13 Jane Hendry1, Bhavan P. Rai6, Alan S. McNeill3, Ghulam Nabi2, Jens‐Uwe Stolzenburg4, Khaver Qureshi1, Nkem Umez‐Eronini1, Grenville Oades1, and Omar M. Aboumarzouk1,5 1 Glasgow Urological Research Unit, Department of Urology, Queen Elizabeth University Hospital, Glasgow, UK 2 NHS Tayside, Dundee, Scotland, UK 3 Department of Urology, Western General Hospital, The University of Edinburgh and NHS Lothian, Edinburgh, UK 4 University of Leipzig, Leipzig, Germany 5 University of Glasgow, School of Medicine, Dentistry & Nursing, Glasgow, UK 6 Urology Department, Freeman Hospital, Newcastle, UK In the last two decades, there has been a considerable rise in the number of renal masses incidentally detected. Although the majority of these masses have distinct clinical and radiological features, a minority share similar patterns leading to diagnostic uncertainty. A clear understating of the evaluation, current management approaches, and awareness of the evolving evidence pertaining to renal masses is essential. With improvement in imaging modalities and pathological assessment techniques, a more precise diagnosis can be made. In the last few years, we have observed a significant evolution in surgical techniques with various minimally invasive approaches showing promising outcomes. The understanding of the molecular basis of many of these lesions is paramount. Translational research has led to the introduction of various novel targeted therapies in an attempt to improve oncological outcomes. Upper urinary tract (UUT) tumours are uncommon cancers of the renal pelvis, calyces, and ureter. Upper urinary tract urothelial (transitional) cell carcinomas (UT‐UCC) are notoriously aggressive cancers with a propensity for local recurrence and advancement to higher‐stage disease. Additionally, they have a tendency for synchronicity and metachronicity. They bear histological resemblance to bladder urothelial cancer. Accurate diagnosis and staging is reliant on a combination of cytology, endoscopic, and UUT imaging modalities. The treatment of UT‐UCC depends on the stage, grade, and volume of the disease. Radical nephroureterectomy (RNU) with ipsilateral cuff excision is the most oncological efficacious treatment option for localised UT‐UCC. Other treatment options for UT‐UCC include ureteroscopic and percutaneous ablation and segmental resection. The role of adjuvant treatment and systemic chemotherapy remain unclear and continue to be under the realms of future research. Keywords: renal cysts; renal cancer; kidney cancer; ureteric cancer; nephrectomy; nephroureterectomy; cryotherapy; radiofrequency ablation Renal masses can be broadly classified into (Table 13.1): (i) malignant, (ii) benign, and (iii) inflammatory. This chapter will comprehensively discuss common types of malignant and benign lesions. Discussion on inflammatory masses was addressed in Chapter 12. Table 13.1 Pathology of renal masses. Renal cell carcinoma (RCC) accounts for nearly 90% of all renal malignancies, making it the most common solid renal lesion. RCC accounts for up to 2.5% of all adult malignancies and accounts for 1–2 per 100 000 of all cancer‐specific mortality worldwide [1–3]. It is most common in the sixth and seventh decades of life. RCCs have a preponderance for male gender with a male to female ratio of around 3:2 [1–3]. Smoking (especially pipe or cigar smoking), obesity, and hypertension have all been implicated in the development of RCCs. The relative risk for male and female smokers for the development of RCC was 1.54 and 1.22, respectively [2]. Smoking cessation for 10–15 years also appeared to reduce the chance of one developing RCC [2, 4–6]. Although smoking is the principal risk factor for RCC, obesity is on the rise as a direct risk factor. Interestingly however, the prognosis of RCC in patients who are obese is better than in patients who are not obese [2, 4, 5, 7]. Again weight loss and optimisation of hypertension has been suggested to reduce chances of RCC. Patients with a family history of RCC in a first‐degree relative have been reported to have more than a fourfold increased risk of RCC [8, 9]. Familial syndromes with distinct heredity forms of RCC have also been described. Von Hippel–Lindau (VHL) is an autosomal dominant disease that affects 1 in 36 000 live births and is manifested by a group of tumours including: (i) clear cell RCC, (ii) central nervous system haemangioblastoma, (iii) pheochromocytoma, (iv) retinal angiomas, (v) rarely pancreatic cysts or tumours and (vi) epididymal cystadenomas [10–12]. RCC develops in about 50% of patients with the disease, typically in their third to fifth decades of life [10–12]. The genetic characterisation of VHL disease is the loss or mutation of both alleles of the VHL tumour suppressor gene located at chromosome 3p25‐26 [13, 14]. This has been confirmed as the cause for RCC development [13, 14]. Three variants exist: Type I VHL has a low risk of pheochromocytoma; type II VHL has a high risk of pheochromocytoma and is subdivided into type IIa: low risk of developing RCC, type IIb: high risk of RCC, and type IIc: risk of pheochromocytoma only; and type III VHL disease which is an autosomal recessive form. The VHL protein or VHL complex normally targets transcription factors such as the hypoxia inducible factors (HIF) 1 and 2 (which play a role in the cellular response to hypoxia and starvation). The inactivation of the VHL gene leads to disregulation of the HIF‐1 and ‐2. HIF ‐1 and ‐2 accumulation leads to up‐regulation and overexpression of vascular endothelial growth factor (VEGF) mainly; however, in addition to this change, overexpression in expression of platelet‐derived growth factor and transforming growth factor‐α have been reported and have also been implicated in RCC. Familial papillary RCC or hereditary papillary RCC (HPRCC) is an autosomal dominant disease characterised by trisomy for chromosomes 7 and 17 and abnormalities in chromosomes 1, 12, 16, 20, and Y [15, 16]. Activation of a proto‐oncogene c‐MET located on chromosome 7q31 leads to production of hepatocyte growth factor, which acts through the tyrosine kinase receptors, which leads to cellular proliferation and tumorigenic effects on organs [15–19]. Hereditary leiomyomatosis and RCC syndrome is an autosomal dominant disease that is manifested by cutaneous leiomyomas, uterine fibroids, and papillary RCC [11, 20]. Normally developing in the fourth decade of life, it is characterised by loss or mutation of the fumarate hydratase tumour suppressor gene located on chromosome 1q42–44 [20]. Unlike the previous two hereditary diseases, HLRCC syndrome is more aggressive and invasive [18, 19]. Birt‐Hogg‐Dubé (BHD) Syndrome is an autosomal dominant disease manifested by cutaneous fibrofolliculomas (i.e. hair follicle hamartomatous tumours), lung cysts, pneumothoraxes, and chromophobic RCC [11, 15, 20, 21]. The RCC develops in the fifth decade of life and is characterised by loss or mutation in the BHD gene located on chromosome 17p11.2, which encodes for folliculin a tumour suppressor gene [21, 22]. RCCs are adenocarcinomas originating from the epithelium of the renal tubules. Through continual understanding of tumour histology and genetics, the subtypes of RCCs have drastically changed in the last decade [16]. Generally there have been three more common subtypes of RCC: (i) clear cell (80–90%), (ii) papillary (6–18%) (Type 1 and Type 3), and (iii) chromophobe (4–6%) [16, 23]. The classification has recently been expanded from the previously adopted World Health Organisation histological classification based on the advances and development in cytogenetics and immunohistochemistry (Table 13.2) [16]. Table 13.2 Renal cell carcinoma subtype histological classification. More than half of RCCs are incidentally detected when imaging is undertaken for another condition and are asymptomatic on presentation [23, 24]. The classical presentation of RCC is a combination of flank pain, palpable loin mass, and visible haematuria. This triad is a reflection of advanced disease and is fortunately uncommonly seen in contemporary urological practice [24, 25]. Table 13.3 depicts the more common clinical features encountered [24–30]. Table 13.3 Clinical features of renal cell carcinoma. RCC can be associated with paraneoplastic syndromes, which can be particularly distressing. The normal physiological function of the kidney (i.e. production of renin, erythropoietin, prostaglandins, and 1, 25‐dihydroxycholecalciferol) is inappropriately increased in RCC. The increased production of these hormones and proteins give rise to an array of symptoms (Table 13.3). In addition to the normal kidney hormones produced, RCCs also have been found to produce adrenocorticotropic hormone giving rise to Cushing syndrome, prolactin leading to galactorrhea, insulin leading to hypoglycaemia, and gonadotrophins leading to gynecomastia, decreased libido in men or hirsutism, amenorrhea, and male pattern balding in women [30]. These symptoms tend to resolve once the diseased kidney has been removed. However, persistent symptoms would indicate residual or metastatic disease, implying a poorer prognosis. The majority of RCCs are initially diagnosed by an ultrasound or a computed tomography (CT) scan while investigating a different medical ailment [27]. Ultrasonography is the most common investigation for haematuria and can accurately distinguish between cystic and solid mass (Figure 13.1). Figure 13.1 Ultrasounds of different‐sized renal cell carcinomas (RCCs). Triple‐phase contrast CT scans are the gold standard renal characterisation imaging modality. Enhancement seen on the CT scan is an important criteria to distinguish