EAU Pocket Guidelines 2012

European Association of Urology
Pocket Guidelines
2012 edition
Introduction
The EAU Guidelines Office is pleased to present the 2012 edition of the Pocket Guidelines. These ultra-short versions of Europes most read and used urological clinical Guidelines have been updated and improved to meet the high standards of the EAU and its members. To maintain this quality, we advise that the Pocket Guidelines should be used in combination with the extended documents of the clinical Guidelines, which are available in hard copy, on CD, and at the EAU website. Over 160 contributors have worked throughout the year to integrate the latest scientific research into the recommendations found in these Pocket Guidelines. Their dedication and perseverance has resulted in this updated publication; without them none of this would have been possible. We are extremely grateful to all contributing panel members who devote their time and energy to the guidelines project. The Pocket Guidelines are also published online, at www.uroweb.org/guidelines/online-guidelines/. to facilitate consultation of all Guidelines on computer, tablet device, or smartphone.
The Guidelines Office Board and contributors endeavour to compile a user-friendly and informative document. We hope that we have succeeded in making these latest Pocket Guidelines helpful to you and, ultimately, your patients. On behalf of the Guidelines Office Board, Mr. K.F. Parsons Chairman
EAU Guidelines Office Board Prof.Dr. J. Irani, Vice-Chairman Prof.Dr. C.R. Chapple Prof. M. Fall Prof.Dr. T. Hnu Prof.Dr. C. Llorente Abarca Prof.Dr. T. Loch Prof.Dr. D. Mitropoulos Prof.Dr. J. NDow Prof.Dr. H-P. Schmid Prof.Dr. R. Sylvester
The European Association of Urology use the following rating system:
Table 1: Level of evidence*

Level Type of evidence 1a Evidence obtained from meta-analysis of randomised trials 1b Evidence obtained from at least one randomised trial 2a Evidence obtained from one well-designed controlled study without randomisation 2b Evidence obtained from at least one other type of well-designed quasi-experimental study 3 Evidence obtained from well-designed non-experimental studies, such as comparative studies, correlation studies and case reports 4 Evidence obtained from expert committee reports or opinions or clinical experience of respected authorities *Modified from Sackett et al. (1) It should be noted, however, that when recommendations are graded, the link between the level of evidence and grade of recommendation is not directly linear. Availability of RCTs may not necessarily translate into a grade A recommendation where there are methodological limitations or disparity in published results. Alternatively, absence of high level evidence does not necessarily preclude a grade A recommendation, if there is overwhelming clinical experience and consensus. In addition, there may be exceptional situations where corroborating Introduction 3
studies cannot be performed, perhaps for ethical or other reasons and in this case unequivocal recommendations are considered helpful for the reader. Whenever this occurs, it has been clearly indicated in the text with an asterix, as upgraded based on panel consensus. The quality of the underlying scientific evidence - although a very important factor - has to be balanced against benefits and burdens, values and preferences and cost when a grade is assigned (2-4).
Table 2: Grade of recommendation*

Grade Nature of recommendations A Based on clinical studies of good quality and consistency addressing the specific recommendations and including at least one randomised trial B Based on well-conducted clinical studies, but without randomised clinical trials C Made despite the absence of directly applicable clinical studies of good quality *Modified from Sackett et al. (1)
References
1.
2. 3. 4.
Oxford Centre for Evidence-based Medicine Levels of Evidence (May 2009). Produced by Bob Phillips, Chris Ball, Dave Sackett, Doug Badenoch, Sharon Straus, Brian Haynes, Martin Dawes since November 1998. Updated by Jeremy Howick March 2009. [Access date January 2012] http://www.cebm.net/index.aspx?o=1025 Atkins D, Best D, Briss PA, et al; GRADE Working Group. Grading quality of evidence and strength of recommendations. BMJ 2004 Jun 19;328(7454):1490. http://www.ncbi.nlm.nih.gov/pubmed/15205295 Guyatt GH, Oxman AD, Vist GE et al. GRADE: an emerging consensus on rating quality of evidence and strength of recommendations. BMJ 2008;336(7650):924-6. http://www.ncbi.nlm.nih.gov/pubmed/18436948 Guyatt GH, Oxman AD, Kunz R et al; GRADE Working Group. Going from evidence to recommendations. BMJ 2008 May 10;336(7652):1049-51. http://www.bmj.com/content/336/7652/1049.long
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Non-muscle Invasive Bladder Cancer Upper Urinary Tract Urothelial Cell Carcinomas Muscle-invasive and Metastatic Bladder Cancer Prostate Cancer Renal Cell Carcinoma Penile Cancer Testicular Cancer Management of Male LUTS,
incl. benign prostatic obstruction Erectile Dysfunction and Premature Ejaculation
Male Sexual Dysfunction: Penile Curvature Male Infertility Male Hypogonadism Urinary Incontinence Urological Infections
Neurogenic Lower Urinary Tract Dysfunction Urological Trauma Pain Management in Urology Chronic Pelvic Pain Urolithiasis Renal Transplantation Paediatric Urology
GUIDELINES ON NON-MUSCLEINVASIVE BLADDER CANCER

(Limited text update December 2010)
M. Babjuk, W. Oosterlinck, R. Sylvester, E. Kaasinen, A. Bhle, J. Palou, M. Rouprt Eur Urol 2011 Apr;59(4):584-94
Introduction
The EAU Working Group on Non-muscle-invasive Bladder Cancer has published a short and long version of guidelines on non-muscle-invasive bladder cancer which contains information on its background, classification, risk factors, diagnosis, prognostic factors, and treatment. The current recommendations for non-muscle-invasive bladder cancer are ultra short and are based on the current literature (until end of 2010), with emphasis being placed on (evidence based) results from randomised clinical trials and meta-analyses. These guidelines can be used as a quick reference on the management of patients with non-muscleinvasive bladder cancer. The recommendations of this working panel apply to patients with papillary stage Ta and T1 tumours as well as to carcinoma in situ (CIS), a flat neoplasm. The classification of non-muscle-invasive tumours (Ta, T1, and CIS) is given in Non-muscle-invasive Bladder Cancer 7
the TNM Classification of Malignant Tumours, 7th Edition, 2009 (Table 1).
Table 1: TNM classification 2009 for urinary bladder

T - Primary Tumour Non-invasive papillary carcinoma Ta Carcinoma in situ: flat tumour Tis Tumour invades subepithelial connective tissue T1 Tumour invades muscularis T2 T2a Superficial muscle (inner half) T2b Deep muscle (outer half) Tumour invades perivesical tissue (beyond muscuT3 laris) T3a Microscopically T3b Macroscopically (extravesical mass) Tumour invades any of the following: prostate, uterT4 us, vagina, pelvic wall, abdominal wall T4a Prostate, uterus, or vagina T4b Pelvic wall or abdominal wall N - Lymph Nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metatstases N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac, or presacral) Mestastasis in multiple lymph nodes in the true N2 pelvis (hypogastric, obturator, external iliac, or presacral) Metastasis in a common iliac lymph node(s) N3
Non-muscle-invasive Bladder Cancer
M - Distant Metastasis MX Metastasis not assessed M0 No distant metastasis M1 Distant metastasis
Characteristics of stages Ta, T1, and CIS

