MRI with gadolinium contrast may be used for imaging the IVC, locally advanced disease, ren al insuf \201 ciency, or for patients allergic to iodinated contrast. Doppler USS may also evaluate IVC tumor thrombus. Renal arteriography is seldom used in the diagnostic setting, but may be helpful to delineate the number and position of renal arteries in preparation f or nephron-sparing surgery or surgery for horseshoe kidneys. Houns \201 eld units are a measure of X-ray attenuation applied to CT scanning: \200\2231 000 units equates with air, 0 units equates with water, and +1000 equates with bone. RADIOLOGICAL ASSESSMENT OF RENAL MASSES 243 Ultrasound or CT-guided \201 ne needle aspiration (FNA) or needle biopsy This is increasi ngly indicated due to the trend in managing small masses with surveillance or minimally inv asive ablative therapies. Also, a histo- logical diagnosis is usually required prior to tre ating inoperable patients with systemic therapies. Needle biopsy is highly speci \201 c, b ut less sensitive for detecting malignancy: 80% of biopsy cores are diagnostic, of which 75 % are RCC. Repeat biopsy is diagnostic in 80%. There are also risks of hemorrhage (5%) and tumor spillage (rare). FNA is useful for aspiration of renal abscess or infected cyst or to diagnose suspected lymphoma or metastatic lesions. Table 7.3 shows a practical radiologica l classi \201 cation of renal masses. Table 7.3 Classi \201 cation of renal masses by radiographic appearance Others (excluding rarities) Simple cyst Complex cyst Fatty mass Cyst Renal carcinoma Angiomyolipoma Renal cell carcinoma Multiple cysts Cystic nephroma Lipoma Metastasis Parapelvic cyst Haemorrhagic cyst Liposarcoma Lymphoma Calyceal diverticulum Metastasis Sarcoma Wilms \200\231 tumor Abscess Infected cyst Tuberculosis Lymphoma Oncocytoma Tuberculosis Xanthogranulomatous pyelonephritis Renal artery aneurysm Phaeochromocytoma (adrenal) Arteriovenous malformation Wilms \200\231 tumor Hydrocalyx Transitional cell carcinoma It has been suggested that abdominal USS could be used as a screen- ing test for early dete ction and treatment of RCC; this has been piloted in Germany and Japan. While there is curr ently no plan for population screening in the UK, it would be appropriate to offer USS to h igh-risk individuals such as relatives of VHL syndrome patients. 1 Bosniak MA (1986) The current radiological approach to renal cysts. Radiology 158:1 \200 \22310. CHAPTER 7 Urological neoplasia 244 Benign renal masses The most common (70%) are simple cysts, present in >50% of those aged > 50y. Rarely symptomatic, treatment by aspiration or laparoscopic de- roo \201 ng is seldom considered. Most benign renal tumors are rare; the two most clinically important are oncocytoma and angiomyolipoma. Oncocytoma This is uncommon, accounting for 3 \200\2237% of renal tumors. Males are twice a s commonly affected as females. They occur simultaneously with RCC in 7 \200\22332% of case s. Pathology Oncocytomas are spherical, capsulated, brown/tan color, mean size 4 \200\2236cm. Half contain a central scar. They may be multifocal and bilateral (4 \200\22313%) and 10 \200\22320% extend into perinephric fat. Histologically, they com- prise aggregates of eosi nophillic cells thought to arise from intercalated cells of the collecting duct. Cells are packed with mitochondria, mitoses are rare, large nucleoli are present; they are considered benign, not known to metastasize. There is often loss of the Y chromosome. Presentation Oncocytomas often (83%) present as an incidental \201 nding or with loin pai n or haematuria. Investigations Oncocytoma cannot often be distinguished radiologically from RCC; they may c oexist with RCC. Rarely, they exhibit a \200\230spoke-wheel \200\231 pattern on CT scannin g, caused by stellate central scar. Percutaneous biopsy is not usu- ally recommended since there is often continuing uncertainty about the diagnosis. The main differential diagnosis of renal oncocytoma is chromo- phobe RCC oncocytic variant which, like the