between benign and malignant complex cystic masses (Figure 13.2) [31]. A difference in Hounsfield units of 15 or more between a pre‐ and postcontrast CT image of the mass is considered enhancement and strongly suggestive of a malignancy. A chest and abdominal CT scan is indicated once a malignancy is suspected for staging. This can adequately assess the extent of the primary tumour, anatomical consideration such as renal artery location, and the presence of accessory arteries, venous, and lymphatic involvement, presence of metastases, as well as assess the contralateral kidney. Figure 13.2 Computed tomography (CT) scans of different staging of renal cancer: (a and b) T1; (c and d) T2; (e) T3; (f and g) T4. Investigating bone and brain metastasis is indicated only if there are symptoms; otherwise they are not required [31–34]. In addition, a renogram and renal function assessments are carried out in patients with impaired renal function to best optimise their management plan. Angiography is rarely needed; however, it can accurately delineate the arterial supply of the kidney and tumour and can be done during renal artery embolisation (Figure 13.3). CT scans are also used during follow‐up post‐treatment to detect recurrences (Figure 13.4). Figure 13.3 Angiogram showing (a and b) tumour circulation followed by embolisation; (c and d) renal circulation followed by embolisation. Figure 13.4 Computed tomography (CT) showing (a and b) tumour recurrence near nephrectomy bed (c and d) lymph node recurrence. If a CT is contraindicated because of an allergy to the contrast medium, renal impairment, equivocal venous involvement, or if the patients is pregnant, a magnetic resonance image (MRI) scan can also accurately characterise the mass (Figure 13.5). MRI is superior to CT in establishing whether or not invasion into adjacent structures is present, in addition to a detailed delineation of the vasculature (Figures 13.5 and 13.6) [31, 32, 35–38]. Figure 13.5 Magnetic resonance image (MRI) showing (a) right renal simple cyst (b) left kidney renal cell carcinoma (RCC) (c and d) left renal vein RCC. Figure 13.6 Tumour invading the inferior vena cava: (a–c) computed tomography (CT) scan (d) magnetic resonance image (MRI). The role of percutaneous renal core biopsy has evolved over the last few years. Concerns such as diagnostic inaccuracy and complications (such has bleeding and pneumothorax) have been largely mitigated by the improvement in image guidance techniques. Furthermore up to 20% of T1a renal tumours are benign, and hence, aggressive surgical intervention maybe needless in these patients. Some of the specific indications for image guide renal biopsy include: The tumour, node, and metastasis (TNM) classification has been adopted for RCC staging based on the primary tumour, lymph node involvement, and presence of metastasis (Table 13.4) (Figure 13.7) [39]. The Fuhrman (F) nuclear grade has been used for histological grading based on the nuclear size, outline, and nucleoli [40]. The Fuhrman grading system groups RCCs into four categories: Table 13.4 TNM classification of renal cancer. Figure 13.7 Staging of adenocarcinoma of the kidney (see text for further details). The classification allows for a distinction for low‐grade disease (F1 and 2) and high‐grade disease (F3 and 4) (Table 13.5) [41, 42]. Table 13.5 Fuhrman (nuclear) grading system. Despite the advancement in our understanding of RCC and its management, 20–40% of patients with localised disease develop recurrence even with optimal surgical excision [43]. Important prognostic factors in assessing the likelihood of disease recurrence and survival rates are the TNM classification, histological grading (Fuhrman grade), pathological subtype, and the patients overall health status and comorbidity [40, 43–45]. The presence of sarcomatoid or rhomboid differentiation, tumour necrosis, and microvascular invasion features indicate a poorer prognosis [42]. Using various prognostic factors or nomograms have been developed, which can aid clinicians on management plans by predicting the likelihood of disease recurrence and survival [43, 45–47]. There is not yet consensus on one standardised nomogram; however, their importance in predicting cancer survival is evident, and therefore, they are commonly used in clinical practice to guide treatment decision making [43, 45–48] There is a wide array of treatment options available for patients with RCCs. These include Factors influencing treatment of renal tumours are tumour stage, renal function, function of contralateral kidney, availability of local expertise, and associated comorbidities. Contemporary evidence would suggest that partial nephrectomy shares oncological equivalence with radical nephrectomy for T1 tumours [49]. Additionally by nephron preservation, partial nephrectomy, irrespective of approach employed, confers an overall survival benefit and improved quality of life (QoL) [49, 50]. It is therefore currently recommended that, if technically feasible, partial nephrectomy should be offered to all patients with T1a and selected T1b tumours. In terms of the approach employed, laparoscopic partial nephrectomy tends to be associated with higher complications compared to the open approach. Open approaches have, therefore, tended to be the favoured option. There is some evidence to suggest that robotic partial nephrectomy may have favourable early outcomes. The eventual approach employed is usually dependent on available local expertise and is discussed on an individual patient basis. Organ‐confined tumours lager than 7 cm (T2) and smaller tumours not suitable for partial nephrectomy should ideally be managed with a laparoscopic radical nephrectomy. Minimal invasive approaches (laparoscopy and robotic) have better immediate outcomes than their open counterpart [50]. Laparoscopic and robotic procedures have similar operative and postoperative outcomes [50, 51], although robotic surgery is potentially less cost effective. Therefore, laparoscopic radical nephrectomy should be the first choice and considered the gold standard if appropriate expertise exists. In expert hands, selected locally advanced cases (T3 or higher) can be managed with a laparoscopic approach, although the majority are managed with open approaches, particularly if there is venous involvement. In some of cases RCC, tumour thrombus grows into the renal vein and can extend into the inferior vena cava and even into the right atrium of the heart. The resulting venous tumour thrombus occurs in up to 10% of cases with cardiac involvement occurring in at least 1% of cases. This can give rise to clinical features of venous occlusion such as lower limb oedema, nonreducing varicocele, or isolated left‐sided varicocele, dilated superficial vessels (dilated to accommodate the increased venous drainage required), or the thrombus might embolise and lead to signs of a pulmonary tumour embolus [52–54]. The management of such advanced disease requires thorough preoperative planning of the surgery and collaborative involvement of cardiovascular and hepatic surgeons. The need for vascular bypass depends on the level of tumour thrombus. The described levels of venous involvement are: Despite the higher stage of the disease (Table 13.4), five‐year survival rates have been reported to be between 30 and 75% of patients that undergo a radical nephrectomy and tumour thrombectomy [52, 53]. However, the procedure comes with significant morbidity (8–39%) and mortality (2–13%). Adrenalectomy improves oncological outcomes only if there is radiological or intra‐operative evidence of local invasion or metastasis, and hence, is only indicated only in these situations [49]. The role of template lymphadenectomy remains debatable, and it is currently not routinely recommended and should only be carried out if there are palpable or enlarged nodes. Routine preoperative embolisation does not improve outcomes; however, in patients who are surgically unfit with a nonresectable cancer and significant symptoms, palliative embolisation can be considered [55–57]. The anterior approach of a radical nephrectomy includes an incision through a midline or transverse; the colon and duodenum are reflected medially. The renal artery is tied in continuity before ligating and dividing the renal vein (Figure 13.8). Figure 13.8 (a) On the right side the colon and (b) duodenum are mobilised medially to reveal (c) the inferior vena cava and the right renal vessels. (d) The right renal artery is ligated in continuity. On the right side when there is a very large tumour, the renal artery can be dissected on the left side of the vena cava where it lies between the aorta and vena cava (Figure 13.9). On the left side, the left renal artery may be located behind the duodenojejunal flexure. If necessary, access may be improved by dividing the inferior mesenteric vein (Figure 13.10). Figure 13.9 The right renal artery may be ligated in continuity where it lies between the inferior vena cava and the aorta. Figure 13.10 (a and b) With large tumours the left renal artery may be found by dividing the peritoneal reflexion over the lateral aspect of the duodenum, if necessary dividing the inferior mesenteric vein. In approaching the renal veins, watch out for large lumbar veins which can enter the renal vein just where it joins the vena cava, whereas on the left side, a double vein encircling the aorta is a common anatomical variant (Figure 13.11). Figure 13.11 A large lumbar vein often enters the back of the left renal vein, which may encircle the aorta. For large tumours of the upper pole of either kidney, a 10th rib thoracoabdominal incision may give good access (Figure 