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Renal Cell Carcinoma Part 1 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY: Epidemiology Renal cell carcinoma represents around 3% of all cancers, with the highest incidence occurring in Western countries [1,2]. In Europe, and worldwide, the highest incidence rates are found in the Czech Republic and Lithuania [2]. Generally, during the last two decades until recently, there has been an annual increase of about 2% in incidence both worldwide and in Europe leading to approximately 99,200 new RCC cases and 39,100 kidney cancer-related deaths within the European Union in 2018 [1,2]. In Europe, overall mortality rates for RCC increased until the early 1990s, with rates generally stabilising or declining thereafter [3]. There has been a decrease in mortality since the 1980s in Scandinavian countries and since the early 1990s in France, Germany, Austria, the Netherlands, and Italy. However, in some European countries (Croatia, Estonia, Greece, Ireland, Slovakia), mortality rates still show an upward trend [1,2]. Renal cell carcinoma is the most common solid lesion within the kidney and accounts for approximately 90% of all kidney malignancies. It comprises different RCC subtypes with specific histopathological and genetic characteristics [4]. There is a 1.5:1 predominance in men over women with a higher incidence in the older population [2,5]. Aetiology Established risk factors include lifestyle factors such as (hazard ratio [HR]: 1.23-1.58), obesity (HR 1.71), BMI (> 35 vs. < 25), and hypertension (HR: 1.70) [2,5]. 50.2% of patients with RCC are current or former smokers. By histology, the proportions of current or former smokers range from 38% in patients with chromophobe carcinoma to 61.9% in those with collecting duct/medullary carcinoma [6]. In a recent systematic review diabetes was also found to be detrimental [7]. Having a first-degree relative with kidney cancer is also associated with an increased risk of RCC. Moderate alcohol consumption appears to have a protective effect for reasons as yet unknown, while any physical activity level also seems to have a small protective effect [2, 7–11]. A number of other factors have been suggested to be associated with higher or lower risk of RCC, including specific dietary habits and occupational exposure to specific carcinogens, but the literature is inconclusive [5]. The most effective prophylaxis is to avoid cigarette smoking and reduce obesity [2,5]. Histological Diagnosis diagnosis Strong Renal cell carcinomas comprise a broad spectrum of histopathological entities described in the 2016 World Health Organization (WHO) classification [4]. There are three main RCC types: clear cell (ccRCC), papillary (pRCC type I and II) and chromophobe (chRCC). The RCC type classification has been confirmed by cytogenetic and genetic analyses [4,12]. Histological diagnosis includes, besides RCC type; evaluation of nuclear grade, sarcomatoid features, vascular invasion, tumour necrosis, and invasion of the collecting system and peri-renal fat, pT, or even pN categories. The four-tiered WHO/ISUP (International Society of Urological Pathology) grading system has replaced the Fuhrman grading system [4]. Clear-cell RCC Overall, clear-cell RCC (ccRCC) is well circumscribed and a capsule is usually absent. The cut surface is golden-yellow, often with haemorrhage and necrosis. Loss of chromosome 3p and mutation of the von HippelLindau (VHL) gene at chromosome 3p25 are frequently found. The loss of von Hippel-Lindau protein function contributes to tumour initiation, progression, and metastases. The 3p locus harbours at least four additional ccRCC tumour suppressor genes (UTX, JARID1C, SETD2, PBRM1) [12]. In general, ccRCC has a worse prognosis compared to pRCC and chRCC, but this difference disappears after adjustment for stage and grade [13,14]. Papillary RCC Papillary RCC is the second most commonly encountered morphotype of RCC. Papillary RCC has traditionally been subdivided into two types [4]. Type I and II pRCC, which were shown to be clinically and biologically distinct; pRCC type I is associated with activating germline mutations of MET and pRCC type II is associated with activation of the NRF2-ARE pathway and at least three subtypes [15]. Type II pRCC presents a heterogenous group of tumours and future substratification is expected, e.g., oncocytic pRCC [4]. A typical histology of pRCC type I (narrow papillae without any binding, and only microcapillaries in papillae) explains its typical clinical signs. Narrow papillae without any binding and a tough pseudocapsule explain the ideal rounded shape (Pascal’s law) and fragility (specimens have a “minced meat” structure). Tumour growth causes necrotisation of papillae, which is a source of hyperosmotic proteins that cause subsequent “growth” of the tumour, fluid inside the tumour, and only a serpiginous, contrast-enhancing margin. Stagnation in the microcapillaries explain the minimal post-contrast attenuation on CT. Papillary RCC type 1 can imitate a pathologically