestational choriocarcinoma, malignant melanoma, neuroblastoma. It is one of the pervasive tales of “oncological folklore”. The true rate of regression is less than 1%, they tend to occur in pulmonary metastasis following resection of primary tumour, or following immune reaction or following sepsis. RCC is the most common recipient of the curious phenomenon of metastasis of a cancer into the another cancer. Lung cancer is the most common donor resulting in microscopic appearance leading to interesting problems in interpretation.4 Metastasis of RCC in different organs may develop years or decades after removal of primary tumour. Isolated rib metastasis are rare, surgical wide resection is the effective treatment.24

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7 ANATOMY OF KIDNEYS Kidneys are bilaterally paired excretory organs located in the retroperitoneum. Typically each kidney weighs 150 gm in male and 135 gm in female. External features Each kidney is a pear shaped organ. It has two poles  upper pole is broad and in contact with corresponding suprarenal gland.  Lower pole is pointed. Two surfaces  Anterior surface  Posterior surface Two borders  Lateral border – convex  Medial border – concave with presence of hilum Hilum: From anterior to posterior following structures of kidney are seen Renal vein The renal artery The renal pelvis

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8 Located mainly in lumbar regions. Extends vertically from the upper border of 12th thoracic vertebra to the centre of the body of third lumbar vertebra. The right kidney is slightly lower than left kidney. Figure 1: Location of the kidneys Each kidney weighs about 150 gm in males and 135 gm in females. Each kidney is 12 cm long and 6 cm broad,and 3 cm thick. Reddish brown in colour.

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9 Relations of kidneys Anterior relations of both kidneys Figure 2: Structures related to the anterior surfaces of each kidney

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10 Posterior relations of kidneys Figure 3: Structures related to the posterior surface of the kidney

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11 Coverings of kidney 1. Fibrous capsule: This is a thin membrane which closely invests the kidney, which can be easily stripped. 2. Perirenal fat: This is a layer of adepose tissue lying outside the fibrous capsule. 3. Renal fascia (Gerotas fascia): This is a fibro-areolar sheath which surrounds the kidney and perirenal fat. It has anterior layer of Toldt and posterior layer of Zuckerkandl. Superiorly they enclose the suprarenal gland in a separate compartment and fuse with each other, and finally they will blend with fascia covering the under surface of the diaphragm. Inferiorly the anterior layer blends with extraperitoneal connective tissue of the tear fossa while posterior layer blends with fascia ileaca. Laterally the two layers get fused and become continuous with fascia transversalis. Medially the anterior and posterior layers form a septum which is pierced by renal vessels. Because of the septum, perirenal effusions cannot cross the midline. 4. Pararenal or paranephric fat: Present outside the Gerota’s fascia, forming a cushion.

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12 Figure 4: Organization of the fat and fascia surrounding the kidney

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13 Renal vasculature The renal pedicle consists of a single renal artery and a single vein that enter the kidney via the renal hilum. These are the branches from the aorta and tributary of IVC just below the origin of SMA. From anterior to posterior are vein, artery and renal pelvis. Renal artery Renal artery arises from the aorta at right angles at the level of inter-vertebral disc between L1 and L2 vertebra. After approaching the kidney, the renal artery splits into four and more branches with five being common. Each segmental artery supplies distinct portion of the kidney with no collateral circulation in between. The occlusion or injury to a segmental branch will cause segmental renal infarction.

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14 Anterior division supplies Apical  Upper Segments  Middle  Lower Posterior division supplies Posterior segment Brodel’s line (avascular plane): Important surgical landmark, junction of the area supplied by anterior and posterior divisions of the renal artery, marked 2/3rd of the way from the hilum to the lateral margin of the kidney (i.e. 1 cm from the convex margin).

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15 Figure 5: Typical segmental circulation of the right kidney

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16 Renal veins The venous drainage closely correlates with arterial supply. The renal vein is located directly anterior to the renal artery. Left renal vein in addition receives the left adrenal vein superiorly, lumbar vein posteriorly and gonadal vein inferiorly, which is of great clinical significance. Figure 6: Venous drainage of the left kidney showing potentially extensive venous collateral circulation

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17 Figure 7: Renal vasculature

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18 Renal lymphatics On the left side drains into left lateral para-aortic lymph nodes including nodes anterior and posterior to the aorta. On the right side it drains into right interaortocanal and right paracaval nodes. Nerve supply Sympathetic preganglionic nerves originate from the eighth thoracic through first lumbar spinal segments and then travel to the celiac and aortico-renal ganglia. Parasympathetic from vagus nerve.

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19 Internal structure of the kidney a. Gross structure Cross section shows  Outer cortex  Inner medulla  A space – renal sinus Figure 8: Internal structure of the kidney

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20 The renal cortex is lighter in colour than medulla and not only covers the renal pyramids peripherally. But also extends between the pyramids. These are called the columns of Bertin. The renal medulla is made up of 10 conical masses, which are called pyramids, their apices form the renal papillae which ident the minor calices. There are around 7 minor calyces and 3 major calyces. Figure 9: The renal collecting system (left kidney) showing major divisions into minor calyces, major calyces, and renal pelvis. A, anterior minor calyces; C, compound calyces at the renal poles; P, posterior minor calyces

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21 b. Histologically 1. Secretory part of kidney is called nephron which consists of renal corpuscle made up of tuft of capillaries and renal tubule which consist of proximal convoluled tubule, loop of Henle, and distal convoluled tubule. 2. Collecting duct system Figure 10: Placement of the uriniferous tubule in various zones of kidney

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22 Key points regarding anatomy of kidneys The kidney is divided into peripheral cortex and medulla. The upper pole of the kidneys are situated more medially and posteriorly than lower poles.Also medial aspect of kidney is more anteriorly than lateral aspect. Gerota’s fascia envelops the kidney on all aspects except inferiorly, where it is not closed, instead remains a potential space. Progression of arterial supply to the kidney is as follows renal artery segmental arteryinterlobar artery  arcuate arteryinterlobular artery  afferent artery. There is no anastomotic network. Anatomic variation of renal vasculature in 25% to 40% of kidneys.

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23 Renal Physiology Kidneys serve a number of important functions required to maintain normal human physiologic function. They are the primary organ for maintaining fluid and electrolyte balance and they play a large role in maintaining acid-base balance. They produce renin in controlling blood pressure, erythropoietin production. They affect calcium metabolism by converting a precursor of vitamin D to the most active form 1,25 dihydrocholecalciferol. Functional unit of kidney Nephron is the functional unit of kidney. It consists of glomerulus and renal tubule. There are about 1.3 million nephrons in the kidney.23

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24 Parts of nephron Figure 11: Placement of the uriniferous tubule in various zones of kidney

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25 Glomerulus: A tuft of capillaries measuring 200 m. It has afferent and efferent arterioles.The PCT is 15 mm long and 55 mm in diameter. Loop of Henle  Thin descending loop – 14 mm  Thick ascending loop – 12 mm Distal convoluled tubule: 5 mm long Collecting ducts: measure 20 mm long. Juxtaglomerular apparatus Consists of JG cells: Granular epithelioid cells located in the media of the different arterioles. They secret renin. Lacis cells: Agranular cells located between the junction of offerent and efferent arterioles. They also secrete renin. Macula densa: This is a modified epithelium near the origin of DCT.

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26 Functions of kidney The most important function of kidney is production of urine. Production of erythropoietin in response to hypoxia and anemia. Bone mineral regulation: Normal regulation of bone mineralisation, through maintenance of serum calcium and phosphorus levels through the actions of vitamin D and PTH. Important role in maintaining fluid and electrolyte balance. Maintains important role in acid-base balance. Embryology of kidneys The kidney appears in 5th week of intra-uterine life. The definitive human kidney arises from two distinct sources. The excretory tubules are derived from the lowest part of nephrogenic cord, the metanephros. The collecting duct portion of the kidney which arises from the lower part of the mesonephric duct.