Stage Ta tumours are confined to the urothelium, have a papillary configuration of their exophytic part, and do not penetrate from the urothelium into the lamina propria or detrusor muscle. Stage T1 tumours originate from the urothelium but penetrate the basement membrane which separates the urothelium from the deeper layers. T1 tumours invade into the lamina propria, but are not so deep that they reach the detrusor muscle. Carcinoma in situ (CIS) is a high-grade (anaplastic) carcinoma confined to the urothelium, but with a flat non-papillary configuration. Unlike a papillary tumour, CIS appears as reddened and velvety mucosa and is slightly elevated but sometimes not visible. CIS can be local or diffuse. Three types of CIS are distinguishable; primary CIS (no previous or concurrent papillary tumours); secondary CIS (with a history of papillary tumours); concurrent CIS (in the presence of papillary tumours).
Characteristics of grade
1973 WHO classification Apart from their architecture, the individual cells show difNon-muscle-invasive Bladder Cancer 9
ferent degrees of anaplasia: Grade 1: well differentiated tumour Grade 2: moderately differentiated tumour Grade 3: poorly differentiated tumour 2004 WHO Classification A new classification system was initially proposed by the WHO/ISUP in 1998 and updated by the WHO in 2004. For non-invasive urothelial neoplasias, the categories described in Table 2 are used.
Table 2: 2004 WHO classification of non-invasive urothelial neoplasia

Flat lesions Hyperplasia (flat lesion without atypia or papillary) Reactive atypia (flat lesion with atypia) Atypia of unknown significance Urothelial dysplasia Urothelial carcinoma in situ (CIS) Papillary lesions Urothelial papilloma (a completely benign lesion) Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma The 2004 WHO grading system defines CIS as a non-papillary, i.e. a flat, lesion in which the surface epithelium contains cells that are cytologically malignant. Papillary tumours are classified as either papillary urothelial neoplasms of low 10 Non-muscle-invasive Bladder Cancer
malignant potential (PUNLMP) or as urothelial carcinomas, with the latter being subdivided into two grades: low grade and high grade (Table 2). The intermediate group (G2) has been eliminated; this group was the subject of controversy in the 1973 WHO classification. Use of the 2004 WHO classification is advocated, as this should result in less diagnostic variability among pathologists. However until the 2004 WHO classification has been validated clinically, both classifications can be used. The majority of clinical trials published so far on TaT1 bladder tumours have been performed using the 1973 WHO classification, and therefore the following guidelines are based on the 1973 WHO grade classification.
Diagnosis and initial treatment steps

The diagnosis mainly depends on the cystoscopic examination of the bladder, biopsy, and urine cytology. To date, molecular urinary markers have not improved the combination of cystoscopy and cytology. The standard initial therapy for Ta and T1 papillary bladder tumours is complete macroscopic transurethral resection (TUR) including a part of the underlying muscle. A second TUR should be considered if there is a suspicion that the initial resection was incomplete, e.g. when multiple or large tumours are present, or when the pathologist reported no muscle tissue in the specimen, or when a high-grade tumour or a T1 tumour was detected. The technique of TUR is described in the EAU guidelines on non-muscleNon-muscle-invasive Bladder Cancer 11
invasive urothelial carcinoma of the bladder (Eur Urol 2011 Jun;59(6):997-1008). The diagnosis of CIS is based on the histology of biopsies from the bladder wall. Biopsies are taken from suspect areas. In patients with positive urine cytology and no papillary tumour, multiple biopsies from normal looking mucosa including prostatic urethra (random biopsies) are recommended. Fluorescence cystoscopy is recommended in these cases as it improves the detection rate of CIS. Urine cytology is an important tool in the diagnosis and follow-up of CIS because of its high sensitivity and specificity (over 90%). Carcinoma in situ cannot be eradicated by TUR and further treatment is mandatory.
Prognostic factors and adjuvant treatment

TaT1 papillary tumours Since there is considerable risk for recurrence and/or progression of tumours after TUR, adjuvant intravesical therapy is recommended for all stages (Ta, T1, and CIS). All patients should receive an immediate post-operative instillation of chemotherapy within 6 hours after TUR, except in cases of bladder perforation or severe bleeding. An immediate instillation is considered as standard, the choice of drug (mitomycin C, epirubicin, or doxorubicine) is optional. The choice of further intravesical adjuvant therapy depends on the patients risk of recurrence and/or progression which can be assessed using the European Organization for the Research and Treatment of Cancer (EORTC) scor12 Non-muscle-invasive Bladder Cancer
ing system (Table 3) and risk tables (Table 4). Patients with multiple tumours, large tumours (> 3 cm), and highly recurrent tumours (> 1 recurrence/year) are at the highest risk of recurrence while patients with stage T1 tumours, high grade tumours, and CIS have the highest risk of progression. Intravesical chemotherapy reduces the risk of recurrence but not progression and is associated with minor side-effects. Intravesical immunotherapy with Bacillus Calmette-Gurin (BCG) (induction and maintenance) is superior to intravesical chemotherapy in reducing recurrences and in preventing or delaying progression to muscle-invasive bladder cancer. However, intravesical BCG is more toxic.
Recommendations for low risk tumours

Patients with a single, small, low grade Ta tumour without CIS, who are at low risk for both recurrence and progression, should receive: 1. A complete TUR. 2. An immediate single post-operative instillation with a chemotherapeutic agent (drug optional). 3. No further treatment is recommended prior to recurrence. GR
A A A
Recommendations for high risk tumours

Patients with TaT1 high grade tumours with or without CIS and those with CIS alone are at high risk of progression. Treatment should consist of: GR
13
1. Complete TUR of papillary tumours followed by an immediate post-operative instillation with a chemotherapeutic agent (drug optional). 2. A second TUR after 46 weeks. 3. Adjuvant intravesical immunotherapy with BCG (full dose or reduced dose in case of side-effects). Maintenance therapy for at least 1 year is necessary although the optimal maintenance scheme has not yet been determined. 4. Immediate cystectomy may be offered to patients at highest risk of tumour progression. 5. In patients with BCG failure, cystectomy is recommended. BCG = Bacillus Calmette-Gurin; CIS = carcinoma in situ; TUR = transurethral resection.
B A
C B
Intermediate risk tumours In the remaining intermediate risk patients, adjuvant intravesical therapy is necessary but no consensus exists regarding the optimal drug and the most appropriate scheme. BCG is more effective than chemotherapy in both reducing recurrence and progression but it is associated with more systemic and local side-effects.
Recommendations for intermediate risk tumours

The major issue in the management of intermediate GR risk tumours is to prevent recurrence and progression, of which recurrence is clinically the most frequent. Treatment should include: 14 Non-muscle-invasive Bladder Cancer
1. Complete TUR followed by an immediate postoperative instillation with a chemotherapeutic agent (drug optional). 2. A second TUR after 46 weeks when the initial resection was incomplete. 3a Adjuvant intravesical chemotherapy (drug optional), schedule: optional although the duration of treatment should not exceed 1 year. Or 3b Adjuvant intravesical immunotherapy with BCG (full dose or reduced dose in case of side-effects). Maintenance therapy for at least 1 year is necessary although the optimal maintenance schedule has not yet been determined. BCG = Bacillus Calmette-Gurin; CIS = carcinoma in situ; TUR = transurethral resection.
B A
Table 3: Calculation of recurrence and progression scores

Factor Number of tumours Single 2 to 7 >8 Tumour diameter < 3 cm > 3 cm Prior recurrence rate Recurrence 0 3 6 0 3 Progression 0 3 3 0 3
15
0 0 Primary < 1 recurrence/year 2 2 2 4 > 1 recurrence/year Category Ta 0 0 T1 1 4 Concomitant CIS No 0 0 Yes 1 6 Grade (1973 WHO) 0 0 G1 0 1 G2 5 2 G3 Total Score 0 - 17 0 - 23 CIS = carcinoma in situ; WHO = World Health Organization.
Table 4: Probability of recurrence and progression according to total score