renal oncocytoma , has eosin- ophilic cytoplasm, but has perinuclear clearing and typically, some degree of nuclear atypia. Treatment Radical or partial nephrectomy is indicated as for renal carcinoma. Minimally inv asive techniques such as radiofrequency ablation (RFA) or high intensity focused ultrasound (HIFU) could be considered for smaller tumors. No follow-up is necessary. Angiomyolipoma (AML) Eighty percent of these benign clonal neoplasms (PEComa, formerly cons idered as a hamartoma) occur sporadically, mostly in middle-aged females. Twenty percent ar e in association with tuberous sclerosis (TS), an autosomal dominant syndrome characterized by mental retardation, epilepsy, adenoma sebaceum, and other hamartomas. Up to 80% of TS p atients develop AMLs, mean age 30y, 66% female, frequently multifocal, and bilateral. BENIGN RENAL MASSES 245 Pathology AML is composed of perivascular epithelioid cells (PEC) containing blood vessels, immature smooth muscle, and fat. They are always considered be- nign although extrarenal A MLs have been reported in venous system, hilar lymph nodes, and liver. Macroscopically, it looks like a well circumscribed lump of fat. Solitary AMLs are more frequently found in the right kidney. Presentation AMLs frequently present as incidental \201 ndings (>50%) on USS or CT scans. They may present with \202 ank pain, palpable mass, or painless haema- turia. Massive an d life-threatening retroperitoneal bleeding occurs in up to 10% of cases (Wunderlich \200 \231s syndrome). Investigations Ultrasound re \202 ects from fat, hence a characteristic bright echo patter n. This does not cast an \200\230acoustic shadow \200\231 beyond, helping to distinguish a n AML from a calculus. CT shows fatty tumor as low density (Houns \201 eld units <10) in 8 6% of AMLs. If the proportion of fat is low, a de \201 nite diagno- sis cannot be made as other renal tumors may contain fat. Measurement of the diameter is relevant to treatment. Treatment In studies, 52 \200\22382% of patients with AML >4cm are symptomatic compared wit h only 23% with smaller tumors. Therefore, asymptomatic AMLs can be followed with serial US S if <4cm while those bleeding or >4cm should be treated surgically. Emergency nephrectomy or selective renal artery embolization may be life-saving. Patients with kidney loss should be moni- tored for hypertension (and treated for it if discovered) and avoid neph- rotoxic drugs such as certain pain relievers and IV contrast agents. In patients with TS, in whom multiple bilateral lesions are present, annual renal USS and conservative treatment should be attempted. HIFU could be considered for asymptomatic tumors. CHAPTER 7 Urological neoplasia 246 Renal cell carcinoma: pathology, staging, and prognosis RCC is adenocarcinoma of the renal cortex, believed to arise from the proximal convoluted tubule (although the majority of VHL gene deletions occur in the distal tubule). Usually tan-colored, lobulated, and solid, 7% are multifocal, 1 \200\2232% bilateral, 10 \200\22320% contain calci \201 cation, and 10 \200\22325% contain cysts or are predominantly cystic. There may be zones of haemor- rhage, necrosis, and scarring. Rarely grossly in \201 ltrative, they are usually circumscribed b y a pseudocapsule of compressed tissue. Spread is by: direct extension to adrenal gland (7.5% in tumors >5cm), through the renal ca psule (25%), into renal vein (up to 44%), IVC (5%), right atrium; by lymphatics to hilar an d para-aortic lymph nodes; hae- matogenously to lung (75%), bone (20%), liver (18%), and br ain (8%). Histological classi \201 cation of RCC - Conventional (80%) clear cells (glycogen, cholesterol) or granular (eosinophillic cytoplasm , mitochondria); involves loss of VHL, PBRM1, and others genes on chromosome 3. Papillary ( 10 \200\22315%) small incidental tumors could equate with Bell \200\231s legendary \200 \230benign adenoma \200\231; trisomy 7, 16, 17. Chromophobe (5%) duct; possesses a perinucl ear halo of microvesicles; hypodiploid with loss of chromosomes 