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27 The ureteric bud penetrates the meta-nephric tissue which is molded over its distal end as a cap. The bud subsequently forms primitive renal pelvis and splits into future calyces. The ureteric bud gives rise to the ureter, the renal pelvis, the major and minor calyces and approximately 1 to 3 million collecting tubules. Figure 12: Pronephros, mesonephros and metanephros

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28 Ascent of kidney The definitive human kidney (metanephros) which lies in the sacral region, making it a pelvic organ. The ascent of kidney is caused by diminution of body curvature and differential growth of body in the lumbar, and sacral region. During their ascent, the kidneys pass through the fork like interval between right and left umbilical arteries. If the arteries come in the way of ascent, the kidney may remain in the sacral region.

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29 CLINICAL ANATOMY OF KIDNEYS 1. Renal angle is the angle between lower border of the 12th rib and outer border of erector spinae. Normal renal angle is resonant to percuss due to overlying colonic band of resonance. It becomes dull when the kidney enlarges. 2. Movement with respiration: Though kidney is a retroperitoneal organ, it moves with respiration. It has been described as Tree-Top mobility, cranio-caudal movement also has been demonstrated. 3. Bimanual palpation: It is characteristic of kidney because of presence of pedicle. In very large masses, locally advanced RCCs, or renal swellings with inflammation, kidney may not be bimanually palpable. 4. Ballotment: Renal swellings are ballotable because the perinephric fat surrounding the kidney act as a cushion, which is in fluid status in normal body temperature. 5. There is a danger of opening of pleura when the kidney is exposed along the bed of 12th rib.

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30 Etiology of Renal Cell Carcinomas RCCs were traditionally thought to arise primarily from proximal convoluted tubules and this is probably true for most clear cell and papillary variants. More recent data suggest that other histologic types of RCC such as chromophobe and collecting duct RCC are derived from the more distal components of nephron. The only generally accepted environmental risk factor for RCC is tobacco exposure: cigarette smokers, pipe and cigar smokers are equally susceptible. Obesity (particularly in women) Hypertension Unopposed oestrogen therapy Exposure to asbestos, lead compounds, trichloroethelene

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31 Aromatic hydrocarbons (petroleum products) Chronic renal failure Polycystic kidney diseases Tuberous sclerosis (Hamartomas in CNS, AML in kidney and other tissues) Low socio-economic status Thorostat Radiation therapy (for testicular cancer – retroperitoneal lymph nodes) Antihypertensive medications Acquired cystic disease (after long term dialysis) Neuroblastoma: There are several cases of RCC developing in children who had been treated for neuroblastoma (Auckerman’s). Analgesic abuse: Both renal pelvis and RCC. High consumption of fat, oils, milk. Balkan nephropathy is associated with pelvicalyceal tumours. People of North European origin (Scandinavian people). Familial renal cancers: Sporadic RCC in young patients have lower tumour stages and grades, and better outcomes compared to elderly.19 Most renal cancers are sporadic, but unusual forms of autosomal dominant familial cancers occur, usually in younger individuals. They account for only 4% of all renal cell carcinomas.

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32 1. Von Hippel Lindau’s Syndrome They have a predisposition to develop tumours in kidney, brain, spine, eyes, adrenal glands, pancreas, inner ear and epididimis. Autosomal dominant: Major manifestations include development of RCC, pheochromocytoma, retinal angiomas, hemangioblastomas of the brain stem, cerebellum or spinal cord. RCC develop in about 50% of patients with Von Hippel Lindau’s syndrome, often manifest in third, fourth or fifth decade with bilateral, multifocal involvement. Von Hippel Lindau’s Gene: Located in chromosome 3p-25-26. It is a tumour suppressor gene. As with most tumour suppressor genes, both alleles of the VHL gene must be mutated or inactivated for the development of the disease. The important function of the VHL protein complex is to target the hypoxia inducible factor 1 for ubiquitin mediated degradation keeping the levels of HIF low under normal conditions. HIF-1 is an intracellular protein that plays an important role in regulating cellular responses to hypoxia, starvation and other stresses. Inactivation or mutation of the VHL gene leads to disregulated expression of HIF 1. This in turn leads to a several fold upregulation of the expression of VEGF, the primary pro-angiogenic growth factor in RCC, contributed to the pronounced neovascularity associated with clear renal cell carcinoma. Von Hippel Lindau gene associated with clear cell type of RCC.

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33 2. Hereditary papillary renal carcinoma HRPC is a form of hereditary renal cell carcinoma in which there is a risk of development of bilateral, multifocal papillary renal cell carcinoma. MET proto-oncogene responsible for HRPCC. Histological type in HRPCC is type 1 papillary renal cell carcinoma. 3. Birt-Hogg-Dube syndrome These are associated with chromophobe RCC, Oncocytic neoplasms, clear cell RCC, benign hair follicle tumours, pulmonary cysts, spontaneous pneumothorax. 4. Hereditary Leiomyomatosis Renal Cell Carcinoma associated with Cutaneous Leiomyoma Uterine Leiomyoma Uterine Leiomyosarcomas Type 2 Papillary renal cell carcinoma more aggressive, early metastasing carcinoma.

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34 Tumour biology and clinical implications in RCC There are several tumour associated antigens have been identified in RCC. The most specific tumour associated antigen in RCC is CA-9 (also known as MN-9) expressed in 70-90% of RCC, primarily in clear cell histology. Clinical observations such as spontaneous tumour regression, prolonged disease stabilization and durable responses to immunotherapy also support the immunogenicity of RCC (spontaneous regression seen in neuroblastoma, RCC, melanoma, lymphoma or leukemia). Multidrug resistance: Expression of multidrug proteins such as MDR-1 (also known as p-Glycoprotein) contributes to the refractory nature of RCC. It is a Glycoprotein (170 KD transmembrane protein) expressed by 80%-90% of RCCs that act as an energy dependent efflux pump for a wide variety of large hydrophobic compounds, including several cytotoxic drugs (vinca alkaloids, paclitaxel, actinomycin D, mitomycin C). Angiogenesis: RCC has long been recognised as one of the most vascular cancers reflected by the most distinctive neovascular pattern exhibited on renal angiography. The primary angiogenesis inducer in clear cell RCC appears to be VEGF, which is suppressed by the wild type VHL protein under normal conditions and is dramatically upregulated during tumour development. The concept of cancer cell derived vascular channels which are lined by mosaic pattern of Endothelial cells, tumour cells and ECM secreted by cancer cells (cf Normal blood vessel is lined by endothelial cell) referred as VASCULAR MIMICKRY contributes to the pathogenesis in tumour angiogenesis. Hepatocytic growth factor and its receptor, the met proto-oncogene may also contribute to the pathogenesis of RCC. Proteases, Adhesion and Extracellular matrix Down regulation of E-Cadherin, Cadherin-6 which mediate adhesion between cancer cells is well documented in RCC and has correlated with poor prognosis.

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35 CLASSIFICATION OF RENAL TUMOURS Renal masses classified by Pathological features CLASSIFICATION OF RENAL TUMOURS Renal masses classified by Pathological features

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36 PATHOLOGY OF RCC20 Figure 13: Other gross appearances of renal cell carcinoma

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37 Figure 14: Gross appearance of renal cell carcinoma. Both tumours are relatively well circumscribed and variegated with a combination of cystic, solid and hemorrhagic area

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38 Figure 15: Renal cell carcinoma with multinodular gross appearance

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39 Gross Pathology Most RCCs are round to avoid and circumscribed by a pseudocapsule of compressed parenchyma and a fibrous tissue rather than a true histologic capsule, they are not grossly infiltrative with exception of collecting duct and sarcomatoid variants. Tumour may arise from any portion of the kidney, but mostly affects the poles. The average size may range from 5-8 cm in most series, but can vary from a few millimeters to large enough to fill the entire abdomen. Most renal cell carcinomas are well delineated and centred on the cortex. On occasion only a small portion is connected with the cortex, the bulk of the tumour appearing as an extra-renal mass. Cut Section Typical cut section in typical renal cell carcinoma shows a solid golden yellow (lipid accumulation) tumour sharply separated from the surrounding tissues by a fibrous pseudo-capsule. Occurrences of hemorrhage, necrosis, calcification and cystic change result in the variegated appearance that is very characteristic of this neoplasm.