Recurrence score 0 1-4 5-9 10-17 Progression score 0 Prob. recurrence 1 year 15% 24% 38% 61% Prob. progression 1 year 0.2% Prob. recurrence 5 years 31% 46% 62% 78% Prob. progression 5 years 0.8% Recurrence risk group Low risk Intermediate risk High risk Progression risk group Low risk
16 Non-muscle-invasive Bladder Cancer
2-6
1%
6%
Intermediate risk
7-13 5% 17% High risk 14-23 17% 45% Note: electronic calculators for Tables 3 and 4 are available at http://www.eortc.be/tools/bladdercalculator/ Eur Urol 2006;49(3):466-77. Carcinoma in situ Carcinoma in situ has a high risk of progression to muscleinvasive disease which exceeds 50% in some studies. BCG intravesical immunotherapy (induction and maintenance) is superior to intravesical chemotherapy in increasing the complete response rate and the overall percent of patients remaining tumour free. Moreover, BCG reduces the risk of progression as compared to either intravesical chemotherapy or a different immunotherapy. Early radical cystectomy at the time of diagnosis provides excellent disease-free survival, but over-treatment occurs in up to 50% of patients.
Recommendations for the treatment of CIS

1. In concurrent CIS, the initial strategy (TUR, early intravesical instillation, a second TUR) is based on the features of the papillary tumour. 2. Intravesical BCG immunotherapy including at least 1 year maintenance.
GR
17
3. After the 6 week induction course, a second course B of 6 weekly BCG instillations or maintenance cycles consisting of 3 weekly instillations may be considered in non-responders since about 40-60% of these patients will respond to additional treatment with BCG. 4. In BCG non-responders at 6 months radical cystec- B tomy is recommended. BCG = Bacillus Calmette-Gurin; CIS = carcinoma in situ; TUR = transurethral resection.
Follow-up for non-muscle-invasive bladder tumours

Patients with non-muscle-invasive bladder tumours need to be regularly followed up because of the risk of recurrence and progression; however, the frequency and duration of cystoscopies should reflect the individual patients degree of risk. Using the risk tables (Tables 3 and 4), the short-term and long-term risks of both recurrence and progression in individual patients can be predicted and the follow-up schedule adapted accordingly: a. The prompt detection of muscle-invasive and high-grade non-muscle-invasive recurrences is critical since a delay in diagnosis and therapy threatens a patients life. b. Tumour recurrence in the low-risk group is nearly always low stage and low grade. Small, non-invasive (Ta), low grade papillary recurrences do not present an immediate danger to the patient and their early detection is not essential for successful therapy. c. The result of the first cystoscopy after TUR at 3 months is 18 Non-muscle-invasive Bladder Cancer
a very important prognostic factor for recurrence and for progression. The first cystoscopy should thus always be performed 3 months after TUR in all patients with nonmuscle-invasive bladder tumour. The following recommendations are only based on retrospective experience.
Recommendations for follow-up cystoscopy

Patients with tumours at low risk of recurrence and progression should have a cystoscopy at 3 months. If negative, the following cystoscopy is advised at 9 months and consequently yearly for 5 years. Patients with tumours at high risk of progression should have a cystoscopy and urinary cytology at 3 months. If negative, the following cystoscopies and cytologies should be repeated every 3 months for a period of 2 years, every 4 months in the third year, every 6 months thereafter until 5 years, and yearly thereafter. A yearly exploration of the upper tract is recommended. Patients with intermediate-risk of progression (about one-third of all patients) should have an in-between follow-up scheme using cystoscopy and cytology, adapted according to personal and subjective factors.
GR C
19
Patients with CIS should be followed up for life due to the high risk of recurrence and progression, both within the bladder and extravesically. Urine cytology together with cystoscopy (and bladder biopsies in cytology positive cases) is essential for monitoring of treatment efficacy. The follow-up schedule is the same as for patients with high-risk tumours.
This short booklet text is based on the more comprehensive EAU guidelines (ISBN 978-90-79754-96-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
20 Non-muscle-invasive Bladder Cancer
GUIDELINES ON UPPER URINARY TRACT UROTHELIAL CELL CARCINOMAS

M. Rouprt, R. Zigeuner, J. Palou, A. Boehle, E. Kaasinen, M. Babjuk, R. Sylvester, W. Oosterlinck Eur Urol 2011 Apr;59(4):584-94
Introduction
The EAU Working Group for upper urinary tract urothelial cell carcinomas (UUT-UCCs) has recently updated guidelines for this tumour type. This document provides a brief overview of the updated EAU guidelines. UUT-UCCs are uncommon and account for only 5-10% of UCCs. The estimated annual incidence of UUT-UCCs in Western countries is about 1-2 new cases per 100,000 population. Pyelocaliceal tumours are about twice as common as ureteral tumours. The principal environmental factors which contribute to the development of UUT-UCCs are similar to those associated with bladder cancer, namely tobacco and occupational exposure. Other environmental factors that are specifically associated with UUT-UCCs include phenacetin, aristolochic acid nephropathy, and blackfoot disease.
Upper Urinary Tract Urothelial Cell Carcinomas
21
The morphology of UUT-UCCs is similar to those of bladder carcinomas. Over 95% of UCCs are derived from the urothelium, comprising of either UUT-UCCs or bladder carcinomas.
Classification
The classification of UUT-UCCs is given in the TNM classification of Malignant Tumours 7th edition, 2009.
Table 1: TNM classification 2009 for renal pelvis and ureter*

T - Primary tumour Primary tumour cannot be assessed TX No evidence of primary tumour T0 Non-invasive papillary carcinoma Ta Carcinoma in situ Tis Tumour invades subepithelial connective tissue T1 Tumour invades muscularis T2 (Renal pelvis) Tumour invades beyond muscularis T3 into peripelvic fat or renal parenchyma (Ureter) Tumour invades beyond muscularis into periureteric fat Tumour invades adjacent organs or through the kidT4 ney into perinephric fat
22 Upper Urinary Tract Urothelial Cell Carcinomas
N - Regional lymph nodes NX Regional lymph nodes cannot be assessed No regional lymph node metastasis N0 Metastasis in a single lymph node 2 cm or less in the N1 greatest dimension Metastasis in a single lymph node more than 2 cm N2 but not more than 5 cm in the greatest dimension or multiple lymph nodes, none more than 5 cm in greatest dimension Metastasis in a lymph node more than 5 cm in greatN3 est dimension M - Distant metastasis M0 No distant metastasis M1 Distant metastasis *All EAU guidelines advocate the TNM system of tumour classification.
Tumour grade
Until 2004, the most common classification used for UUTUCCs was the WHO classification of 1973, which distinguishes among three grades (G1, G2 and G3). Since 2004, the new WHO classification distinguishes among three groups of non-invasive tumours: papillary urothelial neoplasia of low malignant potential, low-grade carcinomas, and high-grade carcinomas. Both classifications are in use currently for UUT-UCCs. There are almost no tumours of low malignant potential in the UUT.
Diagnosis
The diagnosis of a UUT-UCC depends on imaging, cystoscopy, urinary cytology, and diagnostic ureteroscopy. Upper Urinary Tract Urothelial Cell Carcinomas 23
GR Urinary cytology A Cystoscopy to rule out a concomitant bladder tumour A MDCT urography A MDCT = multidetector computed tomography. In addition, the possible advantages of ureteroscopy should be discussed in the preoperative assessment of any UUTUCC patient.
Recommendations for diagnosis of UUT-UCC
Prognostic factors
UUT-UCCs that invade the muscle wall usually have a very poor prognosis. The recognised prognostic factors in decreasing order of importance include: tumour stage and grade; concomitant carcinoma in situ (CIS); age; lymphovascular invasion; tumour architecture; extensive tumour necrosis; molecular markers; tumour location; gender.
Treatment
Localised disease The radical management of UUT-UCC consists of radical nephroureterectomy (RNU) by open surgery with excision of the bladder cuff. This is the gold standard treatment for UUT-UCC, regardless of the location of the tumour in the UUT. Resection of the distal ureter and its orifice is per24 Upper Urinary Tract Urothelial Cell Carcinomas
formed because this part of the urinary tract carries a considerable risk of recurrence. Lymph node dissection associated with RNU is of therapeutic interest and allows for optimal staging of the disease.
Recommendations for radical management of UUT-UCC: RNU