13.12). However, many surgeons have adopted a ‘rooftop’ subcostal incision (supra 12th or 11th rib) which gives better access with a smaller incision. Be wary of the pleura posteriorly. Figure 13.12 Tenth rib thoracoabdominal approach to the kidney. (a) The anterior part of the incision is made first, to make sure the tumour is operable; and (b) the incision is carried back along the 12th rib. If the periosteum is stripped off the upper border of the rib there is no need to resect it. Once the vessels have been secured, the kidney and all its surrounding tissues within the envelope of Gerota fascia are removed. For a partial nephrectomy, expose the kidney through an adequate incision. Tape the renal artery and occlude it with a vascular clamp (Figure 13.13). Remove the tumour with a good margin of healthy tissue. Before the renal artery is unclamped, vessels in the cut surface of the kidney are secured by meticulous suturing to achieve haemostasis. Remove the clamp and identify and control any remaining vessels. Figure 13.13 Partial nephrectomy. (a) After clamping the renal artery, a clean guillotine amputation is made well clear of the tumour. (b and c) Haemostasis is obtained by suture ligature of every cut artery and vein. For tumours in the middle third of the kidney, a similar procedure can be carried out, taking a wedge of parenchyma. When a prolonged dissection is anticipated, cooling of the kidney with sterile ice slush protects function. Management of tumour in the renal vein depends on how far it has grown into the inferior vena cava. Often only a small finger of tumour thrombus protrudes into the vena cava from a cancer in the right kidney. On the right side, having ligated the right renal artery in continuity, the back of the vena cava is exposed by dividing the lumbar veins. The vena cava above and below the right renal vein and the left renal vein are all secured with a tourniquets (Figure 13.14). Only then is the cava opened, the tumour thrombus extracted and the vein sutured (Figure 13.15). Figure 13.14 When there is a tumour in the right renal vein and vena cava, after ligating the right renal artery, the cava and left renal vein are secured with tapes. Figure 13.15 (a) The vena cava is opened, (b) the tumour is extracted, and the cava is closed. (c) If the tumour thrombus is limited to the renal vein a Satinsky clamp may be applied to the inferior vena cava after (d) making sure the Rummel tapes are in readiness. If the thrombus is growing into the edge of the cava, it is necessary to remove a cuff of cava along with the renal vein. If the whole thickness of the vena cava is invaded by tumour, it is safe to remove a segment of the vein, knowing that collateral venous circulation will prevent infarction of the opposite kidney (Figure 13.16). Figure 13.16 (a) When tumour has blocked the inferior vena cava (IVC), there will be an adequate collateral circulation, and the entire segment of vena cava (b) may be removed. When tumour thrombus is discovered in the left renal vein, it is essential to make a wide anterior approach to gain safe access to the vena cava and the large veins that drain into it (Figure 13.17). Figure 13.17 When the vena cava is invaded by tumour from the left renal vein a wide anterior approach is used (a) the vena cava is (b) taped and opened, the tumour extracted and the cava closed (c and d). If the CT or MRI scans have shown tumour thrombus extending above the liver, the cardiothoracic team should be involved in planning the operation. In principle, a long midline incision is made, first into the abdomen to confirm the preoperative findings and then it is carried up into the chest by splitting the sternum. The inferior vena cava is occluded where it enters the right atrium, unless tumour thrombus has extended into the right atrium. The superior vena cava and ascending aorta are cannulated, and the patient is put on a cardiopulmonary bypass. Thermal ablation includes renal cryotherapy and radiofrequency ablation. Both of which can be performed either percutaneously or laparoscopically [58]. Though this modality option is readily available to all localised RCC disease, it is best suited for a select group of patients. These patients include patients who are elderly or with significant comorbidities who are at a high‐risk surgery, but want active treatment, patients with local recurrence after a partial nephrectomy, or patients with multifocal lesions in a single kidney as part of a hereditary renal cancer [59]. The long‐term oncological outcomes for these approaches remain undetermined. The principle of cryotherapy is rapid freezing of the tissue leads to ice formation of the extracellular space while the intracellular space is initially more resilient to icing. This leads to an increase in the osmolarity in the extracellular space which in turn causes a hypertonic environment, which causes a change in the pH, intracellular solute composition, and protein denaturation [60]. The eventual icing of the intracellular space leads to cellular structural changes and death follows. Following rapid freezing is a gradual thawing then repetition of the cycle, this causes delayed microcirculatory failure which further leads to cellular death through anoxic environment [58, 60, 61]. The freezing temperature required is <−20 °C with a distance of 3.1 mm beyond the edge of the target lesion [60]. Cryotherapy can be done by either CT guidance or during laparoscopy [62]. Radiofrequency ablation uses high‐frequency, alternating current within the target lesion by generating frictional heat, which denatures intracellular proteins resulting in cellular destruction [58, 59, 61, 63]. Temperatures between 45 and 55 °C lead to irreversible cellular damage whereas 55–60 °C result in cellular death. Both these modalities have been reported to have high success rates in ablating the tumour completely with report of 80–100% [61, 63, 64]. Active surveillance is commonly reserved for patients who are elderly, who are unfit, or who haves mall renal masses (<T1a) thought to be benign [65]. Regular active surveillance with serial imaging (ultrasound, CT, or MRI scans) is done to detect any change in size of tumour, which might indicate a progression in the disease and trigger treatment. In a pooled analysis of patients under active surveillance, Smaldone et al. have shown that small renal masses potentially grow at a relatively slow rate; the mean linear growth rate was 0.31 + − 0.38 cm per year with a mean follow up of 33.5 + − 22.6 months, with a mean initial greatest tumour diameter of 2.3 + − 1.3 cm, [66]. However, about 23% of patients displayed no growth at all and only a small proportion (2%) of the masses progressed, while almost 0.02% progressed to metastatic disease [66]. Therefore, it is safe to say that surveillance can be considered as an alternative treatment modality in a select group of patients who are elderly and might have significant comorbidity leading to a limited life expectancy, understanding that intervention might be required if the tumour progresses, and therefore, the risks of comorbidity, risks of intervention, and risks of cancer progression need to be weighed. Furthermore, nephrectomy has shown to have a 9.4% increased survival benefit at five years compared to surveillance, and therefore, surveillance should not be considered in patients who are healthy with small renal masses who can undergo intervention as risk of progression increases with increasing age >75 years of age, in patients with large tumours >4 cm, or tumours increasing in size >0.8 cm per year [66, 67]. Metastatic disease has a poor prognosis, estimated survival of 7–16.7 months with a 10–20% survival at five years [68]. However, treatment modalities exist that have been shown to improve survival outcomes such as immunotherapy or surgical resection. Based on the presence of certain risk factors, patients can be stratified into three groups to aide prediction of survival (Table 13.6) [69]. Table 13.6 Prognostic stratification for survival of patients with metastatic renal cell carcinoma (RCC). The body’s immunity has been believed to play a vital role in cancer control. This can be witnessed when a primary cancer has been resected and metastatic lesions then reduce in size. Furthermore, the presence of Tcytotoxic T cells in resected specimens seems to justify the immunological strategies for treating RCC. This gives the rise to the use of cytokines such as interferons and interleukins in the management of metastatic RCC, specifically clear cell subtype. Interferon‐α has been shown to have a modest survival benefit in that it can reduce the risk of death at one year by 46% and at two years by 36%; however, it has a low chance of shrinking cancers with a partial remission seen only in 12.5% of patients [70]. Nonetheless, based on certain risk factors, prognostic stratification for survival can be predicted that allows management to be tailored (Table 13.7) [29]. Trials comparing anti‐angiogenic drugs have shown superiority to interferon‐α, and therefore, its use has been limited to a select group of patients (those with good performance status, clear cell RCC, and lung metastases only) [71–74]. Table 13.7 Prognostic stratification for survival of patients with metastatic renal cell carcinoma treated with interferon‐α. Interleukin‐2 has been used for metastatic RCC since the 1980s, and although it does have modest survival benefits, it is associated with significant toxicity. Furthermore, no added survival benefit was found from administering a high‐dose interleukin‐2 compared to a low‐dose interleukin‐2 plus interferon‐α [70]. Its use is limited to a select