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40 HISTOPATHOLOGY OF RCC All RCC are by definition, adenocarcinomas derived from renal tubular epithelial cells. Histological Classification of RCC 1. Conventional (70-80%)Clear cell  More hypervascular Granular  More aggressive Mixed  May respond to immunotherapy Figure 16: Renal cell carcinoma, clear cell type

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41 2. Chromophilic (10-15%)Type I  Typically hypovascular (Papillary type)  Multicentric Figure 17: Renal cell carcinoma of papillary type

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42 3. Chromophobic (3-5%) Type I Classic  Prognosis better Type II Eosinophilic  aggressive variants exists Figure 18: Gross appearance of renal Figure 19:Microscopic appearance of Chromophobe cell carcinoma chromophobe cell carcioma

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43 4. Collecting duct of Bellini (1%) - Centrally located infiltrate, poor prognosis may respond to chemotherapy Figure 20: Gross appearance of Figure 21: Collecting duct carcinoma collecting duct carcinoma

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44 5. Sarcomatoid renal cell carcinoma (spindle cell carcinoma, anaplastic carcinoma, carcinosarcoma)  Can be identified by FNAC  Extremely aggressive  Extra-renal invasion-usual  Multiple skeletal metastasis are common 6. RCC with Rhabdoid features: Very aggressive form 7. RCC resembling alveolar soft part sarcoma

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45 1. Conventional Renal Cell Carcinoma They are further classified into clear, granular and mixed variety. They account for 70-80% of all renal cell cancers. Grossly they are typically yellow in colour when they are bivalved and are highly vascular containing delicate network of vascular sinusoids interspersed between sheets or acini of tumour cells. On microscopic examination: There are clear cell, granular cell and mixed variety. Clear cell are typically polygonal with abundant cytoplasm containing glycogen, cholesterol, cholesterol esters, granular cells have eosinophilic cytoplasm conventional RCC is more likely to have a venous extension compared to others (chromophilic and chromophobic type). Chromosome 3 with VHL gene mutations are common in clear cell carcinoma.

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46 2. Chromophilic carcinoma (Papillary carcinoma): which has also been designated as Papillary carcinoma in other series. It represents 10-15% of all RCCs. They are more common in end-stage renal disease, acquired cystic disease (chronic hemodialysis), also in some cases of hereditary forms. Papillary renal cell carcinoma is characteristically hypovascular on radiographic studies, grossly it may exhibit extensive areas of necrosis. More likely to be multicentric or bilateral. Microscopy: Consists of basophilic or eosinophilic cells arranged in papillary or tubular configuration. These are associated with mutation of met-proto-oncogene, that serves as tyrosine kinase receptor for hepatocyte growth factor; which mediates growth, cell mobility, invasion and morphogenic differentiation.

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47 3. Chromophobe renal cell carcinoma Accounts for 5% of all RCC. Derived from cortical portion of collecting duct. Grossly well circumscribed, solitary with a homogeneous gray to brown cutsurface devoid of hemorrhage and necrosis. Microscopically: There is characteristic nesting arrangement of tumour cells which have sharply defined borders and abundant cytoplasm. The microvesicles characteristically stain for Hale’s colloidal iron. It has an excellent prognosis than conventional carcinomas. 4. Collecting duct carcinoma (Bellini duct carcinoma) These account for 1% of RCC. These tumours centred in the medulla. Cells show hobnail pattern (short heavy headed nail).

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48 5. Sarcomatoid renal cell carcinoma Also known as spindle cell carcinoma, anaplastic carcinoma, carcino-sarcoma makes up 1% of all renal tumour in adults. It is largely composed of spindle or pleomorphic tumour giant cells and may simulate sarcoma. It can be identified by FNAC. These tumors have an aggressive course. Treatment is mainly surgical. Fuhrman’s Classification System for Nuclear Grade in RCC

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49 Spread and metastasis of RCC RCCs are vascular tumours that tend to spread either by direct invasion through renal capsule into perinephric fat and adjacent structures or by direct extension into the renal vein (i.e. by contiguity and continuity). 1. Local invasion: The tumour gradually invades the adjacent parts of medulla invards and renal capsule outwards. After the invasion of real capsule has been penetrated the surrounding perinephric fat is gradually invaded. Later the tumour may involve the neighbouring viscera. e.g.: colon, pancreas, liver, duodenum, etc. 2. Lymphatic spread: Lymphatic spread is not a important thing. When it penetrates the perinephric fat, it then metastasis to the lymph nodes in relation to the hilum of kidney, from there to para-aortic group of lymph nodes. 3. Hematogenous spread: Because of numerous thin walled vessels which are present in the tumour, blood spread is the most important mode of spread.

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50 Blood spread by two ways: a. Embolism: The pieces of growth become detached and swept into the venous circulation to become first arrested in lungs. In the lungs the metastasis produces cannon-ball deposits which are revealed in X-ray as round opaque metastasis in the lungs and later it may spread to other organs. b. Permeation: The tumour grow along the lumen as a polypoid lesion, eventually the tumour thrombus distends the vein. First the renal vein is involved and latter the inferior vena cava is involved. Thus the tumour may extend through the inferior vena cava into the right atrium keeping continuing with the parent tumour. Sometimes the solid tumour thrombus inside the renal vein may cause obstruction to the testicular vein particularly on left side. So a rapidly developing non-reducible varicocele in a old man should arouse the suspicion of adenocarcinoma affecting the left kidney.

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51 Approximately % venous spread in RCC Renal vein spread  23% Inferior vena caval spread  9% Right atrial spread  0.43% Approximately 25-30% of patients have evidence of metastatic disease at presentation. The most common site of distant metastasis is the lung (cannon ball metastasis) and skeleton, and adrenal glands. The bones most often involved are the pelvic bones and femur, but also there is predilection for the sternum, scapula and small bones of the hand and feet. These are pulsatile metastases. (Other pulsatile bony metastases are seen in follicular carcinoma of thyroid). Metastasis can also develop in the liver, skin, soft tissue, central nervous system, ovary and almost any other site. Because of the fact that the primary tumour is silent, these metastasis tend to be confused with the primary tumours of the organs in which they lodge. Another additional source of misinterpretation stems from the fact that sometimes these metastasis develops years or decades after removal of primary tumour. Metastasis are extremely rare in tumours that measure  3 cm in diameter.

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52 Clinical Features of Renal Cell Carcinoma Because of the sequestred location of the kidney within the retro-peritoneum, many renal masses remain asymptomatic and non-palpable until they advanced with the more non-invasive imaging techniques available >50% of RCC are now detected incidentally. Occasionally an ectopic kidney e.g.: pelvic kidney may develop a tumour (unascended kidney). Symptoms of RCC may be due to Local tumour growth Haemorrhage Paraneoplastic syndromes Metastatic disease

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53 The classic triad of flank pain, flank mass, hematuria is rare, flank pain is due to clot obstruction and hemorrhage. IT IS ALSO CALLED AS TOO LATE TRIAD. Paraneoplastic syndromes are found in 20% of RCC. RCC was referred to internists tumour because of the predominance of systemic symptoms rather than local manifestations. Because of incidental detection of this tumour it is referred to radiologist’s tumour. Bilateral lower extremely oedema, non-reducing varicocele, cervical lymphadenopathy, suggests venous involvement. Pulsatile bony metastasis or chronic cough with haemoptysis may indicate metastatic disease. A less but important presentation of RCC is spontaneous perirenal hemorrhage. Weight loss, fever, night sweats suggests advanced disease.