Indications for radical management of UUT-UCC Suspicion of infiltrating UUT-UCC (imaging) High-grade tumour (urinary cytology) Multifocality (with two functional kidneys) Techniques for RNU in UUT-UCC Open and laparoscopic access are equally effective Bladder cuff removal is imperative Several techniques for bladder cuff excision are acceptable, except stripping Lymphadenectomy is recommended in the case of invasive UUT-UCC RNU = radical nephroureterectomy. The conservative management of low-risk UUT-UCC consists of conservative surgery, which allows for preservation of the upper urinary renal unit. Conservative management of UUT-UCC can be considered in imperative cases (renal insufficiency, solitary functional kidney) or in selected elective cases (functional contralateral kidney) for low-grade, low-stage tumours. The choice of technique (ureteroscopy, segmental resection, percutaneous access) depends on technical constraints, the anatomical location of the tumour, and the experience of the surgeon. Upper Urinary Tract Urothelial Cell Carcinomas 25 GR B B B B A C C
Recommendations for conservative management of UUT-UCC

Indications for conservative management of UUTUCC Unifocal tumour Small tumour (size < 1cm) Low-grade tumour (cytology or biopsies) No evidence of an infiltrative lesion on MDCT urography Understanding of close follow-up Techniques used for conservative management of UUT-UCC Laser should be used in the case of endoscopic treatment Flexible ureteroscopy is preferable to rigid ureteroscopy Open partial resection is an option for pelvic ureteral tumours A percutaneous approach is an option for small, lowgrade, caliceal tumours unsuitable for ureteroscopic treatment MDCT = multidetector computed tomography. The instillation of Bacillus Calmette-Gurin (BCG) or mitomycin C in the urinary tract by percutaneous nephrostomy or via a ureteric stent is technically feasible after conservative treatment of UUT-UCCs. However, benefits have not been confirmed. GR B B B B B
C C C C
Advanced disease There are no benefits of RNU in metastatic (M+) disease, although it can be considered as a palliative option. As UUT-UCCs are urothelial tumours, platinum-based chemotherapy is expected to produce similar results to those seen in bladder cancer. Currently, insufficient data are available to provide any recommendations. Radiation therapy appears to be scarcely relevant nowadays both as a unique therapy and associated with chemotherapy as tumour adjuvant.
Follow-up
Strict follow-up of UUT-UCC patients after radical management is necessary in order to detect metachronous bladder tumours (in all cases), local recurrence and distant metastases (in the case of invasive tumours). With conservative management, the ipsilateral UUT requires careful follow-up due to the high risk of recurrence.
Recommendations for follow-up of UUT-UCC patients after initial treatment

After radical management, over at least 5 years Non-invasive tumour Cystoscopy/urinary cytology at 3 months and then yearly MDCT urography yearly Invasive tumour Cystoscopy/urinary cytology at 3 months and then yearly GR C C C
Upper Urinary Tract Urothelial Cell Carcinomas 27
MDCT urography every 6 months for 2 years and then C yearly After conservative management, over at least 5 years Urinary cytology and MDCT urography at 3 months, C 6 months and then yearly C Cystoscopy, ureteroscopy and cytology in situ at 3 months, 6 months, every 6 months for 2 years and then yearly MDCT = multidetector computed tomography; RNU = radical nephroureterectomy.
Figure 1: Proposed flowchart for the management of UUTUCC

UUT-UCC
Diagnostics evaluation: CT-urography, urinary cytology, cystoscopy ( ureteroscopy with biopsies)
- Unifocal tumour - Size < 1 cm - Low-grade tumour - Superficial aspect on MDCTU
Gold standard treatment: Radical nephroureterectomy
Conservative management: ureteroscopy, segmental resection, percutaneous approach Recurrence Close and stringent follow-up
Open
Laparoscopic
MDCT = multidetector computed tomography.
This short booklet text is based on the more comprehensive EAU guidelines (ISBN: 978-90-79754-96-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
Upper Urinary Tract Urothelial Cell Carcinomas 29
MUSCLE-INVASIVE AND METASTATIC BLADDER CANCER

(Text update February 2012)
A. Stenzl (chairman), J.A. Witjes (vice-chairman), E. Comprat, N.C. Cowan, M. De Santis, M. Kuczyk, T. Lebret, M.J. Ribal, A. Sherif
Introduction
Publications concerning muscle-invasive and metastatic bladder cancer are mostly based on retrospective analysis, including some larger multicentre studies and well-designed controlled studies. The studies underpinning the current guidelines were identified through a systematic literature research. It is evident that optimal treatment strategies for MIBC require the involvement of a specialist multidisciplinary team and a model of integrated care to avoid fragmentation of patient care.
Staging system
The UICC 2009 TNM (Tumour, Node, Metastasis Classification) is used for staging (Table 1).
30 Muscle-invasive and Metastatic Bladder Cancer
Table 1: 2009 TNM classification of urinary bladder cancer

T - Primary tumour TX Primary tumour cannot be assessed T0 No evidence of primary tumour Ta Non-invasive papillary carcinoma Tis Carcinoma in situ: flat tumour T1 Tumour invades subepithelial connective tissue Tumour invades muscle T2 T2a Tumour invades superficial muscle (inner half) T2b Tumour invades deep muscle (outer half) T3 Tumour invades perivesical tissue T3a Microscopically T3b Microscopically (extravesical mass) T4 Tumour invades any of the following: prostate, uterus, vagina, pelvic wall, abdominal wall T4a Tumour invades prostate, uterus or vagina T4b Tumour invades pelvic wall or abdominal wall N - Lymph nodes NX Regional lymph nodes cannot be assessed No regional lymph node metastasis N0 N1 Metastasis in a single lymph node in the true pelvis (hypogastric, obturator, external iliac or presacral) N2 Metastasis in multiple lymph nodes in the true pelvis (hypogastric, obturator, external iliac or presacral) Metastasis in a common iliac lymph node(s) N3 M - Distant metastasis M0 No distant metastasis M1 Distant metastasis Muscle-invasive and Metastatic Bladder Cancer 31
Table 2: WHO grading 1973 and 2004

(Both classifications are used for the current guidelines since most of the retrospective studies were based on the old WHO 1973 grading system). 1973 WHO grading Urothelial papilloma Grade 1: well differentiated Grade 2: moderately differentiated Grade 3: poorly differentiated 2004 WHO grading Urothelial papilloma Papillary urothelial neoplasm of low malignant potential (PUNLMP) Low-grade papillary urothelial carcinoma High-grade papillary urothelial carcinoma Morphological subtypes can be important for helping with prognosis and treatment decisions. Currently the following differentiation is used: 1. urothelial carcinoma (more than 90% of all cases) 2. urothelial carcinomas with squamous and/or glandular partial differentiation; 3. micropapillary urothelial carcinoma; 4. small-cell carcinomas; 5. some urothelial carcinomas with trophoblastic differentiation; 6. nested carcinoma: 7. spindle cell carcinomas.
Specific recommendations for primary assessment of presumably invasive bladder tumours (General information for assessment of bladder tumours, see EAU Guidelines on Non-muscle-invasive Bladder cancer)
Recommendations
Cystoscopy should describe all macroscopic features of the tumour (site, size, number and appearance) and mucosal abnormalities. A bladder diagram is recommended. Biopsy of the prostatic urethra is recommended for cases of bladder neck tumour, when bladder CIS is present or suspected, when there is positive cytology without evidence of tumour in the bladder, or when abnormalities of the prostatic urethra are visible. If biopsy is not performed during the initial procedure, it should be completed at the time of the second resection. In women undergoing a subsequent orthotopic neobladder, procedure information is required (including a histological evaluation) of the bladder neck and urethral margin, either prior to, or at the time of cystoscopy The pathological report should specify the grade, the depth of tumour invasion and whether the lamina propria and muscle tissue are present in the specimen.
GR C
Muscle-invasive and Metastatic Bladder Cancer 33
Recommendations for staging of verified bladder GR tumour