group of patients with good performance status and clear cell RCC only [74]. Through the mapping of the VHL gene, its role in normal physiology has come to be understood, whereby it encodes for a protein that targets a protein transcription factor, the HIF for proteolysis and degradation [75]. This is important because in hypoxic conditions coupled with VHL gene inactivation, the HIF accumulation leads to subsequent overexpression of genes that cause tumour angiogenesis [75]. With understanding the physiological function of VEGF, specific drugs have been designed for anti‐angiogenic effect, such as tyrosine kinase inhibitors and monoclonal antibodies, against circulating VEGF [75]. Tyrosine kinase inhibitors (TKI) include sorafenib, sunitinib, pazopanib, axitinib, and tivozanib all of which have shown to increase the overall response rate (by 8, 25–40, 27, 44, and 28%, respectively), the progression‐free survival (by 3–4, 6, and five months for sorafenib, sunitinib, and pazopanib), and overall survival rates [76–86]. Sunitinib is recommended as first‐line therapy in favourable and patients with an intermediate risk, whereas sorafenib is recommended as second‐line therapy after cytokine failure, pazopanib as first‐line or after cytokine failure in favourable and patients with an intermediate risk, and axitinib as second‐line treatment after failure of cytokines or other TKIs [74]. Bevacizumab alone and in combination with interferon‐α was found to a higher response rate as well as increased progression‐free survival when compared to an interferon alone or a placebo [71, 87, 88]. Therefore, advocated for use as first‐line therapy in favourable and patients with an intermediate risk [74]. Mammalian target of rapamycin inhibitors (MTOR) include temsirolimus and everolimus, which were both, found to improve overall response rates, survival rates, and progression‐free survival [73, 89, 90]. Temsirolimus is advocated as first‐line treatment in patients in the poor risk group, and everolimus is recommended as second‐line treatment after failure of cytokines or TKIs [74]. Resection of lung metastases increased the five‐year cancer‐specific survival rate from 19 to 74% in patients with lung‐only metastases, whereas complete resection of non‐lung metastases improved five‐year survival from 12 to 33% [91]. Chemotherapy or radiotherapy for metastatic disease do not offer improvement in survival, and their use has not been advocated; however, radiotherapy can be offered for palliative treatment for symptom control [92–94]. Recurrences after radical or partial nephrectomy are dependent on the stage and grade of the cancer [95–99]. Local recurrences in the tumour bed are about 1–4% for tumours <4 cm and up to 10% recurrence for tumours >4 cm [59, 63, 95–100]. Contralateral kidney recurrences, about 1–6%, are associated with positive surgical margins and multifocality for clear cell RCC and the nuclear grade for papillary RCC [95–97, 101]. The recurrence after primary radiofrequency ablation has been reported to be about 6.5–18%, whereas post‐cryoablation recurrence is about 3–7% [59, 63, 102–104]. Early detection with in the first three months to a year is vital because subsequent management can be offered in some cases, such as repeated ablation or surgical resection which can still lead to a cure [48, 95–97, 103, 104]. Although, repeated excision of an isolated local recurrence increases overall survival (30–40%), it comes with an increased risk of surgical complications (13–33%), and therefore, the benefits and risks need to be weighed [95]. All patients who undergo intervention for RCC have to be therefore kept under surveillance with regular blood profiling, clinical evaluation, and imaging. The objective for postintervention surveillance is for evaluation of complications, renal function, detection of loco‐regional recurrence, and metastatic disease. The frequency and period of surveillance is variable and has not been standardised. However, recent validated nomograms have been designed, based on patient risk factors, to classify them into various risk groups. These normograms are a useful guide for clinicians to formulate their follow up protocols (Table 13.8) [74, 105, 106]. Table 13.8 Based on European Association of Urology recommendation for renal cell carcinoma follow up after treatment. CT, computed tomography. This is the most common paediatric malignancy and accounts for 3% of adult cases [107]. Wilms tumour contains metanephric blastema (primitive renal tubular epithelium) and connective tissue. Pathological staging is similar for both adults and children; therefore, management protocols follow similar patterns [107]. Clinically and radiologically, these tumours are similar to RCC and can only be differentiated pathologically by having three cell type appearances a distinctive blastemal stromal, and epithelial cells, [107, 108]. As there is lack of sufficient data on the adult population, the following discussion will be based on paediatric Wilms tumour. Nearly 1% of Wilms tumour is familial; 10% of patients have associated congenital malformations such as Wilms, aniridia, genitourinary malformation, and mental retardation (WAGR) syndrome, Denys–Drash syndrome (male pseudohermaphroditism and renal failure secondary to progressive, diffuse glomerular nephropathy), and Beckwith‐Wiedemann syndrome (i.e. macroglossia, macrosomia, hypoglycaemia, visceromegaly, and omphalocele, in addition to a predisposition to several tumours) [108–110]. Loss of chromosome 11p13 (WT1) tumour suppressor gene was identified as the genetic cause behind the development of the cancer [108, 111]. However, only 5–10% of tumours have been demonstrated to have the WT1 mutation [112]. Other mutations include 11p15.5 (WT2), X chromosome (WTX), and CTNNB1. Tumour‐specific loss‐of‐heterozygosity (LOH) for chromosomes 1p and 16q (WT3) identifies a subset of Wilms tumour who have worse prognosis. The majority are asymptomatic and are incidental findings on general routine check‐ups whereby an abdominal mass is felt [108]. However, they may present with classical features such as fever, haematuria, loin pain, or hypertension. Investigations are similar to those for RCC, whereby ultrasound, urography, CT, and MRI scans are the main stay, and the diagnosis of nephroblastoma is made after surgical resection. Intravenous involvement occurs in 11% of cases with inferior vena caval extension occurring in 6% [108]. Staging is vital as with all other cancers to determine the most appropriate management plan (Table 13.9) (Figure 13.18) [107, 108]. Table 13.9 Staging and risk stratification for Wilms tumour. Figure 13.18 Staging of nephroblastoma of the kidney (see text for explanation of stages I–V). Similar to RCC treatment, radical nephrectomy is considered the gold standard [108]. However, partial nephrectomy is only possible in 8–33% of cases, whereas minimally invasive surgery is still in development in the paediatric cancer field [108]. These tumours can be big and can extend to the contralateral side; therefore, careful resection should be done (Figure 13.19). Figure 13.19 (a and b) Nephrectomy for Wilms tumour: the renal vein on the side of the tumour is often compressed, and it is all too easy to ligate the contralateral renal vein by mistake. Wilms tumours are chemo‐ and radiosensitive and recommendations for treatment are shown in Table 13.10 [107]. Table 13.10 Postoperative treatment of Wilms tumour based on stage and histology from Society of Paediatric Oncology; GPOH, Society for Paediatric Oncology and Haematology. NOTE. Preoperative treatment for metastatic disease: AVA six weeks. A, actinomycin D 15 ug kg−1; A1, adriamycin 50 mg m−2; C, carboplatinum 600 mg m−2; CCSK, clear‐cell sarcomas of the kidney; CR, complete remission; E, etoposide 100 mg m−2; I, ifosfamide 3000 mg m−2; V, vincristin 1.5 mg m−2. Prognosis is good with a 10‐year survival between 78 and 96% for those with favourable histology (Table 13.11) [108, 109]. Poor prognostic indicators are the presence of features of anaplastic tumours (extreme nuclear and cytological atypia), clear cell sarcoma, or rhabdoid tumours. Recurrence will occur in about 15% of those with favourable histology and 50% of anaplastic tumours; metastases most commonly occur in the lung (60%) or abdomen (30%) [108]. Table 13.11 Pathological prediction of survival. Nearly 12% of patients will have metastatic disease at diagnosis, 80% of which are in the lung [108]. However, a good prognosis can still be achieved with metastasectomy followed by chemotherapy. Sarcoma represents <2% of malignant renal tumours, with a peak incidence in the fifth decade of life [113, 114]. Clinical presentation, investigation, and treatments are similar to RCC, and only pathological examination can provide the diagnosis [113, 114]. Various subtypes exists, with leiomyosarcoma comprising 50% of sarcomas; the remaining subtypes include fibrosarcoma, liposarcoma, haemangiosarcoma, osteogenic sarcoma, malignant schwannoma, and Ewing sarcoma. Renal sarcoma has a poor prognosis with nearly 15% of cases having metastatic disease at presentation and a recurrence‐free survival at one year being around 75–100% dropping to 42–48% at three years and 25% at five years, in addition to a metastasis‐free survival at one year around 74% dropping to 29% at three years [113]. Renal involvement with lymphoma or leukaemia is common (47%) in patients suffering with these disease and represent <1% of all renal tumours [115]. Clinical presentation is usually rare (15%) and is similar to RCC clinical features [115]. Treatment is usually along the line of medical therapy with chemotherapy with