1, 2, 6, 10, 13, 17, 21. Co llecting duct (Bellini) Medullary cell sufferers; poor prognosis. : arise from the proximal tubule; highly vascular; : papillary, tubular, and solid variants; 40% multifocal; : arises from the cortical portion of the collecting : rare, young patients, poor prognosis. : rare, arises from calyceal epithelium; young sickle cell \200\230Sarcomatoid \200\231 \200\231 describes an in \201 ltrative poorly differentiated variant of any type in 5 \200\22325%. Coagulative necrosis is seen in 30%. Array-based kar yo- typing performs well on paraf \201 n-embedded tumors and can be used to identify chara cteristic chromosomal aberrations in renal tumors with challenging morphology. Genetic changes associated with RCC are described on b p. 250. RCC is an unusually immunoge nic tumor, expressing numerous antigens (e.g. RAGE-1, MN-9). Reports of spontaneous regress ion, prolonged stabilization, and complete responses to immunotherapy support this. Tumor-i n \201 ltrating lymphocytes are readily obtained from RCCs, includ- ing T-helper, dendriti c, natural killer, and cytotoxic T cells. RCC is also unusually vascular, overexpressing an giogenic factors, principally VEGF, but also bFGF and TGF- . Grading is by the Fuhrman system (1 = well differentiated; 2 = moder- ately differentiated; 3 and 4 = poorly differentiated), based on nuclear size, outline, and nucleoli. It is an i ndependent prognostic factor. RENAL CELL CARCINOMA: PATHOLOGY, STAGING, PROGNOSIS 247 Staging Staging is by the TNM classi \201 cation following histological con \201 rmation of the diagnosis (see Table 7.4 and Fig. 7.1). All rely upon physical examina- tion and ima ging; the pathological classi \201 cation (pre \201 xed \200\230p \200\231) corresponds to the TNM categories. Staging is the most important prognostic indicator for RCC. Table 7.4 UICC 2009 TNM staging of RCC Tx Primary tumor cannot be assessed T0 No evidence of primary tumor T1 Tumor (cid:100)7cm, limited to the kidney a. (cid:100)4cm b. \200\2237cm T2 Tumor >7cm, limited to the kidney 7 \200\22310cm >10cm T3 Tumor extends outside the kidney, but not into ipsilateral adrenal or beyond Gerota \200 \231s (perinephric) fascia T3a Tumor invades renal sinus, renal vein, or perinephric fat T3b Tumor grossly extends into subdiaphragmatic IVC T3c Tumor grossly extends into supradiaphragmatic IVC, atrium or invades wall of vena cava T4 Tumor directly invades beyond Gerota \200\231s fascia into surrounding structures, e.g. ips ilateral adrenal, liver Nx Regional (para-aortic) lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single regional node N2 Metastasis in 2 or more regional nodes Mx Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis present Prognosis (Table 7.5) Factors for RCC survival include: - - - - TNM Fuhrman grade, necrosis, or sarcomatoid features. Performance status and systemic sympt oms. Molecular factors (under investigation: expression pro \201 ling). stage. VEGF, HIF-1, p53, gene CHAPTER 7 Urological neoplasia 248 (a) Adrenal gland Liver Perinephric (Gerota \200\231s) fascia Renal veins Kidney Tumor Inferior vena cava Ureter (b) (c) (d) Fig. 7.1 Renal cell carcinoma staging. (a) Primary tumor limited to kidney (T1/ T2). (b) Pr imary tumor invading perinephric fascia or adrenal gland (T3a). (c) Primary tumor extends i nto renal veins or IVC below diaphragm (T3b); above diaphragm/into right atrium (T3c); outs ide perinephric fascia (e.g. into liver, bowel, or posterior abdominal wall) (T4). (d) N an d M staging: multiple para-aortic/para- caval nodes; pulmonary, bone, or brain metastases ( T1 \200\2234N2M1). RENAL CELL CARCINOMA: PATHOLOGY, STAGING, PROGNOSIS 249 Table 7.5 RCC: 5y survival Organ-con \201 ned T1 N0M0 (AJCC stage I) 70 \200\22394%(depends on grade) Organ-con \201 ned T2 N0M0 (AJCC stage II) 50 \200\22375% Locally advanced T3 or N1 (AJCC stage III) 22 \200\22370% (25% in T3c IVC wall invasion) Metastatic T4, N2 or M1 (AJCC stage IV) 5 \200\22340% A prognostic nomogram has been developed to predict 5y