Computed tomography (CT) or magnetic resonance imaging is recommended if there is suspicion of locally advanced or metastatic disease precluding radical treatment. In patients considered eligible for radical treatment, for optimal T-staging, either MR imaging with fast dynamic contrast-enhancement or multidetector computed tomography with contrast enhancement are recommended In patients with confirmed muscle-invasive bladder cancer, computed tomography of the chest, abdomen and pelvis is the optimal form of staging, including CT urography for complete examination of the upper urinary tracts. If CT is not available, lesser alternatives are excretory urography and a chest X-ray. In patients with a verified muscle invasive lesion (TUR), abdominal pelvis and chest imaging is mandatory. MR imaging and CT are equivalent in diagnosing local and distant abdominal metastases. Computed tomography is preferred to magnetic resonance imaging for the detection of pulmonary metastases. MR = magnetic resonance; CT = computed tomography.
Treatment failure of non-muscle invasive bladder tumours Recommendations for treatment failure of nonmuscle invasive bladder cancer
In all T1 tumours at high risk of progression (i.e. high grade, multifocality, carcinoma in situ, and tumour size, as outlined in the EAU guidelines for Non-muscle-invasive bladder cancer), immediate radical cystectomy is an option. In all T1 patients failing intravesical therapy, cystectomy should be performed. GR B
Muscle-invasive bladder cancer - standard treatment

Radical Surgery and Urinary Diversion
Conclusions
For muscle-invasive bladder cancer radical cystectomy is the curative treatment of choice A higher case load reduces morbidity and mortality of cystectomy. Radical cystectomy includes removal of regional lymph nodes, the anatomical extent of which has not been sufficiently defined. Radical cystectomy in both sexes must not include the removal of the entire urethra in all cases, which may then serve as outlet for an orthotopic bladder substitution. Terminal ileum and colon are the intestinal segments of choice for urinary diversion.
LE 3 3 3
The type of urinary diversion does not affect oncological outcome. Laparoscopic and robotic-assisted laparoscopic cystectomy is feasible but still investigational. In patients with invasive bladder cancer older than 80 years cystectomy is an option. Co-morbidity, age, previous treatment for bladder cancer or other pelvic diseases, surgeon and hospital volume of cystectomy, and type of urinary diversion influence surgical outcome. Surgical complications of cystectomy and urinary diversion should be reported in a uniform grading system. Currently, the best-adapted, graded system for cystectomy is the Clavien grading system.
3 3 3 2
Contraindications for orthotopic bladder substitution are positive margins at the level of urethral dissection, positive margins anywhere on the bladder specimen (in both sexes), if the primary tumour is located at the bladder neck or in the urethra (in women), or if tumour extensively infiltrates the prostate (in men).
Recommendations for radical cystectomy
GR Radical cystectomy is recommended in T2-T4a, N0 A* M0, and high risk non-muscle-invasive BC (as outlined above). Do not delay cystectomy more than 3 months since it B increases the risk of progression and cancer-specific death.
Pre-operative radiotherapy is not recommended in case of subsequent cystectomy with urinary diversion. Lymph node dissection should be an integral part of cystectomy, but the extent of the dissection has not been established. The urethra can be preserved if margins are negative. If no bladder substitution is attached, the urethra must be checked regularly. Laparoscopic and robot-assisted laparoscopic cystectomy are both options. However, current data have not sufficiently proven the advantages or disadvantages for both oncological and functional outcomes of laparoscopic and robotic-assisted laparoscopic cystectomy. Before cystectomy, the patient should be fully informed about the benefits and potential risks of all possible alternatives, and the final decision should be based on a balanced discussion between patient and surgeon. Pre-operative bowel preparation is not mandatory, fast track measurements may reduce the time of bowel recovery. An orthotopic bladder substitute should be offered to male and female patients lacking any contraindications and who have no tumour in the urethra and at the level of urethral dissection. *Upgraded following panel consensus
Neoadjuvant chemotherapy
Neoadjuvant cisplatin-containing combination chemotherapy improves overall survival, irrespective of the type of definiMuscle-invasive and Metastatic Bladder Cancer 37
tive treatment (LE: 1a). It has its limitations regarding patient selection, current development of surgical technique, and current chemotherapy combinations.
Recommendations
Neoadjuvant chemotherapy should always be cisplatinum based. Neoadjuvant chemotherapy is not recommended in patients with PS > 2 and/or impaired renal function.
GR A B
Neoadjuvant/adjuvant radiotherapy in muscle-invasive bladder cancer Conclusions

No data exist to support that pre-operative radiotherapy for operable muscle-invasive bladder cancer increases survival Pre-operative radiotherapy for operable muscleinvasive bladder cancer, using a dose of 45-50 Gy in fractions of 1.8-2 Gy results in down-staging after 4-6 weeks. Pre-operative radiotherapy with a dose of 45-50 Gy in fractions of 1.8-2 Gy does not significantly increase toxicity after surgery. There are suggestions in older literature that preoperative radiotherapy decreases local recurrence of muscle-invasive bladder cancer. LE 2
Figure 1: Flowchart for the management for T2-T4a N0M0 urothelial bladder cancer
Diagnosis Cystoscopy and tumour resection Evaluation of urethra CT imaging of abdomen, chest, UUT MR can be used for local staging 1 - males: biopsy apical prostatic urethra or frozen section during surgery 1 - females: biopsy of proximal urethra or frozen section during surgery
Findings: pT2-3, clinical N0M0 urothelial carcinoma of the bladder
pT2N0M0 selected patients - Multimodality bladder sparing therapy can be considered for T2 tumours (Note: alternative, not the standard option)
Neoadjuvant chemotherapy Should be considered in selected patients 5-7% 5 year survival benefit
2 - neoadjuvant radiotherapy is not recommended
Radical cystectomy Know general aspects of surgery o Preparation o Surgical technique o Integrated node dissection o Urinary diversion o Timing of surgery A higher case load improves outcome
Direct adjuvant chemotherapy Not indicated after cystectomy
Bladder-sparing treatments for localised disease

Transurethral resection of bladder tumour (TURB) TURB alone is only possible as a therapeutic option if tumour growth is limited to the superficial muscle layer and if re-staging biopsies are negative for residual tumour.
External beam radiotherapy External beam radiotherapy alone should only be considered as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach. Radiotherapy can also be used to stop bleeding from the tumour when local control cannot be achieved by transurethral manipulation because of extensive local tumour growth (LE: 3).
Surgically non-curable tumours

Palliative cystectomy for metastatic disease Primary radical cystectomy in T4b bladder cancer is not a curative option. If there are symptoms, radical cystectomy may be a therapeutic/palliative option. Intestinal or nonintestinal forms of urinary diversion can be used, with or without, palliative cystectomy.
Recommendations
LE In patients with inoperable locally advanced tumours (T4b), primary radical cystectomy is a palliative option and cannot be offered as curative treatment. In patients with symptoms palliative cystectomy may be offered. 3 Prior to any further interventions, surgeryrelated morbidity and quality-of-life should be fully discussed with the patient.
GR B
Chemotherapy and best supportive care

Urothelial carcinoma is a chemo-sensitive tumour. With cisplatin-based chemotherapy as primary therapy for locally advanced tumours in highly selected patients, complete and 40 Muscle-invasive and Metastatic Bladder Cancer
partial local responses have been reported. (LE: 2b).
Recommendation
GR Chemotherapy alone is not recommended as primary A therapy for localised bladder cancer.
Adjuvant Chemotherapy Adjuvant chemotherapy is under debate. Neither randomised trials nor a meta-analysis have provided sufficient data to support the routine use of adjuvant chemotherapy (LE: 1a).
Recommendation
Adjuvant chemotherapy is advised within clinical trials, but not as a routine therapeutic option.
GR A
Multimodality treatment Conclusions