or without radiotherapy, and therefore, enlisting the consultation of the haematologists and oncologists are the mainstay of treatment [116]. Metastatic foci to the kidney from other organs occur in 7–20% of patients who died of cancer [116]. Clinically the majority of patients are asymptomatic (95%); however, it can present with haematuria (3%) or flank pain (2%) [116]. Scanning typically finds multiple small nodularities that slightly enhance. Biopsy of the lesion can give an indication to the primary [116]. Treatment is usually of the primary cancer, with systemic therapy for more likely palliative care with nephrectomy rarely needed. Other types of malignant renal cancers such as carcinoid and small cell carcinoma are exceedingly rare and are limited to case reports. Renal cysts are the most common renal lesions and make up about 70% of all asymptomatic renal masses. Risk factors for developing renal cysts include being a male, increasing age, having hypertension, renal impairment, or end‐stage renal failure [117, 118]. Renal cysts range from being simple cysts to indeterminate and complex. The Bosniak classification is the most widely accepted method for classing renal cysts based on the cystic wall, presence of septa, calcification, solid components, and enhancing nature of the cyst (Table 13.12) [35]. Table 13.12 Bosniak classification of renal cysts. Though the vast majority of these lesions are detected incidentally on routine imaging of other organs, patients can present with symptoms specific to the cysts. Clinical features usually arise if the cyst gets infected, bleeds, ruptures, or expands. In which case, the patient can present with loin pain, discomfort, haematuria, or signs and symptoms of an infection. Initial renal ultrasound can easily detect the cysts and provide an initial assessment of whether the cysts are simple or complex. If the cysts are irregular, septated, calcified, or seem to have a solid component, then a CT scan is indicated to further characterise the lesion according to the Bosniak classification. In instances where CT was unhelpful, or there is a contraindication to obtaining a CT scan, an MRI can also aid classification of the cysts [35]. This aids the management in that Bosniak I and II lesions are more likely benign, while a classification of IIF will require regular follow up and assessment. However, classes III or IV might require surgical interventions. This is based on the incidence of malignant conversion, whereby class I has an incidence of 1.7%, class II: 18.5%, class III: 33%, and class IV: 92.5% [119]. Though it is recommended that classes III and IV cysts are surgically excised, cysts that cause recurrent or severely distressing symptoms as a result of pressure associated with size or hypertension will also require surgical or radiological intervention [120, 121]. Interventions available are radiological aspiration, sclerotherapy injection, surgical resection, or decortication. However the risk of recurrence and further intervention needs to be discussed with the patients to be weighed against the symptoms. Oncocytoma is one of the most common benign masses composed of epithelial cells with granular eosinophilic cytoplasm. Oncocytomas account for 3–7% of all renal masses [122]. They have a male predominance and are usually solitary and unilateral. Several genes have been associated with oncocytomas. These include loss of chromosome 1, Y, or 14q rearrangement of 11q13, or translocations in the short arm of chromosome 11 [123, 124]. The majority present as an incidental finding of a renal mass; however, they can also present with loin pain or haematuria. Oncocytomas are a diagnostic challenge. They share similar radiological appearances with RCC and core renal biopsies cannot conclusively differentiate between these two entities [125, 126]. More often than not, the diagnosis is made after surgical excision of a tumour thought to be RCC. Oncocytomas have an angiographic ‘spoke wheel’ appearance due to the arterioles around the mass and the capsule gives a ‘lucent rim sign’; however, even these features typical of an oncocytoma are seen in some RCCs [127, 128]. In view of their benign nature, oncocytomas do not require any treatment. However, in real life practise, because of the diagnostic uncertainty, they are often treated aggressively similar to a RCC [129, 130]. A nephron‐sparing approach is recommended to avoid needless loss of nephrons [129, 130]. Their prognosis is good [131]. Angiomyolipomas (AMLs) are benign tumours that account for less than 10% of renal masses and have an incidence of about 13 per 10 000 adults [132]. As the name suggests, AMLs are characterised by containing mature fat cells, with smooth muscles and blood vessels. AMLs are found in patients with tuberous sclerosis (TS), which is an inherited autosomal dominant disorder comprising of adenoma sebaceum, mental retardation, and epilepsy. However, these signs may not necessarily all be present. Almost 60% of TS will develop renal manifestations, AMLs being the most occurring, followed by renal cysts and a small proportion will develop RCCs (4%) [133]. TS2 mutations (chromosome 16p13.3) are associated with AMLs and cysts more than TS1 mutations (chromosome 9q34) [133–135]. As with most benign renal masses, AML is more commonly incidentally detected and asymptomatic [132, 136]. However, nearly 25% of AMLs commonly present with spontaneous rupture and perirenal haemorrhage which can be massive and life threatening (Wunderlich syndrome) [136, 137]. Otherwise, symptoms can be related to an increase in the size of the tumour and present with pain, palpable mass, or bleeding and haematuria [136]. AMLs can be confidently diagnosed on radiological imaging. High‐intensity echogenicity are seen on ultrasounds which are typical for AMLs, whereas on a CT scan they are typically non‐enhancing with −20 to −80 Hounsfield units [138, 139]. Angiography can show increased neovascularization and 50% of AMLs are found to have aneurysms of the vessels [139]. If CT scans are contraindicated, then an MRI scan is indicated. In addition, if the AML is not confidently diagnosed on a CT scan, due to low lipid content of the AML making it appear similar to an RCC, then an MRI can aid the distinction [139–141]. Liposarcomas or an RCC with high lipid content can also be mistaken for AMLs. In which case, a biopsy of the mass may have a role to determine more definitive management. The management of an AML is based on an individual basis depending on the symptomology, tumour size, and the patient’s comorbidity. Increasing tumour size correlates with worsening symptoms as well as a higher risk of haemorrhages [136, 142–144]. If the patient is asymptomatic and the lesion is <4 cm, then conservative management with regular surveillance by either CT or ultrasound is recommended. However, if the mass is >4 cm, or present with significant symptoms, then the patient should undergo nephron‐sparing surgery or arterial embolisation [136, 143–145]. Special care is warranted in pregnant women with an AML, whereby there is an increased risk of growth and bleeding and consideration for early interventions [145]. If there is severe haemorrhage, then selective embolisation can be considered before or as an alternative to surgical exploration because invariably exploration will lead to loss of the kidney [146]. Furthermore, in patients with TS with bilateral AMLs, the mainstay should be conservative management where possible. MTOR inhibitors have been used in this group of patients. The incidence of renal cortical adenoma (RCA) is between 7 and 23% [128, 147]. Although RCA has been traditionally classified as a benign renal mass, recent studies have suggested RCAs are premalignant precursors to papillary RCC [147]. Nonetheless, RCA are mainly asymptomatic and their treatment is still debated. The majority of these adenomas are asymptomatic; however when present, they can mimic the clinical features of RCC. These tumours are rare and difficult to distinguish from RCC; however, if a high level of suspicion exists, then percutaneous biopsy and fine‐needle aspiration of the mass and histological staining can aid the distinction [148–152]. These adenomas express the Wilms tumour marker, WT1; poorly express the α‐Methylacyl‐CoA racemase (highly expressed in papillary RCC); and highly express S‐100 protein (poorly expressed in Wilms tumour and absent in papillary RCC) [148–150]. This is a rare benign tumour that is difficult to distinguish from cystic RCC and Wilms tumour in adults or children, respectively. Therefore, the mainstay of treatment is surgical excision with either radical or partial nephrectomy where possible. Leiomyomas are rare benign lesions (<1.5% of all benign masses) that arise from the renal capsule. Though they may have variable enhancements on CT scan, differentiation from RCC is difficult and have been treated as such. A variant of normal anatomy, when a duplex collecting system or an extrarenal system is present, then an extra‐large normal kidney tissue is apposed in between the junction of the two moieties of the collecting system; these are called columns of Bertin (Figure 13.20). These are easily distinguishable from a pathological renal mass in that they have the same density as the rest of the renal parenchyma. If doubt exists, however, a biopsy will show normal renal tissue. Figure 13.20 A large column of Bertin may mimic a renal cell cancer. Figure 13.21 Ultrasound showing an obstructing renal pelvis transitional cell carcinoma (TCC); computed tomography (CT) of tumour in Figure 13.25. Figure 13.22 Computed tomography (CT) scan showing an obstructing renal pelvis