probability of treatment failure for patients with newly diagnosed RCC. It is available for download at: M http://www.mskcc.org /mskcc/html/6156.cfm. CHAPTER 7 Urological neoplasia 250 Renal cell carcinoma: epidemiology and etiology Renal cell carcinoma (RCC) (also known as h ypernephroma since it was erroneously believed to originate in the adrenal gland, clear cel l carci- noma, and Grawitz tumor) is the commonest of renal tumors, consti- tuting 2 \200 \2233% of all cancers. It is an adenocarcinoma, accounting for 85% of renal malignancies; t he remainder are TCC (10%), sarcomas, Wilms \200\231, and other rarities (5%). It occurs in sporadic (common) and hereditary (rare) forms. Incidence, mortality, and survival In the UK, both incidence and mortality are rising, with 8228 patients diagnosed (compared with 3676 patients in 1999) and 3848 deaths in 2008. RCC is the most lethal of all urological tumors, approximately 50% of patients dying of the co ndition; it is the tenth most common cause of cancer death. Relative 5y survival, heavily d ependent on stage at diagnosis, is 50% while 10y survival fell to 43% for UK patients. Surv ival has increased since the 1970 \200\231s. As with most cancers, there is a steady fall i n survival with advancing age at diagnosis: rates for patients under 50y are twice that for patients over 80. Etiology Males are affected 1.5 times as commonly as females; peak incidence of sporadic RC C is between 60 \200\22370y of age. Environmental Studies have shown associations with cigarette pipe or cigar smoking (1.4 \200\2232.3-fold risk), renal failure and dialysis (30-fold risk), obesity, hyper- tension (1.4 \200\2232-fold risk), urban dwelling, low socio-economic status, to- bacco chewing, oc cupational asbestos and cadmium exposure, the analge- sic phenacitin, thorium dioxide, and sickle cell trait (medullary carcinoma only). Nutrition is considered important: Asian migr ants to western coun- tries are at increased risk of RCC; vitamins A, C and E, and fruit/ve getable consumption are protective. Anatomical risk factors include polycystic and horsesho e kidneys. Genetic VHL syndrome: 50% of individuals with this autosomal dominant syn- drome, character ized by phaeochromocytoma, renal and pancreatic cysts, and cerebellar haemangioblastoma, de velop RCC, often bilateral and mul- tifocal. Patients typically present in 3rd, 4th, or 5th decades. VHL syn- drome occurs due to loss of both copies of a tumor suppressor gene at ch romosome 3p25 \200\22326; this and other 3p genes (RASSF1A; PBRM1) are implicated in causin g >80% of sporadic RCCs. Inactivation of the VHL gene leads to effects on gene transcriptio n, including dysregulation of hypoxia inducible factors 1 and 2, intracellular proteins tha t play an important role in the cellular response to hypoxia and starvation. This results i n an upregulation of VEGF, the most prominent angiogenic fac- tor in RCC, explaining why so me RCCs are highly vascular and enabling targeted treatment approaches (see b p. 258). RENAL CELL CARCINOMA: EPIDEMIOLOGY AND etiology 251 A papillary variant of RCC also has an autosomal dominant familial com- ponent, characteriz ed by trisomy 7 and 17, with activation of the c-MET proto-oncogene. c-MET is the receptor tyrosone kinase for hepatocyte growth factor which regulates epithelial proliferation and d ifferentiation in a wide variety of organs, including the normal kidney. Mutations of the FLCN gene on chromosome 17p results in the auto- somal dominant Birt \200 \223Hogg \200\223Dub syndrome. This rare disease is charac- terized by benign tumors of h air follicles (mainly facial), pulmonary cysts, pneumothoraces, and renal tumors, including oncocytomas and RCC. Screening for RCC Aside from investigating the upper urinary tracts for non-visible asympto - matic haematuria, there is little to support population screening for RCC using USS, give n that a large study of 10 000 men aged >40y yielded RCC in only 0.1%. CHAPTER 7 Urological neoplasia 252 Renal cell carcinoma: presentation