In a highly selected patient population, long-term survival rates of multimodality treatment are comparable to those of early cystectomy. Delay in surgical therapy can compromise survival rates. LE 3
2b
Muscle-invasive and Metastatic Bladder Cancer
41
Recommendations
Transurethral resection of bladder tumour (TURB) alone cannot be offered as a standard curative treatment option in most patients. Radiotherapy alone is less effective than surgery and is only recommended as a therapeutic option when the patient is unfit for cystectomy or a multimodality bladder-preserving approach. Chemotherapy alone is not recommended as primary therapy for muscle-invasive bladder cancer. Surgical intervention or multimodality treatment are the preferred curative therapeutic approaches since they are more effective than radiotherapy alone. Multimodality treatment could be offered as an alternative in selected, well-informed, well selected and compliant patients, especially for whom cystectomy is not an option.
GR B
A B
Metastatic disease Conclusions for metastatic disease

LE Performance status and the presence or absence of 3 visceral metastases are independent prognostic factors for survival. These factors are at least as important as the type of chemotherapy administered. Cisplatin-containing combination chemotherapy is 1b able to achieve a median survival of up to 14 months, with long-term disease-free survival reported in about 15% of patients with nodal disease and good performance status.
Single-agent chemotherapy provides low response rates of usually short duration. Carboplatin-combination chemotherapy is less effective than cisplatin-based chemotherapy in terms of complete response and survival. Non-platinum combination chemotherapy has produced substantial responses in first- and secondline use, but has not been tested against standard chemotherapy in fit patients or in a purely unfit patient group. To date, there is no defined standard chemotherapy for unfit patients with advanced or metastatic urothelial cancer. Vinflunine reached the highest level of evidence ever reported for second-line use. Post-chemotherapy surgery after a partial or complete response may contribute to long-term disease-free survival. Zoledronic acid and denusomab have been studied and approved for all cancer types including urothelial cancer, as they have been shown to reduce and delay skeletal-related events in metastatic bone disease.
2a 2a
2a
2b
1b 3
Recommendations for metastatic disease
GR The selection of treatment should be guided by prog- B nostic factors. First-line treatment for fit patients: Use cisplatin-containing combination chemoA therapy with GC, MVAC, preferably with GCSF, or HD-MVAC with GCSF. Carboplatin and non-platinum combination chemo- B therapy are not recommended. Muscle-invasive and Metastatic Bladder Cancer 43
First-line treatment in patients ineligible (unfit) for cisplatin: Use carboplatin combination chemotherapy or single C agents. For cisplatin-ineligible patients (unfit) with either A PS 2 or impaired renal function, or with 0-1 poor Bajorin prognostic factors, first-line treatment is carboplatin-containing combination chemotherapy, preferably with gemcitabine/carboplatin. Second-line treatment: A* In patients progressing after platinum-based combination chemotherapy for metastatic disease, vinflunine should be offered. Alternatively, treatment within a clinical trial setting may be offered. Zoledronic Acid or denosumab, are recommended for B the treatment of bone metastases. *Grade A recommendation is weak by a problem of statistical significance.
Recommendation for the use of biomarkers

Currently, no biomarkers can be recommended in daily clinical practice since they have no impact on predicting outcome, treatment decisions or monitoring therapy in muscle-invasive bladder cancer. *Upgraded following panel consensus.
GR A
Figure 2: Flowchart for the management of metastatic urothelial cancer

Patient characteristics: PS 0-1/ 2/ >2 GFR >/< 60ml/min Comorbidities
YES
PS 0 -1 and GFR > 60ml/min STANDARD GC MVAC HD MVAC
CISPLATIN? NO
NO
PS 2 or GFR < 60ml/min comb. chemo: Carbo- based
PS > 2 and GFR < 60ml/min NO comb.chemo studies, monotherapy, BSC
Second-line treatment
PS 0-1
PS > 2
1. Progression > 6 -12 months after first-line chemotherapy, adequate renal function a. re-exposition to first line treatment (cisplatin based) b. clinical study
2. Progression > 6 -12 months after first-line chemotherapy, PS 0-1, impaired renal function a. Vinflunine b. clinical study
3. Progression < 6 -12 months after first-line chemotherapy, PS 0-1 a. Vinflunine b. clinical study
a. best supportive care b. clinical study
Health-related quality-of-life (HRQoL)

No randomised, prospective HRQoL study has evaluated the different forms of definitive treatment for muscle-invasive bladder cancer. Important determinants of (subjective) quality of life are a patients personality, coping style and social support.
Recommendations for HRQoL

The use of validated questionnaires is recommended to assess HRQoL in patients with muscle-invasive bladder cancer. Unless a patients co-morbidities, tumour variables and coping abilities present clear contra-indications, a continent urinary diversion should be offered. Pre-operative patient information, patient selection, surgical techniques, and careful post-operative follow-up are the cornerstones for achieving good long-term results. Patient should be encouraged to take active part in the decision-making process. Clear and exhaustive information on all potential benefits and side-effects should be provided, allowing them to make informed decisions.
GR B
Recommendations for general follow-up

Follow-up is based on the stage of initial tumour after cystectomy. At every visit, the following should be performed: history; physical examination; bone scan only when indicated. Tables have been set up (see EAU Guidelines 2012 version), based on expert opinion which, however, do not include non-oncological follow-up. They comprise a minimum set of tests that must be performed during follow-up (GR: C; LE: 4). After 5 years of follow-up, stop oncological surveillance and continue with functional surveillance. 46 Muscle-invasive and Metastatic Bladder Cancer
This short booklet text is based on the more comprehensive EAU guidelines (ISBN978-90-79754-83-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
GUIDELINEs ON PROsTATE CANCER

A. Heidenreich (chairman), P.J. Bastian, J. Bellmunt, M. Bolla, S. Joniau, T.H. van der Kwast, M.D. Mason, V. Matveev, N. Mottet, T. Wiegel, F. Zattoni Eur Urol 2008 Jan;53(1):68-80 Eur Urol 2011 Jan;59(1):61-71 Eur Urol 2011 Apr;59(4):572-83
Introduction
Cancer of the prostate (PCa) is currently the second most common cause of cancer death in men. In developed countries PCa accounts for 15% of male cancers compared with 4% of male cancers in developing countries. Within Europe exist also large regional differences in the incidence rates of PCa. There are three well-established risk factors for PCa: increasing age, ethnic origin, and genetic predisposition. Clinical data suggest that exogenous risk factors, such as diet, pattern of sexual behaviour, alcohol consumption, exposure to ultraviolet radiation, and occupational exposure may also play an important role in the risk of developing PCa. The introduction of an effective blood test, prostate-specific antigen (PSA), has resulted in more early-stage prostate cancer diagnosis where potentially curative treatment options 48 Prostate Cancer
can be provided. However, if effective diagnostic procedures are inappropriately used in elderly men with a short life span, the issue of over-diagnosis and over-treatment may occur. Consequently, the same stage of prostate cancer may require different treatment strategies depending on an individual patients life expectancy.
staging system
The 7th edition Union Internationale Contre le Cancer (UICC) 2009 Tumour Node Metastasis (TNM) classification is used for staging (Table 1).
Table 1: Tumour Node Metastasis (TNM) classification of cancer of the prostate