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54 PRESENTATION OF RCC Classic triad (Gross hematuria, flank pain, mass)  9% also known as too late triad Hematuria  59% Loin pain (sudden pain may indicate haemorrhage)  41% Abdominal mass  45% Fever (pyrexia of unknown origin) IL-1,TNF  7% Weight loss (TNF, IL-1, INF-Y)  28% Anemia (?due to bone marrow infiltration)  21% Erythrocytosis (Erythropoeitin, Lactoferrin)  3% Acute varicocele (non-reducible in recumbuncy)  7% Tumour calcification  13% Metastatic symptoms  10% Incidental  7% Elevated ESR  55.6% HTN  37.5%

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55 Abnormal liver function Hypercalcemia – Due to PTHRP  11% Abnormal liver function  14.4% Neuromyopathy  3.2% Amyloidosis  2% Diabetes mellitus  Gynecomastia due to gonadotropin and placental lactogen Cushing’s syndrome Stauffer’s syndrome Hyperreninsm Elevated alkaline phosphatase LDH Elevated serum ferritin Leukemoid reactions Prolactinemia Enteroglucogon like substance production Prostaglandin A production Lupus like anticoagulant production Various cytokines – IL-1, IFN-Y, IL-6 Nephrotic syndrome ADH

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56 Haematuria: Profuse (or microscopic), painless, intermittent, but painful when associated with clot colic. Hematuria is total (throughout the stream). Loin pain (Flank pain): Renal pain is a dull aching, constant pain felt in the costovertebral angle (renal angle). It can radiate across the flank to the upper abdomen, umbilicus or to the testis, labium that is why in case of testicular discomfort renal/retroperitoneal disease can be considered as a D/D. It is a fixed pain and it is due to stretching of renal capsule by the tumour. Renal pain is less commonly associated RCC because distension occurs seldom.

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57 Characteristics of Renal Mass Reiniform in shape Mass in Loin Moves with respiration  Craniocaudal  Tree top mobility Bimanually palpable Ballottable Obliteration of normal colonic band of resonance in enlarged kidney. Possibility of finger insunation between costal margin and the mass. Renal cell carcinoma – mass does not cross midline (cf. Wilm’s tumour). Clinical DID of Renal Mass Colonic mass Adrenal mass Retroperitoneal tumour

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58 Hypercalcemia It has been reported in 11-13% of patients either due to Paraneoplastic syndrome or osteolytic metastatic disease. Causes are:  PTHRP  1,25 dihydrocholecalciferol  Prostaglandins RCC with hypercalcemia associated with worse prognosis. Signs and symptoms of hypercalcemia includes nausea, anorexia, fatigue, DTR Treatment is vigorous hydration followed by diuresis, furosemide, biphosphonates, calcitonin. Biphosphonates are the established standard care for patients with hypercalcemia of malignancy. More definite treatment will be cytoreductive nephrectomy and systemic immunotherapy. Patients who does not respond to cytoreductive nephrectomy may respond to Biphosphonates. Some patients with localised osteolytic metastasis may respond to focused radiotherapy.

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59 Hypertension and polycythemia Hypertension associated with RCC may be due to Increased production of renin. Compression or encasement of renal artery or its branches by tumour leading to renal artery stenosis, av fistula within the tumour. Less common causes include polycythemia, hypercalcemia, ureteral obstruction, increased ICT associated with cerebral metastasis.

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60 STAUFFER’S SYNDROME It is also called as non-metastatic hepatic dysfunction, reported in 3-20% of cases. Stauffer’s syndrome may show  ALP  PT  Albumin Elevated bilirubin  transaminases Thrombocytopenia/Neutropenia Elevated IL-6 Hepatic function normalizes after nephrectomy in 60-70% cases. Persistence or recurrence of hepatic dysfunction is almost always indicative of viable tumour and represents poor prognostic sign. In general, treatment of Paraneoplastic syndromes associated RCC has required nephrectomy or systemic immunotherapy and except for hypercalcemia, medical therapies have not proved helpful.

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61 Metastatic Symptoms 10% of the patients with symptoms of metastasis with primary tumour being silent. a. Lung metastasis: Persistent cough, haemoptysis, chest pain, dyspnoea, X-ray may show cannon ball metastasis. b. Bone may show painful, pulsatile metastatic deposits in ribs, pelvic bones (flat bones commonly) and ends of long bones with pathological fractures. c. Liver metastasis – jaundice, ascites, hepatomegally. d. Brain metastasis presents with headache, nausea, vomiting. e. Enlarged neck in nodes in the form of Troisier’s sign. f. Signs of IVC involvement in RCC Lower extremity oedema, varicocele, dilated superficial abdominal veins, proteinuria, pulmonary embolism, right atrial mass or non-function of the involved kidney.

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62 SCREENING AND CLINICAL ASSOCIATIONS A number of factors make screening for RCC appealing. Most important is RCC is primarily a surgical disease requiring early diagnosis to optimise the opportunity to cure. The primary factor that limits the widespread implementation of screening for RCC is the relatively low incidence of RCC in general population. Target populations for RCC screening Patients with endstage RF Patients with long life expectancy without any co-morbidities Patients with VHL syndrome Relatives of VHL syndrome patients Relatives of other familial variants of RCC Patients with tuberous sclerosis (adenoma sebaceum, epilepsy, MR, renal cyst, AML) Patients with autosomal dominant polycystic kidney diseases

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63 STAGING AND ASIS OF RCC 1. Robson staging Figure 22: Staging of renal cell carcinoma

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64 2. International TNM staging system for RCC

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65 Clinical staging of renal malignant disease begins with a thorough history, physical examination judicious use of laboratory tests, Symptomatic presentation, significant weight loss, bone pain, poor performance status, palpable mass, and lymphadenopathy, a non-reducing variocele, bilateral lower extremity oedema (venous involvement), abnormal liver function suggests the probability of advanced disease. Radiographic staging of RCC Radiographic staging of RCC is accomplished with a high quality abdominal CT scan and routine chest radiograph in most cases with selective use of MRI. CT findings suggestive of perinephric fat include perinephric stranding. Patients with enlarged adrenal gland on CT, upper pole location, extensive malignant replacement of the kidney, palpable abnormal adrenal gland are at risk for ipsilateral adrenal involvement. Enlarged hilar or retroperitoneal lymph nodes 2 cm or more in diameter on CT almost always Harber malignant change, but this should be confined by perentaneous aspiration or surgical exploration. Sensitivities and specificity of CT for detection of RCC is 78-96%.

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66 Indications for percutaneous renal biopsy or aspiration This has been limited primarily related to concerns about sampling errors, difficulty in interpreting limited tissue given the inherent similarities between the eosinophilic variants of RCC and oncocytoma and recognition of the improved diagnostic accuracy of cross sectional imaging such as CT or MRI. Sensitivities and specifications of FNAB for the diagnosis of RCC are well documented and range from 80-95%. Complication of FNAB Bleeding, infection, AV fistula, tumour dissemination, pneumothorax.

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67 MANAGEMENT OF RENAL CELL CARCINOMA Preoperative evaluation Hb% - Anemia or polycythemia (erythropoietin producing tumours, lactoferrin producing tumour) BT CT TC DC Blood grouping and cross matching ESR RBS BU If blood urea and serum creatinine is abnormal – an effort is done SC to do a partial nephrectomy. Complete haemogram CXR – may indicate canon-ball metastasis Blood calcium and serum alkaline phosphatase indicates metastatic disease Investigations related to paraneoplastic syndromes Urine microscopy  Hematuria  Proteinuria  Malignant cells X-ray abdomen may show calcification and distortion of renal outline.