and investigation At least half of all RCCs are detected incidentally on abdominal imaging carried out to investigate vague or unrelated symptoms. Thus, there has been a downward stage migration at diagnosis since ultrasound and CT scanni ng came into routine use in the 1980 \200\231s. Presentation History: of the symptomatic RCCs diagnosed, 50% of patients present with haema turia, 40% with loin pain, 25% of patients notice a mass, and 30% have symptoms or signs of metastatic disease, including bone pain, night sweats, fatigue, weight loss, and haemoptys is. Less than 10% of pa- tients exhibit the classic triad of haematuria, pain, and abdomina l mass. Less common presenting features include pyrexia of unknown origin (9%), acute varic ocoele due to obstruction of the testicular vein by tumor within the left renal vein (2 \200\2235%), and lower limb oedema due to venous obstruction. Paraneoplastic syndromes due to ectopic hormone secretion by the tumor occur in 30% of patients; these may be associated with any disease stage (Table 7.6). Table 7.6 Paraneoplastic syndromes Syndrome associated with RCC Cause Anemia (30%) Haematuria, chronic disease Polycythaemia (5%) Ectopic secretion of erythropoeitin Hypertension (25%) Ectopic secretion of renin, renal artery compression, or AV \201 stula Hypoglycaemia Ectopic secretion of insulin Cushing \200\231s syndrome Ectopic secretion of ACTH Hypercalcaemia (10 \200\22320%) Ectopic secretion of parathyroid hormone-like substance Gynaecomastia, amenorrhoea, reduced libido, baldness Ectopic secretion of gonadotrophins Stauffer \200\231s syndrome: hepatic dysfunction, fever, anorexia Unknown; resolves in 60 \200\22370% of patients post-nephrectomy Clinical examination: may reveal abdominal mass, cervical lymphadenopa- thy, non-reducing v aricocele, or lower limb oedema (both suggestive of venous involvement). RENAL CELL CARCINOMA: PRESENTATION AND INVESTIGATION 253 Investigations - Radiological evaluation described on b pp. 242 and 270, together with discussion of the rol e of needle biopsy. Urine cytology and culture FBC Serum creatinine and electrolytes, calci um, and liver function tests : are essential. : of haematuria, loin pain, and renal mass is - : should be normal. : may reveal polycythaemia or anemia. When RCC is diagnosed radiologically, staging chest CT will follow and bone scan, if clinic ally indicated. Any suggestion of renal vein or IVC in- volvement on CT may be further inve stigated with Doppler USS or MRI. Angiography may be helpful in planning partial nephrectom y or surgery for horseshoe kidneys. Contralateral kidney function is assessed by the uptake and excretion of CT contrast and the serum creatinine. If doubt persists, isotope renograp hy is used. CHAPTER 7 Urological neoplasia 254 Renal cell carcinoma (localized): surgical treatment I Surgery is the mainstay of treatment for RCC. Increasing diagnosis of smaller, early stage RCC and the concept of cytoreductive surgery for advanced RCC has impacted on investigation and surgical treatment strat- egies while reduction in mortality remains elusive. Localized disease \200\224partial nephrectomy (PN) is now the gold standard Nephron-sparing surgery without adrenalectomy is indicated as follows. - Absolute tumors. : multifocal RCC, particularly if the patient has VHL Relative syndrome, a iming to avoid renal replacement therapy; contralateral kidney threatened by another condit ion. Elective unless the tumor is close to the pelvicalyceal system. : tumor in single anatomical/functioning kidney; bilateral : T1 (up to 7cm) tumors with a normal contralateral kidney Three-dimensional CT reconstructions provide the surgeon with preop- erative identi \201 c ation of the arterial anatomy. Open transperitoneal or loin approaches are used. The renal artery is clamped and the kidney packed with crushed ice to avoid warm ischaemia. If the su rgical margin is clear of tumor, the depth of the margin (>1mm) does not in \202 uence ris k of local recurrence (which is up to 10%). PN for