transitional cell carcinoma (TCC). Figure 13.23 Computed tomography (CT) scan showing (a) large filling defect in the ureter (b) with a tortuous dilated ureter proximal to the tumour. Renal artery aneurysms and arteriovenous malformations will be discussed in another chapter. Over the last few decade, there has been significant development in the understanding and management of RCCs. Despite these commendable efforts, several important aspects of RCC remain unclear and are yet to be elucidated. Understandably several trials are underway in RCC addressing various the various day‐to‐day dilemmas encountered in contemporary practice. Sporadic RCC is considered to have heterogeneous genetic basis, and decoding the genetic biology of RCC has been a subject of significant interest in recent years, leading to the development of various targeted therapies. Trials such as the GPKC study are specifically evaluating the genetic basis of papillary RCC. Several trials are currently addressing various permutations of targeted‐therapy regimes. In the current era of targeted therapy, the role of cytoreductive nephrectomy requires clear establishment. The CARMENA trail is comparing outcomes between sunitinib and sunitinib after cytoreductive nephrectomy. The SURTIME Trial is assessing outcomes based on the timing of sunitinib and cytoreductive nephrectomy. Surgical evolution with larger, advanced tumours being managed with minimally invasive and nephron‐sparing approaches has been a common theme in recent years. Furthermore, there continues to work on novel treatment option such as microwave thermotherapy, high‐intensity focused ultrasound (HIFU) and photodynamic therapy (PDT). Unfortunately though, a significant number of these surgical developments have not been scrutinised by high‐quality evidence, highlighting issues with research in surgery in general. In conclusion, the future of RCC remains exciting, although enigmatic. Upper urinary tract urothelial cell carcinomas (UT‐UCC) are aggressive and uncommon cancers. They represent about 5–10% of all urothelial cancers [153, 154]. More than half of UT‐UCCs are invasive at presentation. Concurrent bladder cancer occurs in 8–17 of cases [154–157]. Bilateral UT‐UCCs are observed in 2.5–6% of patients [154–157]. A number of environmental risk factors have been shown to increase the incidence of developing upper urinary tract cancer (UUTC), and these are depicted in Table 13.13 [154, 158]. Table 13.13 Risk factors for developing upper urinary tract cancer. A hereditary form of UUTC has been seen in patients with hereditary nonpolyposis colorectal carcinoma (HNPCC) or Lynch syndrome, an autosomal dominant multi‐organ cancer syndrome caused by germline mutations of mismatch repair genes [159]. Patients with HNPCC have a 6% risk (22× higher than general population) of developing UUTC and should be closely monitored [159]. Patients are at risk of hereditary status if they are diagnosed with HNPCC at <60 years of age, personal history of HNPCC‐associated cancer, have a first‐degree relative <50 years of age with a HNPCC‐associated cancer, or two first‐degree relatives with a HNPCC‐associated cancer [159]. Genetic polymorphism have been linked to an increased risk of developing UUTC as well as faster disease progression. Two such polymorphisms include a variant allele, SULT1A1*2, which reduces sulfotransferase activity, and polymorphism located at the T allele on chromosome 8q24, which has been linked to aggressive UUTC [154, 160, 161]. Research in to the genetics of UUTC is ongoing, especially differentiating it from bladder carcinoma as two distinct entities with two separate pathophysiological processes [160]. Nephrogenic adenomas, urothelial papillomas, and inverted papillomas (IP) are benign lesions. IP recur in about 1–7% of patients and up to 23% of IP have been reported to be associated with UUTCs and therefore require regular surveillance [162]. Other benign upper tract lesions include fibroepithelial polyps, villous adenomas, squamous papillomas, leiomyoma, neurofibromas, fibrous histiocytomas, haemangiomas, periureteric lipomas, and hibernomas [163]. Urothelial (transitional cell) carcinomas (TCC) represent 90–95% of UUTC and are structurally similar to that of bladder TCC [163, 164]. However, due to the naturally thinner muscular layer of the UUT, muscle invasion is seen earlier than in the bladder. Morphological variants of urothelial carcinomas have been reported and are exceedingly rare, limited to case reports or series. Nonetheless, they are associated with higher‐grade disease and a worse prognosis; these include micropapillay, clear cell, neuroendocrine, sarcomatoid, and lymphoepithelial [164–166]. Squamous cell carcinoma (SCC) and adenocarcinomas represent <10% and < 1% of UUTCs, respectively, and are associated with chronic inflammation such as stones or recurrent or chronic infections, as well as chronic obstruction [164, 165, 167, 168]. Sarcomas of the UUT have also been reported. UUTCs can present with visible or nonvisible haematuria (70–80%), flank or renal pain (20–40%), and the presence of an abdominal mass (10–20%) [163, 164]. Alarming systemic symptoms such as anorexia, weight loss, malaise, fatigue, fever, night sweats, or coughs or palpable lymphadenopathy or hepatomegaly are suggestive of metastatic disease [164]. The diagnosis of UUTCs is reliant on a combination of urinary biomarkers, imaging, and endoscopic evaluation. Urine cytology has a sensitivity rate of 20–77% and a high specificity rates of 90–100% in detecting urothelial cancers [169]. Abnormal urine cytology in the presence of a normal bladder cystoscopy is highly suggestive of an UUTC and should be carefully investigated. However, its use in routine practice has been questioned due to the variable sensitivity (due to interobserver discrepancy in analysis and sampling of the specimen) and additional costs [169, 170]. Intravenous urography and ultrasonography (Figure 13.24) have been replaced by CT urography (CTU) with excretory imaging as the first line investigation for UUTC (Figures 13.25 and 13.26) [153]. CTU has a variable sensitivity ranging from 36 to 96% and a high specificity of 96–99% [153, 171]. CTU can accurately detect any thickening of the UUT, filling defects, non‐visualisation of the collecting system, or obstruction. However, it can miss flat lesions such as CIS and dysplasia; hence, why there is variability in the sensitivity for all UUTC [153]. MR urography (MRU) can be used if CTU is contraindicated [171]. Figure 13.24 Ureteroscopy with retrograde urography showing a filling defect in the renal pelvis; computed tomography (CT) of tumour in Figure 13.25. Ureteroscopy and ureterorenoscopy with or without retrograde urography of the UUT allows for visualisation of the ureter and biopsy of the lesion, especially if the diagnosis is uncertain or questionable (Figure 13.24) [153, 172]. Furthermore, taking urine cytology samples directly from inside the UUT has shown to improve its accuracy rates [170]. The use of photodynamic diagnosis has been shown to increase the diagnostic accuracy and detection rates of UUTC, especially flat lesions that could potentially be missed with standard scoping techniques [153, 172]. The morphological classifications of UUTCs are similar to that of the bladder classification [164, 173]. The previous classification according to differentiating grade (G1: well differentiated, G2: moderately differentiated, and G3: poorly differentiated) has been replaced by a more descriptive histological classification system: dysplasia (preneoplastic falling short of CIS), CIS (flat lesions, whose surface epithelium contains cells that are cytologically malignant), and noninvasive papillary tumours (papillary urothelial tumours of low malignant potential, low‐grade papillary urothelial carcinoma, high‐grade papillary urothelial carcinoma, and invasive papillary carcinoma) (Figure 13.25) [163, 164]. Figure 13.25 TNM staging of transitional cell carcinoma of the upper urinary tract. Ta, papillary, non‐invasive; Tis, carcinoma in situ; T1, not invading muscle; T2, invading muscle; T3, invading renal parenchyma or outside muscle; T4, invading outside kidney. The TNM classification of UUTC is depicted in Table 13.14 [163, 164]. Table 13.14 TNM classification of upper urinary tract cancer. TNM, tumour, node, and metastasis. The stage and grade are the most important prognostic factor [174]. The five‐year cancer survival is <50% for pT2/3 disease and < 10% for pT4 [164]. Other prognostic factors implicated in UT‐UCC include [164, 175–178]: Adjuvant treatment Radical nephroureterectomy (RNU) with ipsilateral bladder cuff excision is the gold standard of UUTC [164, 178, 179]. Surgical intervention should not be delayed beyond 45–90 days because there is risk of disease progression with delay beyond this period [164]. Both open and laparoscopic approaches have similar oncological outcomes, although laparoscopic approach has better early surgical outcomes [179]. Ipsilateral ureteric cuff excision is imperative because recurrences in the ipsilateral ureteral stump or orifice range between 30 and 64% [178]. After initial RNU, the bladder cuff can be excised through a transvesical, extravesical, or endoscopic approach [178]. Robotic RNU and bladder cuff excision has emerged to replace laparoscopic approaches [180]. A RNU can be performed employing open, laparoscopic, or robotic approaches. Both extraperitoneal and transperitoneal approaches have equivalent oncological and early surgical outcomes. It has a similar technique as that of a radical nephrectomy with a midline incision; the kidney is mobilised and its pedicle