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68 Radiographic evaluation of renal masses A. Intravenous pyelography Commonly used for evaluation of hematuria. Nowadays IVP has been replaced by contrast CT. IVP may miss small anterior or posterior lesions that do not distort the collecting systems or contour of kidney. Signs of malignancy in suspected renal mass in IVP: a) Calcification within the mass (Mottled Central Calcifications) b) Increased tissue density c) Irregularity of margin d) Distortion of the collecting system

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69 Ultrasound When a renal mass is identified by intravenous pyelography, unless the mass has the features suggestive of malignancy USG should be the next study performed because it is non-invasive, accurate and relatively inexpensive. It differentiates solid from simple renal cyst. Strict sonographic criteria for simple cyst include a smooth cyst wall, a round or oval shape without internal echoes and through transmission with strong acoustic shadows posteriorly. Sonographic criteria for AML is  echogenicity. A renal mass which does not fit the USG criteria should undergo CT scanning. USG also finds Staging and diagnostic information Extra-renal involvement Adrenal involvement Involvement of lymph nodes Infiltration of adjacent viscera

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70 CT Scan Figure 23:A,CT scan without administration of contrast material shows solid, right posterior renal mass. B, After administration of the contrast agent, CT scan shows that the mass enhances more than 20 Hounsfield units and is thus highly suggestive of renal cell carcinoma.

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71 Figure 24:Bosniak's class IV cysts. A, CT scan shows complex left renal cystic lesion with thick, enhancing walls. B, CT scan shows complex right cystic lesion with enhancing nodular areas and inhomogeneity.

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72 Figure 25: CT scan after administration of contrast agent shows right renal tumor with perinephric stranding suggesting invasion of the perinephric fat.

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73 A thin slice contrast CT remains the single most radiographic test for delineating the nature of renal mass. As renal cell carcinoma is a highly vascular tumour contrast CT is very much useful in evaluating RCC. In general, any renal mass that enhances with intravenous administration of contrast material on CT scanning by >15 Hainsfield units should be considered as RCC until and unless proved otherwise. CT findings include thickened irregular walls, thickened enhanced mass or a multilocular mass. Solid masses that have a substantial areas of negative CT attenuation (-20 HU) indicative of fat are diagnostic of AML. In 10% of solid renal masses, CT findings are indeterminate, surgical exploration may be needed to establish the diagnosis. On occasion, CT scanning demonstrates an enhancing renal segment that is isodense with the remainder of kidney suggestive of renal pseudo tumour. Renal pseudo tumour may be due to hypertrophied renal column of Bertin, renal dysmorphism, unusually shaped kidney. Isotope renography may be helpful (glucoheptonate, Tc99 dimercaptosuccinic acid is used. Renal column of Bertin is nothing but extension of cortex between the renal pyramids.

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74 Magnetic Resonance Imaging MRI is indicated when poorly defined renal masses on CT scan. Allergy to IV contrast/poor renal function. When tumour extends into the renal vein/IVC

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75 Renal arteriography Figure 26: Neovascularity associated with renal cell carcinoma. Right renal angiogram shows right renal mass exhibiting markedly increased neovascularity consistent with renal cell carcinoma.

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76 Infrequently used findings of RCC include and neovascularity av fistulas, pooling of contrast media and accentuation of capsular vessels. Renal arterio-graphy may be helpful in evaluating small renal masses. MRI angiography with intravenous gadolinium labelled diethyltriamino- pentaacetic acid; very helpful in detection of extension into renal artery, renal vein or inferior vena caval involvement. INFERIOR VENOCAVOGRAPHY Rarely performed, when there is a large tumour or uncertainty about involvement of vena cava. This may helpful in defining the vascular aspect of operative surgery. Transoesophageal echocardiography Defines the tumour extension into the inferior vena cava and the right atrium. FNAC It has traditionally limited value in the evaluation of renal masses.

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77 Indications for FNAC a. Renal abscess b. Infected cyst c. When RCC has to be differentiated from metastatic tumours. Drawbacks of FNAC a) Spread of tumour i.e. tumour dissemination b) Perirenal bleeding c) False negative findings in patients with renal malignant neoplasms, especially oncocytoma and common eosinophilic variants. d) AV fistula e) Infection Differential Asis of RCC When a patient presents with clinical findings consistent with metastatic disease and is found to have a renal mass, a diagnosis of RCC can be straight forward. Most patients with a renal mass discovered after an evaluation of hematuria or an incidental finding. The great majority are simple cysts and other solid neomplasms.

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78 Findings on a CT scan that suggest malignancy include amputation of a portion of the collecting system, presence of calcification, poorly defined interface between the renal parenchyma and the lesion; invasion into perinephric fat or adjacent structures, presence of abnormal peri-aortic adenopathy or distant metastasis. Benign lesions are usually less than 7 cms. The diagnostic possibilities are Lymphoma  HL Pyelonephritis  Acute  NHL  Chronic Wilm’s tumour, Renal abscess, Angiomyolipoma, Oncocytoma, Renat adenoma, Metastatic (lung, breast melanoma), Renal cysts, Renal infarction, Renal sarcoma, Carcinoma of renal pelvis, retroperitoneal sarcoma. Angiomyolipomas can be identified by their low attenuation produced by their substantial fat content.

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79 TREATMENT OF LOCALISED RENAL CELL CARCINOMA Surgery remains mainstay of curative treatment of this disease. Objective of surgical therapy is to excise all tumour with an adequate surgical margin. Robson and colleagues established the Radical Nephrectomy as the gold standard operation for localised RCC with 66% and 64% survival for stages I and II tumours. First nephrectomy was performed by Erratus B Walcott in Milwakee, Wisconsin on June 4, 1861 on 58 year old who died 15 days after surgery. The first successful nephrectomy was performed in 1889 with a persistent ureteral fistula. The first successful nephrectomy in a patient with kidney cancer was performed in 1883 by Grawitz.

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80 Concept of Radical Nephrectomy There are two types of radical nephrectomies Adrenal sparing Total radical nephrectomy In total radical nephrectomy includes a) Early ligation of the renal artery and vein b) Removal of kidney with Gerotas facia c) Perinephric fat, adrenal gland (ipsilateral) d) Proximal 2/3 of ureter e) Regional lymphadenectomy from crus of diaphragm to aortic bifurcation Surgical Approach for Radical Nephrectomy is determined by the size and location of the tumour.

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81 Figure 27: Type of incisions used in radical nephrectomy. A: Full flank (thoracoabdominal), B: Anterior-thoracoabdominal, C: Subcostal, D: Chevron, E: Midline.

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82 Usually the transperitoneal approach is preferred either by midline or a transverse (midline when there is a plan for resection of adjacent structures) transverse incision – preferred when only nephrectomy is planned. Subcostal and bilateral subcostal chevoron incision also preferred by some authors. Thoracoabdominal incision was planned when there is a large tumour involving the upper portion of kidney. Laparoscopic Radical Nephrectomy It is used as an alternate to open surgery in the management of low to moderate volume (8-10 cm), localised RCC with no local invasion, renal vein involvement or lymphadenopathy. Advantages Cancer control equivalent with open radical nephrectomy  hospital stay More rapid recovery  postoperative pain Improved cosmesis Laparoscopic radical nephrectomy is most often used as a means of performing minimally invasive cytoreductive nephrectomy in advanced RCC as a preparation for immunological therapy.