T - Primary tumour TX T0 T1 Primary tumour cannot be assessed No evidence of primary tumour Clinically unapparent tumour not palpable or visible by imaging T1a Tumour incidental histological finding in 5% or less of tissue resected T1b Tumour incidental histological finding in more than 5% of tissue resected T1c Tumour identified by needle biopsy (e.g. because of elevated PSA level) Tumour confined within the prostate1 T2a Tumour involves one half of one lobe or less
T2
Prostate Cancer 49
T3
T4
T2b Tumour involves more than half of one lobe, but not both lobes T2c Tumour involves both lobes Tumour extends through the prostatic capsule2 T3a Extracapsular extension (unilateral or bilateral) T3b Tumour invades seminal vesicle(s) Tumour is fixed or invades adjacent structures other than seminal vesicles: external sphinter, rectum, levator ani and/or pelvic wall Regional lymph nodes cannot be assessed No regional lymph node metastasis Regional lymph node metastasis No distant metastasis Distant metastasis M1a Non-regional lymph node(s) M1b Bone(s) M1c Other site(s)
N - Regional lymph nodes3 NX N0 N1 M0 M1
M - Distant metastasis4
1 Tumour
found in one or both lobes by needle biopsy, but not palpable or visible by imaging, is classified as T1c. 2 Invasion into the prostatic apex, or into (but not beyond) the prostatic capsule, is not classified as T3, but as T2. 3 The regional lymph nodes are the nodes of the true pelvis, which are essentially the pelvic nodes below the bifurcation of the common iliac arteries. Laterality does not affect the N classification. 4 When more than one site of metastasis is present, the most advanced category should be used.
50 Prostate Cancer
Gleason grading system

The most commonly used system for grading PCa is the Gleason grading system.
Diagnosis and staging

The decision whether to proceed with further diagnostic or staging work-up is guided by which treatment options are available to the patient, taking the patients age and comorbidity into consideration. Procedures that will not affect the treatment decision can usually be avoided. Synoptic reporting of surgical specimens results in more transparent and more complete pathology reporting. The use of a checklist is encouraged and two examples are presented here. Checklist for pathology reporting of prostate biopsies 1. Histological type of carcinoma 2. Histological grade (global or highest) Primary grade Secondary (= highest) grade 3. Fraction of involved cores Number of cores involved by carcinoma Total number of cores 4. Tumour quantification Percentage of prostatic tissue involved by carcinoma or total mm of cancer length 5. Tumour extent Identification of perineural invasion Identification of extra-prostatic extension Identification of seminal vesicle invasion Prostate Cancer 51
Checklist for processing and pathology reporting of radical prostatectomy (RP) specimens 1. Processing of RP specimens Total embedding of a prostatectomy specimen is preferred, either by conventional (quadrant sectioning) or by whole-mount sectioning The entire surface of RP specimens should be inked before cutting in order to evaluate the surgical margin status The apex should be separately examined using the cone method with sagittal or radial sectioning 2. Histological type 3. Histological grade Primary (predominant) grade Secondary grade Tertiary grade (if exceeding > 5% of PCa volume) Global Gleason score Approximate percentage of Gleason grade 4 or 5 (optional) 4. Tumour quantification (optional) Percentage of prostatic tissue involved Tumour size of dominant nodule (if identified), greatest dimension in mm 5. Pathological staging (pTNM) Presence of extraprostatic extension (focal or extensive), specify sites Presence of seminal vesicle invasion Presence of lymph node metastases, number of retrieved lymph nodes and number of positive lymph nodes 6. Surgical margins Presence of carcinoma at margin 52 Prostate Cancer
If present, specify site(s) and extra- or intra-prostatic invasion 7. Other If identified, presence of angioinvasion Location (site, zone) of dominant tumour (optional) Perineural invasion (optional) If present, specify extra- or intra-prostatic invasion A short summary of the guidelines on diagnosis and staging of PCa are presented in Table 2.
Guidelines for the diagnosis and staging of PCa

Diagnosis of PCa 1. An abnormal digital rectal examination (DRE) result or elevated serum PSA measurement could indicate PCa. The exact cut-off level of what is considered to be a normal PSA value has yet to be determined, but values of approximately < 2-3 ng/mL are often used for younger men. The diagnosis of PCa depends on histopathological (or cytological) confirmation. Biopsy and further staging investigations are only indicated if they affect the management of the patient. GR C
2.
B C
Prostate Cancer 53
3.
Transrectal ultrasound (TRUS)-guided systemic biopsy is the recommended method in most cases of suspected PCa. At least 8 systemic, laterally directed, cores are recommended, with perhaps more cores in larger volume prostates. Transition zone biopsies are not recommended in the first set of biopsies due to low detection rates. One set of repeat biopsies is warranted in cases with persistent indication for PCa (abnormal DRE, elevated PSA or histopathological findings suggestive of malignancy at the initial biopsy). Overall recommendations for further (three or more) sets of biopsies cannot be made; the decision must be made based on an individual patient.
4.
Transrectal peri-prostatic injection with a local A anaesthetic can be offered to patients as effective analgesia when undergoing prostate biopsies. Staging of PCa Local staging (T-staging) of PCa should be based on magnetic resonance (MR) imaging. Further information is provided by the number and sites of positive prostate biopsies, the tumour grade and the level of serum PSA. C
1.
54 Prostate Cancer
Despite its high specificity in the evaluation of extraprostatic extension (EPE) and seminal vesicle invasion or involvement (SVI), TRUS is limited by poor contrast resolution, resulting in low sensitivity and a tendency to understage PCa. Even with the advent of colour- and power Doppler to assist in identifying tumour vascularity, the accuracy of TRUS in local staging remains inadequate. In comparison with DRE, TRUS and computed tomography (CT), MR imaging demonstrates higher accuracy for the assessment of uni- or bi-lobar disease (T2), EPE and SVI (T3), as well as the invasion of adjacent structures (T4). The addition of dynamic contrast-enhanced MR imaging (DCE-MRI) can be helpful in equivocal cases. The addition of magnetic resonance spectroscopic imaging (MRSI) to MRI also increases accuracy and decreases inter-observer variability in the evaluation of EPE. 2. Lymph node status (N-staging) is only important when potentially curative treatment is planned. Patients with stage T2 or less, PSA < 20 ng/mL and a Gleason score < 6 have a lower than 10% likelihood of having node metastases and can be spared nodal evaluation. Given the significant limitations of pre-operative imaging in the detection of small metastases (< 5 mm), pelvic lymph node dissection (PLND) remains the only reliable staging method in clinically localised PCa.
Prostate Cancer 55
Currently, it seems that only methods of histological detection of lymph node metastases with high sensitivity, such as sentinel lymph node dissection or extended PLND, are suitable for lymph node staging in PCa. 3. Skeletal metastasis (M-staging) is best assessed by bone scan. This may not be indicated in asymptomatic patients if the serum PSA level is < 20 ng/mL in the presence of well or moderately differentiated tumours. In equivocal cases, 11C-choline-, 18F-flouridePET/CT or whole body MRI are an option.
Treatment of prostate cancer

An overview of the treatment options for patients with PCa, subdivided by stage at diagnosis, is presented in Table 3. Due to a lack of randomised controlled trials in PCa, one therapy option cannot be considered superior to another. However, based on the currently available literature, the recommendations presented in Table 3 can be made.
56 Prostate Cancer
Guidelines for the primary treatment of PCa