changed cyst (Bosniak IIF or III). The typical signs of pRCC type 1 are as follows: an ochre colour, more frequently exophytic, extrarenal growth, low grade, and low malignant potential; over 75% of these tumours can be treated by NSS surgery. A substantial risk of renal tumour biopsy tract seeding exists (12.5%), probably due to the fragility of the tumour papillae [16]. Papillary RCC type I is more common and generally considered to have a better prognosis than pRCC type II [4, 14, 17]. Chromophobe RCC Overall, chRCC is a pale tan, relatively homogenous and tough, well-demarcated mass without a capsule. Chromophobe RCC cannot be graded by the Fuhrman grading system because of its innate nuclear atypia. An alternative grading system has been proposed, but has yet to be validated [4]. Loss of chromosomes Y, 1, 2, 6, 10, 13, 17 and 21 are typical genetic changes [4]. The prognosis is relatively good, with high fiveyear recurrence-free survival (RFS), and ten-year cancer-specific survival (CSS) [18]. The five- and ten-year recurrence-free survival rates were 94.3% and 89.2%, respectively. Recurrent disease developed in 5.7% of patients, and 76.5% presented with distant metastases with 54% of metastatic disease diagnoses involving a single organ, most commonly bone. Recurrence and death after surgically resected chRCC is rare. For completely excised lesions < pT2a without coagulative necrosis or sarcomatoid features, prognosis is excellent [19]. The new WHO/ISUP grading system merges former entity ‘hybrid oncocytic chromophobe tumour’

Upper Urinary Tract Urothelial Carcinoma Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai EPIDEMIOLOGY, AETIOLOGY AND PATHOLOGY: Epidemiology Urothelial carcinomas are the sixth most common tumours in developed countries [1]. They can be located in the lower (bladder and urethra) and/or the upper (pyelocaliceal cavities and ureter) urinary tract. Bladder tumours account for 90–95% of UCs and are the most common urinary tract malignancy [2]. Upper urinary tract UCs are uncommon and account for only 5–10% of UCs [1] with an estimated annual incidence in Western countries of almost two cases per 100,000 inhabitants. This rate has risen in the past few decades as a result of improved detection and improved bladder cancer survival [3,4]. Pyelocaliceal tumours are approximately twice as common as ureteral tumours and multifocal tumours are found in approximately 10–20% of cases [5]. The presence of concomitant carcinoma in situ of the upper tract is between 11% and 36% [3]. In 17% of cases, concurrent bladder cancer is present [6] whilst a prior history of bladder cancer is found in 41% of American men but in only 4% of Chinese men [7]. This, along with genetic and epigenetic factors, may explain why Asian patients present with more advanced and higher-grade disease compared to other ethnic groups [3]. Following treatment, recurrence in the bladder occurs in 22–47% of UTUC patients, depending on initial tumour grade [8] compared with 2–5% in the contralateral upper tract [9]. With regards to UTUC occurring following an initial diagnosis of bladder cancer, a series of 82 patients treated with bacillus Calmette-Guérin (BCG) who had regular upper tract imaging between years 1 and 3 showed a 13% incidence of UTUC, all of which were asymptomatic [10], whilst in another series of 307 patients without routine upper tract imaging the incidence was 25% [11]. A multicentre cohort study (n = 402) with a 50-month follow-up has demonstrated a UTUC incidence of 7.5% in NMIBC receiving BCG with predictors being intravesical recurrence and non-papillary tumour at transurethral resection of the bladder [12]. Following radical cystectomy for MIBC, 3–5% of patients develop a metachronous UTUC [13, 14]. Approximately two-thirds of patients who present with UTUCs have invasive disease at diagnosis compared to 15–25% of patients presenting with muscle-invasive bladder tumours [15]. This is probably due to the absence of muscularis propria layer in the upper tract, so tumours are more likely to upstage at an earlier time-point. Approximately 9% of patients present with metastasis [3, 16, 19]. Upper urinary tract UCs have a peak incidence in individuals aged 70–90 years and are twice as common in men [18]. Upper tract UC and bladder cancer exhibit significant differences in the prevalence of common genomic alterations. In individual patients with a history of both tumours, bladder cancer and UTUC were always clonally related. Genomic characterisation of UTUC provides information regarding the risk of bladder recurrence and can identify tumours associated with Lynch syndrome [19]. The Amsterdam criteria are a set of diagnostic criteria used by doctors to help identify families which are likely to have Lynch syndrome [20]. In Lynch-related UTUC, immunohistochemistry (IHC) analysis showed loss of protein expression corresponding to the disease-predisposing MMR (mismatch repair) gene mutation in 98% of the samples (46% were microsatellite instable and 54% microsatellite stable) [21]. The majority of tumours