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83 Nephron Sparing Surgery It was first described by Czerny in 1890. Accepted indications for nephron sparing surgeries include in which radical nephrectomy would render the patient anephric or at a high risk for ultimate need of dialysis. Bilateral RCC RCC involving solitary kidney Unilateral RCC with functioning opposite kidney affected by a condition that might threaten its future function, such as renal stenosis, hydronephrosis, chronic pyelonephritis, ureteral reflux, calculus disease, HTN, diabetes, etc. NSS may be indicated in a renal tumour less than 4 cm. Von Hippel Lindau Syndrome Operative methods in NSS 1. Open partial nephrectomy, e.g.: polar nephrectomy 2. Minimally invasive partial nephrectomy (laparoscopic) 3. Other methods are cryotherapy and radiofrequency ablation

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84 TREATMENT OF LOCALLY ADVANCED RENAL CELL CARCINOMA17 1. Inferior vena caval involvement One of the unique features of RCC is its frequent pattern of growth intra- luminally into the renal venous circulation as venous thrombus. In extreme cases the growth may be extend into the IVC with cephalohead migration into the right atrium. RCC with thrombus extension into the IVC can be treated by Radical Nephrectomy and thrombectomy of IVC. Overall involvement of the IVC occurs in 4% to 10% of the patients. Venous tumour thrombus should be suspected in patients a renal tumour who also have lower extremity oedema, isolated right sided varicocele, that does not collapse with recumbency (secondary varicocele), dilated superficial abdominal veins, proteinuria, pulmonary embolism, right atrial mass, nonfunctioning involved kidney.

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85 Staging of IVC thrombus Stage I : adjacent to the ostium of renal vein Stage II : extension upto the lower aspect of liver Stage III : involving the intrahepatic portion of IVC but below the diaphragm Stage IV : extending above the diaphragm MRI is the investigation of choice Contrast inferior vena cavaography is used where MRI findings are equivocal or contra indicated.

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86 2. Locally invasive renal carcinoma Some tumours may have the propensity for invading local structures. Such patients usually presents with pain, generally from invasion of the posterior abdominal wall, nerve roots or paraspinal muscles. Local extension into the liver is uncommon than intrahepatic metastasis. Extension into the duodenum pancreas, colon may be possible. Basic surgery is enblock resection of the adjacent organs are sometimes indicated with complete excision of the tumour, including resection, of the involved bowel, spleen, abdominal wall muscles. Adjuvant therapy for locally advanced RCC a) Vaccine prepared from autologus irradiated tumour cells with BCG vaccine b) Interferon -2 c) Interleukin 2

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87 TREATMENT OF METASTATIC RCC15 CYTOREDUCTIVE NEPHRECTOMY (also known as palliative nephrectomy) Aims of cytoreductive nephrectomy 1. Control of bleeding 2. Pain 3. Paraneoplastic syndromes (hypercalcemia, thrombocytosis,hypertension (Renin) 4. Regression of metastasis (especially pulmonary) Cytoreductive nephrectomy should be followed by systemic treatment in patients with synchronous metastasis, INF- is used as systemic therapy. Complete resection of either synchronous or metachronous solitary metastasis from RCC is justified and contribute to a long term survival. RESECTION OF METASTASIS Only approximately 30% of RCC who presents with metastasis. Only 1.5% to 3.5% have solitary metastasis. Metastatectomy may be tried in selected patients. e.g. lung, brain

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88 Algorithm for Advanced RCC21 Management. MSK (Memorial Sloan Kettering)

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89 ANGIOINFARCTION It is an effort to embolisation of the renal artery in an attempt to reduce renal blood flow to the tumour. It is an accepted current practice for palliation or if renal vessels are encased by tumour to facilitate subsequent surgery and also immunotherapy. CHEMOTHERAPY RCC is a chemoresistant tumour. The following drugs are used either singly or in combination with discouraging results. Single agents Bleomycin Cisplatinum 5-FU Gemcitabine Vinblastine In combination Gemcitabine + 5 FU Gemcitabine + 5 FU + IL2 + IFNA Gemcitabine + Capacitabine Gemcitabine + Oxaliplatinum IFNA + Vinblastine IFNA + Vinblastine Mechanism of chemoresistance in RCC is attributed to p-glycoprotein, 170 KD membrane glycoprotein expressed in RCC cells can act as a efflux pump reducing intracellular concentration of agents such as vinblastine.

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90 HARMONAL THERAPY25 Only useful in symptom palliation. Medroxy progesterone acetate, androgens, and anti-oestrogens tried in symptom palliation of metastatic RCC. This is based on the identification of progesterone receptors in some renal tumours and evidence of antitumour activities. Though the response rate is <10%, the anabolic effects are beneficial in metastatic carcinoma also helpful in metastatic bone disease of RCC helping in reducing osteoclastic activity in bones.

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91 VEGF FACTOR TARGETED THERAPY VEGF ligand binding antibodies Bevacizumab Bevacizumab is an IgGI monoclonal antibody inhibits signaling through the VEGF pathway by sequestring the circulatory overload. Dosage is 10 mg/kg IV every 2 weeks. Side effects are hypertension, thrombo-embolic episodes including stroke, MI, haemorrhage from the primary site, bowel perforations. Pazopanib15,21 It is a multitarget tyrosine kinase inhibitor that inhibits VEGFR-1,2,3, PDGFR-, and C-kit (CD117 commonly expressed in GIST). Thus it inhibits both tumour cell proliferation and angiogenesis. Dosage is 800 mg daily side effects are GIT disturbances, dermatological fatigue, hypotension and proteinuria. Sunitinib and Sorafenib These are the drugs which inhibit tyrosine kinase may be used in metastatic carcinoma. Side effects are diarrhoea, hand foot, syndrome and neutropenia.

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92 Mammlian Target of Rapamycin inhibitors (MTOR)15,21 (a) Temsirolimus (CCL-779) inhibitor of MTOR pathway MTOR pathway is an important regulator of cell proliferation, cell growth and cell survival. It is administered IV 25 mg. Side effects are hypersensitivity reactions; themia, thrombocytopenia, pneumonitis, hyperglycemia, LFT tests. (b) Everolimus: Inhibitor of m-TOR pathway dosage is 10 mg/day. Side effects are rash, fatigue, nausea, anorexia.

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93 CYTOKINES AND IMMUNOLOGIC THERAPY These are  investigational. The demonstration of T-cell infiltrates, the development of T cell lines with specificity for autologus tumour and finding of tumour associated antigens on renal tumours are MHC restricted provide laboratory evidence for a antitumour immune response. Spontaneous regression in some RCC-indicates immunological background. Very late relapses associated with biological therapy. INF- It has antiviral, immunomodulatory and antiproliferative activities. Side effects are flu like syndrome, anorexia, nausea, vomiting, etc. IL-2 It is other primary agent used in the treatment of metastatic RCC. It is a T-cell growth factor administered either IV/SC. Complications include hypotension, multiorgan failure, capillary leak syndrome, pulmonary oedema. Vaccines Vaccines prepared from irradiated tumour cells combined with BCG vaccine also tried. Autologus tumour cells fused with allogenic dendritic cells used for preparation of vaccine.

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94 PROGNOSTIC FACTORS IN RCC14 A unique feature of the natural history of renal cell carcinoma is biological variability in natural history and in response to therapy. It depends on following parameters A. CLINICAL B. LABORATORY C. MOLECULAR MARKERS D. TUMOUR RELATED FACTORS

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95 A. CLINICAL PARAMETERS Clinical findings of compromised prognosis include symptomatic presentation, weight loss >10% of body weight, poor performance status. Anemia and other Paraneoplastic syndromes associated with poor prognosis. Presence of visceral metastasis (lung, lever, bone, brain, adrenals associated with poor prognosis. Number of metastasis. Short interval between diagnosis and metastasis indicates worse prognosis.