divided. If performed using a laparoscopic approach, the specimen can be removed through an extension of a lower port incision. Various techniques have been descried for ipsilateral bladder cuff excision. In a transvesical approach, the bladder is opened (Figure 13.26) and the whole nephroureterectomy specimen is delivered through the wound. Figure 13.26 (a) The bladder is opened obliquely. (b) An ellipse of bladder is removed with the ureter, taking care to protect the other ureter with a catheter (c) The bladder is closed (d). In an extravesical technique, the entire ureter is dissected till the bladder, and then ureter is clamped with a portion of the bladder. The distal segment is then transected and the bladder is closed. The Semple manoeuvre (endoscopic technique) is the least invasive for tumours arising in the upper part of the ureter [181]. With the patient in the cystoscopy position, the bladder is kept semi‐distended to prevent excessive extravasations. A hook electrode incises a circumferential area of bladder cuff mucosa around the ureteral orifice, followed by endoscopic dissection to the perivesical fat, which leads to detachment of the intramural ureter (Figure 13.27). After the nephrectomy part, the distal ureter, including the bladder cuff, is gently retracted and removed (Figure 13.28). The ureter is checked for complete removal by identifying the coagulated edge of the bladder cuff at the distal ureteral end. A Semple manoeuvre is not appropriate for a tumour in the lower third of the ureter, and it should not be used for ureters that are surrounded by fibrosis because that can cause injury to the common iliac artery. Figure 13.27 Semple manoeuvre. The ureter is resected down to fat with the resectoscope. Figure 13.28 After mobilising the kidney, the ureter is followed down between finger and thumb until its lower end comes free. In recent years with the evolution of endoscopic and laser technology nephron‐sparing approaches have gained popularity. Nephron‐sparing surgery is commonly considered for patients with a single functioning kidney or a patient with renal insufficiency. In patients with normal contralateral kidney, nephron‐sparing surgery can be considered in carefully selected patients with low‐grade and stage disease, which are less than 1 cm in size [164]. Endoscopic management of selected low‐grade disease has similar oncological outcomes and survival rates as RNU [177, 179]. However, 20% of patients will proceed to a RNU [177]. For tumours in the renal pelvis or collecting system, the percutaneous approach can be implemented. Recent evidence has suggested that the application of photodynamic diagnosis assistance has the potential to improve the detection rates of superficial flat lesions [153, 172]. Distal ureterectomy and ureteral reimplantation can be considered for distal ureteric tumours. Ureteral resection of diseased section with ureteroureterostomy can be performed for mid‐upper ureteral tumours. Although nephron‐sparing surgery shares oncological equivalences with RNU for low‐grade, stage, and volume disease, the overall oncological efficacy of the nephron‐sparing tend is significantly inferior to RNU. Furthermore, current investigative modalities are unable to accurately stage and grade UT‐UCC. Hence, it is imperative that patients being treated with nephon‐sparing surgery are kept under strict and stringent surveillance. Instillation of the ureter with bacillus Calmette‐Guerin (BCG) or Mitomycin C in the UUT can be done after conservative treatment of UUTC or for treatment of CIS [182, 183], although no long‐term results are available to verify outcomes. However, a single postoperative dose of intravesical Mitomycin C following RNU reduces the risk of bladder tumours within the first postoperative year, (absolute reduction in risk is 11%, the relative reduction in risk is 40%, and the number needed to treat to prevent one bladder tumour is nine) [184]. Surgery is considered in metastatic disease only as a palliative option. Although evidence to date is scanty, platinum‐based chemotherapy has been suggested to achieve recurrence‐free rate of up to 50% [164, 185]. Meticulously close follow‐up regimes for patients treated both surgically and conservatively are vital to detect recurrences either locally, distantly, or in the bladder (Table 13.15). Although local recurrence after radical surgery is rare, bladder recurrence ranges between 14 and 54% [179]. The local and bladder recurrence rate for patients managed ureteroscopically is 52% and 37% for patients managed with percutaneous endoscopy is 34% and 24%, respectively [177]. Table 13.15 European Association of Urology recommended guidelines for upper urinary tract cancer follow‐up regimes. CT, computed tomography.
Kidney and Ureter Neoplasm
Abstract
13.1 Kidney Neoplasms
Inflammatory
Benign
Malignant
Abscess
Simple renal cysts
Renal cell carcinoma
Infected renal cysts
Oncocytoma
Wilms tumour
Xanthogranulomatous pyelonephritis
Angiomyolipoma
Transitional cell carcinoma
Tuberculosis
Renal cortical adenoma
Squamous cell carcinoma
Metanephric adenoma
Sarcomas
Cystic nephroma/mixed epithelial/stromal tumour
Lymphoma
Leiomyoma
Leukaemia
Vascular masses
Metastatic
13.1.1 Malignant Renal Masses
13.1.1.1 Renal Cell Carcinoma
13.1.1.1.1 Incidence
13.1.1.1.2 Aetiology
Modifiable Risk Factors
Nonmodifiable Risk Factors
13.1.1.2 Von Hippel–Lindau Disease
13.1.1.3 Familial Papillary RCC or Hereditary Papillary RCC
13.1.1.4 Hereditary Leiomyomatosis
13.1.1.5 Birt‐Hogg‐Dubé Syndrome
13.1.1.6 Histological Types
Renal cell tumours
13.1.1.7 Clinical Features
Incidence
Asymptomatic, incidentally detected
50%
Localised or locally advanced disease
6–50%
Systemic or metastatic disease
Paraneoplastic syndrome (ectopic hormone production):
10–40%
13.1.1.8 Diagnosis
13.1.1.8.1 Investigations
Histological Evaluation
13.1.1.9 Staging and Grading
T (Primary Tumour)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
T1
Tumour <7 cm in greatest dimension, limited to the kidney
T2
Tumour >7 cm in greatest dimension, limited to the kidney
T3
Tumour extends into major veins or directly invades adrenal gland or perinephric tissues but not into the ipsilateral adrenal gland and not beyond Gerota fascia
T4
Tumour invades beyond Gerota fascia (including contiguous extension into the ipsilateral adrenal gland)
N (Regional lymph nodes)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single regional lymph node
M (Distant metastasis)
M0
No distant metastasis
M1
Distant metastasis
TNM Staging
Stage I
T1 N0 M0
Stage II
T2 N0 M0
Stage III
T3 N0 M0
T1–3 N1 M0
Stage IV
T4 Any N M0
Any T Any N M1
F 1
Small, round, uniform nuclei (10 μm), inconspicuous nucleoli, look like lymphocytes
F 2
Slightly irregular nuclei, see nucleoli at 40× only, nuclear diameter 15 μm, open chromatin
F 3
See nucleoli at 10×, nuclei very irregular, diameter 20 μm, open chromatin
F 4
Mitoses; bizarre, multilobated, pleomorphic cells plus grade 3 features, macronucleoli
13.1.1.10 Prognosis
13.1.1.11 Treatment
13.1.1.11.1 Surgery
Partial Nephrectomy
Radical Nephrectomy
Procedures
13.1.1.11.2 Ablative Approaches
Cryotherapy
Radiofrequency Ablation
13.1.1.11.3 Active Surveillance
13.1.1.11.4 Systemic Therapies
Risk Factors
Cut‐off point
Karnofsky performance status
<80%
Prior nephrectomy
Absence of prior nephrectomy
Haemoglobin
<lower limit of laboratory reference range
Lactate dehydrogenase (LDH)
>1.5× the upper limit of laboratory reference range
Corrected serum calcium
>2.4 mmol l−1
Survival prediction
Number of risk factors
Median survival (months)
1‐year survival (%)
3‐year survival (%)
0 (Favourable)
20
71
31
1 or 2 (Intermediate)
10
42
7
3, 4, or 5 (Poor)
4
12
0
Immunotherapy
Interferon‐α
Risk Factors
Cut‐off point
Karnofsky performance status
<80%
Time from diagnosis to treatment with interferon‐α
<12 months
Haemoglobin
<lower limit of laboratory reference range
Lactate dehydrogenase (LDH)
>1.5× the upper limit of laboratory reference range
Corrected serum calcium
>2.4 mmol l−1
Survival prediction
Number of risk factors
1‐year survival (%)
3‐year survival (%)
0
83
45
1 or 2
58
17
3, 4, or 5
20
2
Progression‐free survival
Number of risk factors
6 months (%)
12 months (%)
0 (Favourable)
60
39
1 or 2 (Intermediate)
45
24
3, 4, or 5 (Poor)
19
10
Vascular Endothelial Growth Factors (VEGF)
Tyrosine Kinase Inhibitors
Monoclonal antibody against VEGF
Mammalian Target of Rapamycin Inhibitors (MTOR)
13.1.1.11.5 Surgery for Metastatic Disease
13.1.1.11.6 Chemotherapy and Radiotherapy
13.1.1.11.7 Surveillance after Curative Treatment
Risk Profile
Treatment
6 months
1 year
2 year
3 year
4 year
5 year
>5 year
Low
Radical/partial nephrectomy
Ultrasound
CT
Ultrasound
CT
Ultrasound
CT
Discharge
Intermediate
Radical/partial nephrectomy
Cryotherapy/radio frequency ablation
CT
Ultrasound
CT
Ultrasound
CT
CT
CT once every 2
High
Radical/partial nephrectomy
Cryotherapy/radio frequency ablation
CT
CT
CT
CT
CT
CT
CT once every 2
13.1.1.12 Other Types of Malignant Renal Masses
13.1.1.12.1 A Wilms Tumour (Nephroblastoma)
Aetiology
Clinical Features, Investigation, and Staging
Stage I (43%)
Tumour limited to kidney and completely excised. The surface of the renal capsule is intact. Tumour was not ruptured before or during removal. There is no residual tumour apparent beyond the margins of excision
Stage II (23%)
Tumour extends beyond the kidney but is completely excised. There is regional extension of the tumour (i.e. penetration through the outer surface of the renal capsule into perirenal soft tissues). Vessels outside the kidney substance are infiltrated or contain tumour thrombus. There is no residual tumour apparent at or beyond the margins of excision.