develop in MSH2 mutation carriers [28]. Patients identified at high risk for Lynch syndrome should undergo DNA sequencing for patient and family counselling [22,23]. Germline mutations in DNA MMR genes defining Lynch syndrome, are found in 9% of patients with UTUC compared to 1% of patients with bladder cancer, linking UTUC to Lynch syndrome [24]. A study of 115 consecutive UTUC patients, reported that 13.9% screened positive for potential Lynch syndrome and 5.2% had confirmed Lynch syndrome [25]. This is one of the highest rates of undiagnosed genetic disease in urological cancers, which justifies screening of all patients under 60 presenting with UTUC and those with a family history of UTUC (see Figure 1) [26,27] or positive reflexive MMR-test by IHC in sporadic UTUC [24, 28-30]. Figure 1: Selection of patients with UTUC for Lynch syndrome screening during the first medical interview Risk factors: A number of environmental factors have been implicated in the development of UTUC [5, 31]. Published evidence in support of a causative role for these factors is not strong, with the exception of smoking and aristolochic acid. Tobacco exposure increases the relative risk of developing UTUC from 2.5 to 7.0 [32–34]. A large population-based study assessing familial clustering in relatives of UC patients, including 229,251 relatives of case subjects and 1,197,552 relatives of matched control subjects, has demonstrated genetic or environmental roots independent of smoking-related behaviours. With more than 9% of the cohort being UTUC patients, clustering was not seen in upper tract disease. This may suggest that the familial clustering of UC is specific to lower tract cancers [35]. In Taiwan and Chile, the presence of arsenic in drinking water has been tentatively linked to UTUC [36,37]. Aristolochic acid, a nitrophenanthrene carboxylic acid produced by Aristolochia plants, which are used worldwide, especially in China and Taiwan [38], exerts multiple effects on the urinary system. Aristolochic acid irreversibly injures renal proximal tubules resulting in chronic tubulointerstitial disease, while the mutagenic properties of this chemical carcinogen lead predominantly to UTUC [38-40]. Aristolochic acid has been linked to bladder cancer, renal cell carcinoma, hepatocellular carcinoma, and intrahepatic cholangiocarcinoma [41]. Two routes of exposure to aristolochic acid are known: (i) environmental contamination of agricultural products by Aristolochia plants, as reported for Balkan endemic nephropathy [42]; and (ii) ingestion of Aristolochia- based herbal remedies [43,44]. Following bioactivation, aristolochic acid reacts with genomic DNA to form aristolactam-deoxyadenosine adducts [45]; these lesions persist for decades in target tissues, serving as robust biomarkers of exposure [1]. These adducts generate a unique mutational spectrum, characterised by A>T transversions located predominately on the non-transcribed strand of DNA [41, 56]. However, fewer than 10% of individuals exposed to aristolochic acid develop UTUC [40]. Two retrospective series

Urological Infections Urosepsis, prostatitis and HPV Part 2 Comprehensive Review Article Prof. Dr. Semir. A. Salim. Al Samarrai Urosepsis: Introduction Patients with urosepsis should be diagnosed at an early stage, especially in the case of a cUTI. Systemic inflammatory response syndrome (SIRS), characterised by fever or hypothermia, leukocytosis or leukopenia, tachycardia and tachypnoea, has been recognised as a set of alerting symptoms [1,2]; however, SIRS is no longer included in the recent terminology of sepsis [3] (Table 1). Table 1. Definition and criteria of sepsis and septic shock Mortality is considerably increased the more severe the sepsis is. The treatment of urosepsis involves adequate life-supporting care, appropriate and prompt antimicrobial therapy, adjunctive measures and the optimal management of urinary tract disorders [4]. Source control by decompression of any obstruction and drainage of larger abscesses in the urinary tract is essential [4]. Urologists are recommended to treat patients in collaboration with intensive care and infectious diseases specialists. Urosepsis is seen in both community-acquired and healthcare associated infections. Nosocomial urosepsis may be reduced by measures used to prevent nosocomial infection, e.g. reduction of hospital stays, early removal of indwelling urinary catheters, avoidance of unnecessary urethral catheterization, correct use of closed catheter systems, and attention to simple daily aseptic techniques to avoid cross-infection. Sepsis is diagnosed when clinical evidence of infection is accompanied by signs of systemic inflammation, presence of symptoms of organ dysfunction and persistent hypotension associated with tissue anoxia (Table 1). Epidemiology, aetiology and pathophysiology Urinary tract infections can manifest from bacteriuria with limited clinical symptoms to sepsis or severe sepsis, depending on localised and potential systemic extension. It is important to note that a patient can move from an almost