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96 B. TUMOUR RELATED a. Pathological stage: Pathological stage has proved to be the single most important prognostic factor in RCC. b. Nuclear Grade of Fuhrman’s is an important prognostic factor for RCC which includes nuclear size, shape and presence or absence of prominent nucleoli. c. Venous involvement: Venous involvement is also considered as adverse prognostic factor. d. Extension beyond Gerotas facia: Tumour extension beyond Gerotas facia to involve contigeous structures used is a bad prognostic sign. e. Lymph node involvement: Considered as a bad prognostic sign. f. Tumour size: Tumour size is inversely related to survival. Five year survival rate for tumour less than 5 cm diameter – 84% Five year survival rate for tumour between 5-10 cm diameter – 50% Five year survival rate for tumour > 10 cm diameter – Nil g. Histological subtypes Presence of sarcomatoid differentiation or collecting duct or medullary cell histology and papillary carcinoma denotes poor prognosis. Chromophobe carcinoma has the excellent prognosis than conventional type RCC. h. Bilateral tumours associated with poor prognosis.

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97 C. LABORATORY PARAMETERS 1. Elevated ESR and C-reactive protein 2. Thrombocytosis > 400,000 mcl 3. Anemia 4. Serum LDH 5. Serum calcium 6. Serum alkaline phosphatase 7. Slauffer’s syndrome All early poor prognostic factors. D. MOLECULAR MARKERS VHL gene mutation is associated better prognosis proved by anti VEGF therapy. Another important prognostic factor is carbonic anhydrase IX, that regulates the pH during hypoxia and is a product of Hypoxia induced factor, these patients have better response to IL-2 therapy.

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98 Key points: Prognostic Factors for RCC

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99 Prognosis of patients in RCC Five year survival rate with stage T-T2 – 80-100% Five year survival rate with stage T3 – 50-60% Five year survival rate with metastatic state – 16-32% Follow-up and Recurrences of RCC The most obvious risk of organ sparing tumour excision lies in the possibility of tumour recurrence. 10% of tumour recurrences occurs within three years of follow-up. The most common sites of relapses are lung, bone, liver. Chest radiography, LFT including serum alkaline phosphatase are other important investigations. For primary tumour recurrences surgery may be indicated, for metastatic diseases, as per treatment protocols used in metastatic disease may be used.

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100 NEPHRECTOMY Types: 1. Simple nephrectomy 2. Subcapsular nephrectomy 3. Radical nephrectomy  Total radical  Adrenal sparing 4. Partial nephrectomy 5. Cytoreductive nephrectomy 6. Nephroureterectomy NEPHRECTOMY TYPES BASED ON METHODS OF APPROACH  Open  Laparoscopic  Robot assisted

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101 Incisions for Nephrectomy  Transperitoneal1-6,10  Retroperitoneal7-11 1. Thoraco-abdominal 2. Anterior thoracoabdominal 3. Subcostal 4. Chevoron 5. Midline 6. Transverse 7. Lumbar approach 8. Approach through the bed of 12th rib 9. Nagamatsu incision 10. Minimally invasive nephrectomy (Laparoscopic) 11. Robot assisted nephrectomy

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102 SIMPLE NEPHRECTOMY Indications 1. Irreversibly damaged kidney due to chronic infection, obstruction, calculus, severe traumatic injury. 2. Renovascular HTN due to non-correctable renal artery disease. 3. Unilateral parenchymal disease from nephrosclerosis, reflux or congenital dysplasia. Approach: An extraperitoneal flank approach is usually preferred. SUBCAPSULAR NEPHRECTOMY It is indicated when severe perirenal inflammation precludes satisfactory dissection between kidney and surrounding structures. The plane of cleavage is developed between renal parenchyma and capsule is developed.

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103 RADICAL NEPHRECTOMY It is the treatment of choice for patients with localised renal carcinoma. There are two types:  Adrenal sparing  Non-adrenal sparing TECHNIQUE OF RADICAL NEPHRECTOMY Radical nephrectomy encompasses basic principles of early ligation of renal artery and vein removal of kidney outside the Gerotas fascia. Removal of perinephric fact, regional lymphoadenectomy from the crus of diaphragm to aortic bifurcation.

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104 Surgical approach for the radical nephrectomy It is always transperitoneal: Because of better access to the vessels(i.e. pedical) The type of incision is determined by the size of tumour and in some times when enblock resection is required. a) Transverse incision: When the tumour is small b) Midline incision: When planned for enblock resection of adjacent organs c) Thoracoabdominal d) Extended subcostal for large upper pole tumours e) Bilateral subcostal (Chevoron)

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105 Procedure of Radical Nephrectomy The abdomen is opened in right subcostal incision. Colon and duodenum on right side are reflected medially to expose the vena cava and aorta. Right sided medial visceral rotation i.e. extended Kocher’s manoeuvre and Cattell Brasch Manoeuvre on right side. Right sided medial visceral rotation – Mattox manoeuvre on left side. Operation is initiated with dissection of renal pedicle. Right renal artery is mobilised. Renal artery is ligated first to prevent engorgement. On left side vein is mobilised completely by ligating its tributaries (gonadal, adrenal and lumbar). Then renal vein is ligated. The kidney is mobilised outside the Gerotas fascia with blunt and sharp dissection. The remaining vascular attachments are secured with non-absorbable sutures and metal clips. Dissection of regional lymph nodes from the crus of diaphragm to aortic bifurcation. Ureter – 2/3rd of the upper ureter is removed.

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106 Management of Retroperitoneal Haemorrhage (Complication of Radical Nephrectomy) During performance of radical nephrectomy intraoperative hemorrhage can occur either from IVC or its tributaries. Lumbar veins Right gonadal vein From renal veins (double renal veins) referred as renal collar Bleeding from adrenal veins Most important control haemorrhage is prevention i.e. careful dissection of the pedicle. In vena caval laceration direct pressure and with vascular clamps. It can be controlled.

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107 Radical Nephrectomy with infrahepatic venacaval involvement (CP By pass may required) Bilateral subcostal or thoracoabdominal incision used. Procedure is same as the original radical nephrectomy. Undue manipulation of renal vein is avoided. Vena cava is dissected free from the surrounding structures above and below the renal vein and opposite renal vein is also mobilised. Using Rummel tourniquets, Satinsky clamps, Harkin clamps or bulldog clamps, and the venous channels around the thrombus should sequentially clamped beginning with the infra-renal IVC, the opposite renal vein and finally suprarenal IVC. Inferior vena-cavatomy done on the anterior surface and thrombectomy will be performed. Inferior vena cavotomy will be closed with 5-0 vascular sutures. Caval narrowing can be reconstructed using pericardial or PTFE graft.

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108 Radical Nephrectomy with intrahepatic or suprahepatic vena caval involvement The preferred approach is to employ cardiopulmonary bypass with deep hypothermic circulatory arrest for most patients with complex supradiaphragmatic thrombi and for all patients with right atrial thrombi. Bilateral subcostal incision is preferred. Under deep hypothermic arrest, the entire lumen of the inferior vena can be directly inspected to ensure that all fragments of the thrombus are completely removed. In patients with non-adherent supradiaphragmatic vena caval tumour thrombi that do not enter into the right atrium veno-venous bypass in the form of cavo-atrial shunt is an useful technique.

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109 Complications of Radical Nephrectomy Postoperative complications are 20%, operative mortality is 2%. a) Bleeding Venous bleeding is most problematic. Causes are Lumbar veins Right gonadal vein Renal vein (double renal vein – renal collar) IVC damage Bleeding from adrenal veins b) Pneumothorax: accidental rent in the pleura especially in thoraco-abdominal and flank incisions. c) Injury to the spleen d) Injury to the liver e) Pancreatic fistula f) Injury to colon g) Temporary renal insufficiency h) Systemic complications: MI, CVA, CHF, pulmonary embolism, adelectasis, pneumonia, thrombophlebitis.