T2 RCC carries increased risk of local r ecurrence. Speci \201 c complications include urinary leak from the collecting system and hyper \201 ltration renal injury which may eventu- ally require renal replacement therapy; proteinuria is a prognostic sign. Oncological outcomes are comparable with radical surgery . Robot-assisted or laparoscopic PN is becoming the standard approach in centers with experti se for small peripheral RCC. Oncological out- comes are comparable with open PN. Disadvanta ges include a longer (up to 30min) warm ischaemia time (this is less with the Da Vinci ) a nd increased peroperative complications. Functional recovery is within hours after 20min of warm ischaemia and days after 30min; it may take several weeks after 60min of clamping. At tempts at achieving cold ischaemia using renal artery or retrograde ureteric infusions or c rushed ice in endo-bags have proved dif \201 cult and laborious. Some enthusiasts are perf orming \200\230zero ischaemia \200\231 laparoscopic PN and accepting signi \201 cant bloo d loss. Radical nephrectomy This remains the gold standard treatment of T2 \200\2234 RCC and in T1 RCC in patients unsuitable for PN. There is no difference in outcome favoring a speci \201 c surgical approach so the default is now laparoscopic for local- ized RCC. In the case of upper pole or T2 tumors, adrenalectomy is also necessary. - Laparoscopic approach : has become a widely available option in centers treating RCC. Appro aches are either transperitoneal or retroperitoneal. The specimen is removed whole or morse lated in a bag through an iliac incision. Advantages over open surgery include RENAL CELL CARCINOMA (LOCALIZED): SURGICAL TREATMENT I 255 less pain, reduced hospital stay, and quicker return to normal activity. Morbidity is repor ted in 8 \200\22338% of cases, including PE and poorly understood effects on renal function . Long-term (10y) results are equivalent to those obtained by open surgery; cancer-specific survival (CSS) was 92% in a mixed US series. Open approach advanced RCCs. The aim is to re move all tumor with adequate surgical margins by excising the kidney with Gerota \200\231s fascia, vein tumor thrombus, adrenal gland (if invasion indicated by imaging), and limited regional nodes for staging. Surgical approach is transperitoneal (good access to hilar vess els) or thoracoabdominal (for very large or T3c tumors). Following renal mobilization (avoi ding tumor manipulation), the ureter is divided; ligation and division of the renal artery or arteries should ideally take place prior to ligation and division of the renal vein to p revent vascular swelling of the kidney. Complications include mortality up to 2% from bleed ing or embolism of tumor thrombus; bowel, pancreatic, splenic, or pleural injury. : this should be carried out only for large or locally Post-operative follow-up aims to detect local or distant recurrence to permit additional tr eatment, if indicated; incidence is 7% for T1N0M0 RCC, 20% for T2N0M0, and 40% for T3N0M0. After partial nephrec- tomy, concern will also focus on recurrence in the remnant kidney. T here is no consensus regarding the optimal regime, typically stage-dependent 6-monthly clin ical assessment and annual CT imaging of chest and abdo- men for 5 \200\22310y. Post-operative prognosis The Leibovich scoring system groups patients into low, intermediat e, or high risk for development of metastasis at 1, 3, 5, 7, and 10y according to tumor sta ge, size, nuclear grade, presence of necrosis, and regional nodal status. This is particula rly useful when selecting patients for trials of adjuvant therapy.1 A nomogram combining prognostic factors for prediction of 5y recur- rence risk following su rgery can be downloaded at: M http://www.mskcc. org/mskcc/html/6156.cfm 1 Leibovich BC, Blute ML, Cheville JC, et al. (2003) Prediction of progression after radica l neph- rectomy for patients with clear cell renal cell carcinoma: a strati \201 cation to ol for prospective clinical trials. Cancer 97:1663 \200\22371.