harmless state to severe sepsis in a very short time. Mortality rates associated with sepsis vary depending on the organ source [5] with urinary tract sepsis generally having a lower mortality than that from other sources [6]. Sepsis is more common in men than in women [7]. In recent years, the overall incidence of sepsis arising from all sources has increased by 8.7% per year [5], but the associated mortality has decreased, which suggests improved management of patients (total in-hospital mortality rate fell from 27.8% to 17.9% from 1995 to 2000) [8]. Although the rate of sepsis due to Gram-positive and fungal organisms has increased, Gram-negative bacteria remain predominant in urosepsis [9,10]. In urosepsis, as in other types of sepsis, the severity depends mostly upon the host response. Patients who are more likely to develop urosepsis include elderly patients, diabetics, immunosuppressed patients, such as transplant recipients and patients receiving cancer chemotherapy or corticosteroids. Urosepsis also depends on local factors, such as urinary tract calculi, obstruction at any level in the urinary tract, congenital uropathy, neurogenic bladder disorders, or endoscopic manoeuvres. However, all patients can be affected by bacterial species that are capable of inducing inflammation within the urinary tract. Diagnostic evaluation For diagnosis of systemic symptoms in sepsis either the full Sequential [Sepsis-related] Organ Failure Assessment (SOFA) score, or the quickSOFA score should be applied (Table 1). Microbiology sampling should be applied to urine, two sets of blood cultures [11], and if appropriate drainage fluids. Imaging investigations, such as sonography and CT-scan should be performed early [12]. Physiology and biochemical markers E. coli remains the most prevalent micro-organism. In several countries, bacterial strains can be resistant or multi-resistant and therefore difficult to treat [10]. Most commonly, the condition develops in compromised patients (e.g. those with diabetes or immunosuppression), with typical signs of generalised sepsis associated with local signs of infection. Cytokines as markers of the septic response Cytokines are involved in the pathogenesis of sepsis [6]. They are molecules that regulate the amplitude and duration of the host inflammatory response. They are released from various cells including monocytes, macrophages and endothelial cells, in response to various infectious stimuli. The complex balance between pro- and anti-inflammatory responses is modified in severe sepsis. An immunosuppressive phase follows the initial pro-inflammatory mechanism. Sepsis may indicate an immune system that is severely compromised and unable to eradicate pathogens or a non-regulated and excessive activation of inflammation, or both. Genetic predisposition is a probable explanation of sepsis in several patients. Mechanisms of organ failure and death in patients with sepsis remain only partially understood [6]. Biochemical markers Procalcitonin is the inactive pro-peptide of calcitonin. Normally, levels are undetectable in healthy humans. During severe generalised infections (bacterial, parasitic and fungal) with systemic manifestations, procalcitonin levels rise [13]. In contrast, during severe viral infections or inflammatory reactions of non-infectious origin, procalcitonin levels show only a moderate or no increase. Mid-regional proadrenomedulline is another sepsis marker. Mid-regional proadrenomedullin has been shown to play a decisive role in the induction of hyperdynamic circulation during the early stages of sepsis and progression to septic shock [14]. Procalcitonin monitoring may be useful in patients likely to develop sepsis and to differentiate from a severe inflammatory status not due to bacterial infection [13,15]. In addition, serum lactate is a marker of organ dysfunction and is associated with mortality in sepsis [16]. Serum lactate should therefore also be monitored in patients with severe infections. Disease management: Prevention Septic shock is the most frequent cause of death for patients hospitalised for community-acquired and nosocomial infection (20-40%). Urosepsis treatment requires a combination of treatment including source control (obstruction of the urinary tract), adequate life-support care, and appropriate antimicrobial therapy [6,12]. In such a situation, it is recommended that urologists collaborate with intensive care and infectious disease specialists for the best management of the patient. Preventive measures of proven or probable efficacy The most effective methods to prevent nosocomial urosepsis are the same as those used to prevent other nosocomial infections [17,18] they include: • Isolation of patients with multi-resistant organisms following local and national recommendations. • Prudent use of antimicrobial agents for prophylaxis and treatment of established infections, to avoid selection of resistant strains. Antibiotic agents should be chosen according to the predominant pathogens at a given site of infection in the hospital environment.