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110 PARTIAL NEPHRECTOMY Partial nephrectomy for malignant disease a) RCC involving a solitary kidney (1/3rd of a solitary kidney can bear the normal renal b) RCC involving bilaterally function) Types are Heminephrectomy Polar nephrectomy Wedge resection Transverse resection Bench nephrectomy It is nothing but removal of the kidney. The lesions are optically magnified. Removal of lesions done. Following which autotransplantation is done. Complications of Partial Nephrectomy Haemorrhage, urinary fistula, ureteral obstruction, renal insufficiency and infection.

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111 Partial nephrectomy in benign diseases Indications 1) Presence of stone in the upper or lower pole 2) Rupture of kidney involving poles 3) Solitary cysts Minimally invasive nephrectomy (Laparoscopic Nephrectomy) Approaches for Laparoscopic Nephrectomy  Transperitoneal  Retroperitoneal  Hand assisted Types of Laparoscopic Nephrectomy  Radical Nephrectomy  Partial Nephrectomy (NSS)  Cytoreductive Nephrectomy First lap nephrectomy was done in an 85 years old women with a right renal mass by Clayman in 1990.

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112 DEBULKING NEPHRECTOMY Also known as cytoreductive nephrectomy, palliative nephrectomy. Basis of Cytoreductive Nephrectomy Spontaneous regression of pulmonary nodules may occur following excision of primary tumour. Debulking is associated with enhanced immune enhancing therapy. Metastatic RCC after cytoreduction responds better to chemo, radiotherapy and biological therapy. Improved survival after cytoreductive therapy observed after several studies. Laparoscopic cytoreductive nephrectomy is the recent advance.

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113 NEPHROURETERECTOMY Radical nephroureterectomy performed in cases of transitional cell carcinoma of renal pelvis and ureter. ROBOT ASSISTED NEPHRECTOMY6 Mainly used in donour nephrectomies. In 2002 Horgan et al. reported 10 living donour nephrectomies using Da Vinci. The mean operative time was 166 minutes and the mean hospital stay was 1.8 days. The blood loss is 68 ml and major complications were fewer as observed in one study. The risks of intra- operative kidney and splenic lacerations are found to be decreased. Robot assisted renal vessel dissection found to be easier than other methods. The Robot assisted technique also enhanced the donour nephrectomy by facilitating the identification and isolation of ureter.

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114 CONCLUSION In conclusion, surgery is the mainstay of treatment in localised renal cell carcinoma. Surgery also plays an important role in locally advanced carcinoma and even in metastatic carcinoma. Metastatic RCC is an incurable disease. There is no evidence that either chemotherapy or radiotherapy improves the survival rate. Standard systemic therapy lies between MPA, interferons, interleukin-2 and anti VEGF antibodies. The response rates seems to be more with interferon  (IFN-) compared to MPA. The role of interleukin-2 remains controversial. Early diagnosis of RCC definitely improves the survival rate.

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115 REFERENCES Steven C Campbell, Andrew C Novick, Ronald M Bukowski. Neoplasms of the upper urinary tract. 9th ed. Chapter 47. Section XII. In: Campbell Walsh Urology, Wein, ed. Philadelphia: Saunders, Elsevier Company; 2007. Badrinath R Konetty, Richard D Williams. Renal parenchymal neoplasms. 17th ed. Chapter 21. In: Smith’s General urology, Emil A Tanagho, Jaack W McAninch, eds. New York: McGraw-Hill Publications; 2008. pp. 328-39. Marston W Linchan, Brian I Rini, James C Yang. Cancer of kidney. Chapter 40.3. In: Devita and Hellman and Rosenber’s Cancer, principles and practice of oncology, Vincent T Devita, Theodore S Lawrence, Steven A Rosenberg, eds. Philadelphia: Lippincott, Williams & Wilkins; pp. 1331-54. Nelson G Ordonez, Juan Rosai. Urinary tract, kidney, renal pelvis and ureter and bladder. 9th ed. Chapter 17. In: Rosai and Anckeman’s Surgical pathology, Juan Rosai, ed. Missourie: Elsevier Publication; 2004. 1:1251-77. Kidney and ureter. 40th ed. Chapter 74. In: Gray’s Anatomy, Susan Standring, ed. London: Elsevier Publication; 2008. pp. 1225-43. William C Dewelf, James C Hu. Radical nephrectomy for renal cell carcinoma. 5th ed. Chapter 154. In: MOS Master of surgery, Joseph E Fischer, ed. Philadelphia: Lippincott, Williams & Wilkins; 2007. pp. 246-7,1688-702. Christopher G Fowler. Kidneys and ureter. 25th ed. Chapter 71. In: Bailey and Love’s Short practice of surgery. London: Hodder Arnold Publisher; 2008. pp. 1285-361. Charles E Alpers. The kidney. 8th ed. Chapter 20. In: Robbin’s Pathological basis of disease, Kumar, Abbas, Faustoaster, eds. Philadelphia: Elsevier Publications; 2010. pp. 963-9. Jeffrey La Rochelle, Brian Shuch, Arie Belldegrun. 9th ed. Chapter 40. In: Schwartz Principles of Surgery, Charles F Brunicardi, ed. New York: McGraw-Hill Medical Publications; 2010. pp. 1459-74.

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116 Kidney and ureter. 5th ed. Chapter 57. In: A concise textbook of surgery, Das S, ed. Published by Das S; 2008. pp. 1149-222. Urological surgery for the general surgeon. 9th ed. Chapter 25. In: Farquharson’s Textbook of operative general surgery, Margarette Farquarson, Brendon Moran, eds. Great Britain: Hodder Arnold Publisher; 2005. pp. 485-503. Aria F Ohumi, Jerome P Richie. Urological surgery. 18th ed. Chapter 77. In: Sabiston’s Textbook of surgery, Townsend, Benchamp, Ever Mattex, eds. Philadelphia: Elsevier Publications; 2008. pp. 2251-86. Howard I Scher, Robert J Motzer, Bladder and renal cell carcinomas. 17th ed. Chapter 90. In: Harrison’s Principles of internal medicine, Fanci Braunwald, Kasper, Hauser, Longo, Jamson Loscalzo, eds. New York: McGraw-Hill Publications; 2008. pp. 589-93. Ljungberg B. Prognostic factors in renal cell carcinoma. Scandinavian Journal of Surgery 2004;118-25. New therapeutic stages for management of RCC. www.medscape.com/view article/718790_3. Yuvaraja B Thyavihalli, Umesh Mahantashetty. Management of renal cell carcinoma with solitary metastasis. World Journal of Surgical Oncology; 2005. 3:48. Jagadish N Kulkarni, Purushothama U Acharya. Surgical management of RCC with IVC involvement. Indian Journal of Cancer. www.indianjcancer.com/ article 2007;44(2):10/02/10. Laura S Wood. New therapeutic strategies for renal cell carcinoma. Urol Neu. www.medscape.com/view article 2010;718-90. Stefan Denzinger, Wolfgang Otto. Sporadic renal cell cancer in young and elderly patients. World Journal of Surgical Oncology 2007;5(16):1477-14795-1-16. Renal cell carcinoma. www.atlasgeneticsoncology.org/tumours/renal cell carcinoma ID 5021.html.

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117 John S Lam, Jobias Klatte. Staging of RCC. Indian Journal of Urology Review Article 2009;25(4):446-54. Renal function and micturition. 21st ed. Chapter 38. In: Review of medical physiology, William F Ganong, ed. New York: McGraw-Hill Publications; 2008. pp. 964-9. Jalal Assoud, Hicham Masmoudi. Isolated rib metastasis from renal cell carcinoma interact. Cardiovascular Surgery 2010;172-5. Jim Cassidy. Genitourinary cancers. Chapter 19. Oxford Handbook of Oncology, Jim Cassidy, ed. Oxford: Oxford University; 2008. pp. 338-43. Jorge A Garcia, Brian I Rini. Recent progress in the management of advanced RCC.

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