Stage III (23%)
Residual nonhaematogenous tumour confined to abdomen. Any one or more of the following occur:
Stage IV (10%)
Haematogenous metastases. Deposits beyond stage III (i.e. lung, liver, bone, and brain).
Stage V (5%)
Bilateral renal involvement at diagnosis. An attempt should be made to stage each side according to the above criteria on the basis of extent of local disease.
Low Risk
Mesoblastic nephroma
Cystic partially differentiated nephroblastoma
Completely necrotic nephroblastoma
Intermediate Risk
Nephroblastoma: epithelial type
Nephroblastoma: stromal type
Nephroblastoma: mixed
Nephroblastoma: regressive type
Nephroblastoma: focal anaplasia
High Risk
Nephroblastoma: blastemal type
Nephroblastoma: diffuse anaplasia
Clear cell sarcoma of the kidney
Rhabdoid tumour of the kidney
Treatment
Intermediate risk
High Risk
Stage
Chemo
Radio
Chemo
Radio
I
VA 18 wks
No
VA 18 wks
No
I with clear cell sarcoma
ECIA1 34 wks
No
II N‐
AVA1 27 wks
No
ECIA1 34 wks
30‐Gy + 5‐Gy boost
II N+
AVA1 27 wks
15‐Gy + 15‐Gy boost
ECIA1 34 wks
30‐Gy + 5‐Gy boost
III
AVA1 27 wks
15‐Gy + 15‐Gy boost
ECIA1 34 wks
30‐Gy + 5‐Gy boost
IV CR after 9
AVA1 27 wks
15‐Gy + 15‐Gy boost
ECIA1 34 wks
30‐Gy + 5‐Gy boost
IV no CR after 9
ECIA1 34 wks
15‐Gy + 15‐Gy boost
ECIA1 34 wks
30‐Gy + 5‐Gy boost
Prognosis and Metastatic Disease
Histology
Stage
10‐year relapse‐free survival (%)
10‐year overall survival (%)
Favourable
I
91
96
II
85
93
III
84
89
IV
75
81
V
65
78
Anaplastic
I
69
82
II–III
43
49
IV
18
18
13.1.1.12.2 Sarcoma
13.1.1.12.3 Renal Haematological Malignancy
13.1.1.12.4 Metastatic Tumours
13.2 Benign Renal Masses
13.2.1 Renal Cysts
Classification
Description
I
Thin wall, no septa, calcification, or solid components. Measures water density with no enhancement
II
Hairline septa, no measurable enhancement, fine calcification in the wall or septa. High‐density cysts <3 cm
IIF
Multiple hairline thin septa or smooth thickening of the wall or septa. Thick, nodular calcification, no measurable enhancement. High‐density cysts >3 cm
III
Thick irregular or smooth walls or septa with measurable enhancement
IV
Thick irregular or smooth walls or septa with measurable enhancement and contain soft tissue components
13.2.2 Oncocytoma
13.2.3 Angiomyolipomas
13.2.4 Renal Cortical Adenoma
13.2.5 Metanephric Adenoma
13.2.6 Cystic Nephroma and Mixed Epithelial or Stromal Tumour
13.2.7 Leiomyoma
13.2.8 Columns of Bertin
13.2.9 Expert Opinion
13.3 Ureter and Renal Pelvis Neoplasms
13.3.1 Incidence
13.3.2 Aetiology
13.3.2.1 Modifiable Risk Factors
Exposure
Relative risk
Odds ration
Incidence
Notes
Tobacco
2.5–7
4–11
—
Multiple inhaled toxic substances (aromatic amine with arylamine, benzopyrene, dimethylbenzanthracene) are metabolised and are carcinogenic
Aromatic amines
—
8.3
—
Exposure of an average 7 with a nonexposure latency of 20 years
Polycyclic aromatic hydrocarbons
—
1.3–1.6
—
—
Chlorinated solvents
—
1.8
—
Phenacetine
1.4–5.4
5.3–6.5
–
An analgesic no longer in production
Aristolochi acid–containing plants
—
—
29.2/100000 in endemic areas in 1998
Plants such as Aristolochia fangchi and Aristolochia clematis, endemic in the Balkans. The acid mutates the p53 gene on codon 139 and is very rarely seen in the nonexposed population
Coffee
1.3
—
—
Consumption of more than 7 cups a day.
Alcohol
1.5
—
—
If drinks two or more of either 12 oz (oz) of beer, 4 oz of wine, or 1 oz of liquor
Chinese herbs nephropathy
—
—
40–46% of exposed patients in Europe
—
Blackfoot disease (arsenic poisoning–induced vasculitis)
—
—
20–26% of upper urothelial cancer in endemic areas
—
Urinary tract calculi
1.5–2.5
—
—
Chronic inflammation of the urothelium by the calculi or obstructive uropathy may promote cancer proliferation.
Long‐term habitual laxative use
9.62
—
—
Particularly anthranoids (e.g. Senna) and chemical laxatives
Chronic urinary tract infections
—
1.5–2
—
Weakening of the urothelium predisposes to carcinogenesis.
Cyclophosphamide
3.2
—
—
Carcinogenic via its metabolite, acrolein.
External beam radiotherapy
1.9
—
—
—
Arterial hypertension
—
1.3
—
—
Yerba mate
—
2.2
Its consumption lead to accumulation of high levels of polycyclic aromatic hydrocarbons.
13.3.2.2 Nonmodifiable Risk Factors
13.3.3 Histology Types
13.3.3.1 Benign
13.3.3.2 Malignant
13.3.4 Clinical Features
13.3.5 Diagnosis
13.3.5.1 Urine Cytology
13.3.5.2 Radiological Investigations
13.3.5.3 Diagnostic Endoscopy and Histological Evaluation
13.3.6 Staging and Grading
T (Primary Tumour)
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Ta
Noninvasive papillary carcinoma
Tis
CIS
T1
Tumour invades subepithelial connective tissue
T2
Tumour invades muscle
T3
(Renal pelvis) Tumour invades beyond muscularis into peripelvic fat or renal parenchyma
(Ureter) Tumour invades beyond muscularis into periureteric fat
T4
Tumour invades adjacent organs or through the kidney into perinephric fat
N (Regional lymph nodes)
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single lymph node 2 cm or less in the greatest dimension
N2
Metastasis in a single lymph node more than 2 cm but not more than 5 cm in the greatest dimension of multiple lymph nodes, none more than 5 cm in the greatest dimension
N3
Metastasis in a single lymph node more than 5 cm in the greatest dimension
M (Distant metastasis)
Mx
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
TNM Staging
Stage 0
Ta N0 M0
TIS N0 M0
Stage I
T1 N0 M0
Stage II
T2 N0 M0
Stage III
T3 N0 M0
Stage IV
T4 N0 M0
Any T N1,2,3 M0
Any T Any N M1
13.3.7 Prognostic Factors
13.3.8 Treatment
13.3.8.1 Surgery
13.3.8.1.1 Radical Nephroureterectomy
Procedure
Nephron‐Sparing Approaches
Ureteroscopy and Percutaneous Approaches
Segmental Resection
13.3.8.2 Adjuvant Treatment
13.3.8.3 Treatment of Advanced Disease
13.3.8.4 Follow‐Up
After RNU, over at least 5
After conservative management, over at least 5
Noninvasive tumour: Cystoscopy and urinary cytology at 3 and then yearly; CT every year
Urinary cytology and CT urography at 3 and 6, and then yearly
Invasive tumour: Cystoscopy and urinary cytology at 3 and then yearly;
CT urography every 6 over 2 and then yearly
Cystoscopy, ureteroscopy and cytology in situ at 3 and 6, and then every 6 over 2, and then yearly
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