Stage Treatment T1a Watchful waiting Comment Standard treatment for Gleason score < 6 and 7 adenocarcinomas and < 10-year life expectancy. Active surveil- In patients with > 10-year life lance expectancy, re-staging with TRUS and biopsy is recommended. Radical pros- Optional in younger patients with a long life expectancy, tatectomy especially for Gleason score > 7 adenocarcinomas Radiotherapy Optional in younger patients with a long life expectancy, in particular in poorly differentiated tumours. Higher complication risks after TURP, especially with interstitial radiation. Hormonal Not an option. Combination Not an option. Active surveil- Treatment option in patients with cT1c-cT2a, PSA lance < 10 ng/mL, biopsy Gleason score < 6, < 2 biopsies positive, < 50% cancer involvement of each biopsy. Patients with a life expectancy < 10 years. GR B
T1bT2b
A C B
Prostate Cancer 57
T1aT2c
Patients with a life expectancy > 10 years once they are informed about the lack of survival data beyond 10 years. Patients who do not accept treatment-related complications. Radical pros- Optional in patients with pT1a A tatectomy PCa. Standard treatment for patients with a life expectancy > 10 years who accept treatment-related complications. Radiotherapy Patients with a life expectancy B > 10 years who accept treatment-related complications. Patients with contraindications for surgery. Unfit patients with 5-10 years of life expectancy and poorly differentiated tumours (combination therapy is recommended; see below). B Brachytherapy Low-dose rate brachytherapy can be considered for low risk PCa patients with a prostate volume < 50 mL and an IPSS < 12.
58 Prostate Cancer
Hormonal
Combination
T3T4
Watchful waiting
Radical prostatectomy
Symptomatic patients, who need palliation of symptoms, unfit for curative treatment. Anti-androgens are associated with a poorer outcome compared to active surveillance and are not recommended. For high-risk patients, neoadjuvant hormonal treatment and concomitant hormonal therapy plus radiotherapy results in increased overall survival. Option in asymptomatic patients with T3, well-differentiated and moderately-differentiated tumours, and a life expectancy < 10 years who are unfit for local treatment. Optional for selected patients with T3a, PSA < 20 ng/mL, biopsy Gleason score < 8 and a life expectancy > 10 years. Patients have to be informed that RP is associated with an increased risk of positive surgical margins, unfavourable histology and positive lymph nodes and that, therefore, adjuvant or salvage therapy such as radiation therapy or androgen deprivation might be indicated.
Prostate Cancer 59
Radiotherapy
Hormonal
Combination
T3 with > 5-10 years of life expectancy. Dose escalation of > 74 Gy seems to be of benefit. A combination with hormonal therapy can be recommended (see below). Symptomatic patients, extensive T3-T4, high PSA level (> 25-50 ng/mL), PSADoubling Time (DT) < 1 year. Patient-driven, unfit patients. Hormone monotherapy is not an option for patients who are fit enough for radiotherapy. Overall survival is improved by concomitant and adjuvant hormonal therapy (3 years) combined with external beam radiation. NHT plus radical prostatectomy: no indication.
60 Prostate Cancer
N+, M0
Watchful waiting
Radiotherapy
Hormonal
Combination M+ Watchful waiting
Asymptomatic patients. Patient-driven (PSA < 20-50 ng/mL), PSA DT > 12 months. Requires very close follow-up. Optional for selected patients with a life expectancy of > 10 years as part of a multimodal treatment approach. Optional in selected patients with a life expectancy of > 10 years, combination therapy with adjuvant androgen deprivation for 3 years is mandatory. Standard adjuvant therapy in more than 2 positive nodes to radiation therapy or radical prostatectomy as primary local therapy. Hormonal therapy should only be used as monotherapy in patients who are unfit for any type of local therapy. No standard option. Patient-driven. No standard option. May have worse survival/more complications than with immediate hormonal therapy. Requires very close follow-up. Not a standard option.
B B
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61
Radiotherapy
Hormonal
Not an option for curative C intent; therapeutic option in combination with androgen deprivation for treatment of local cancer-derived symptoms. Standard option. Mandatory in A symptomatic patients.
For more detailed information and discussion on second-line therapy, please see the full text version of the guidelines.
Follow-up of prostate cancer patients

Determination of serum PSA, disease-specific history and DRE are the cornerstones in the follow-up of PCa patients. Routine imaging procedures in stable patients are not recommended and should only be used in specific situations.
Guidelines for follow-up after treatment with curative intent
GR
In asymptomatic patients, a disease-specific history B and a serum PSA measurement supplemented by DRE are the recommended tests for routine follow-up. These should be performed at 3, 6 and 12 months after treatment, then every 6 months until 3 years, and then annually. After RP, a serum PSA level > 0.2 ng/mL can be asso- B ciated with residual or recurrent disease. After radiation therapy, a rising PSA level > 2 ng/mL B above the nadir PSA, rather than a specific threshold value, is the most reliable sign of persistent or recurrent disease. 62 Prostate Cancer
Both a palpable nodule and a rising serum PSA level can be signs of local disease recurrence. Detection of local recurrence by TRUS and biopsy is only recommended if it will affect the treatment plan. In most cases TRUS and biopsy are not necessary before second-line therapy. Metastasis may be detected by pelvic CT/MRI or bone scan. In asymptomatic patients, these examinations may be omitted if the serum PSA level is < 20 ng/mL. Routine bone scans and other imaging studies are not recommended in asymptomatic patients. If a patient has bone pain, a bone scan should be considered irrespective of the serum PSA level.
B B
Guidelines for follow-up after hormonal treatment GR

Patients should first be evaluated at 3 and 6 months after treatment initiation. Tests should at least include serum PSA measurement, DRE, serum testosterone and careful evaluation of symptoms in order to assess the treatment response and side-effects. If patients undergo intermittent androgen deprivation, PSA and testosterone should be monitored at 3 month intervals during the treatment pause. Follow-up should be tailored to the individual patient, according to symptoms, prognostic factors and the treatment given. In patients with stage M0 disease with a good treatment response, follow-up is scheduled every 6 months, and should include at least a disease-specific history, DRE and serum PSA measurement. B
Prostate Cancer 63
In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every 3 to 6 months. Follow-up should include at least a diseasespecific history, DRE and serum PSA measurement, frequently supplemented with haemoglobin, serum creatinine and alkaline phosphatase measurements. Patients (especially with M1b status) should be advised about the clinical signs that could suggest spinal cord compression. Where disease progression occurs, or if the patient does not respond to the treatment given, follow-up needs to be individualised. Routine imaging of stable patients is not recommended.
Treatment of relapse after curative therapies

An effort should be made to distinguish between the probability of local failure only versus distant (+/- local) failure. Initial pathology, how long after primary therapy the PSArelapse occurs and how fast the PSA-value is rising can all aid in the distinction between local and distant failure. Poorly differentiated tumour, early PSA-relapse and a short PSAdoubling time are all signs of distant failure. Treatment can then be guided by the presumed site of failure, the patients general condition and personal preferences. Imaging studies are of limited value in patients with early PSA-relapse only.
64 Prostate Cancer
Guidelines for second-line therapy after curative treatments

Presumed local failure after radical prostatectomy
GR
B Patients with presumed local failure only may be candidates for salvage radiotherapy. This should be given with at least 64 Gy and preferably before PSA has risen above 0.5 ng/mL. Other patients are best offered a period of active surveillance (active monitoring), with possible hormonal therapy later on. C Selected patients may be candidates Presumed for salvage RP and they should be local failure informed about the high risk of comafter radioplications, such as incontinence and therapy erectile dysfunction. Salvage prostatectomy should only be performed in experienced centres. Other patients are best offered a period of active surveillance (active monitoring), with possible hormonal therapy later on. Presumed dis- There is some evidence that early B tant failure hormonal therapy may be of benefit in +/- local failure, delaying progression, and possibly achieving a survival benefit in comparison with delayed therapy. The results are controversial. Local therapy is not recommended except for palliative reasons.
Prostate Cancer 65
Treatment of relapse after hormonal therapy

Castration-refractory PCa (CRPC) is usually a debilitating disease, often affecting elderly patients. A multidisciplinary approach is required with input from medical oncologists, radiation oncologists, urologists, nurses, psychologists and social workers. In most cases the decision whether to treat or not is made based on counselling of the individual patient, which limits the role of guidelines.
Guidelines for secondary hormonal management in GR patients with CRPC

Anti-androgen therapy should be stopped once PSA B progression is documented. No clear-cut recommendation can be made for the C most effective drug for secondary hormonal manipulations because data from randomised trials are scarce. However, abiraterone and MDV3100 may address this issue once final data from the prospective randomised Phase III clinical trials are analysed. Comment: An eventual anti-androgen withdrawal effect should become apparent 4-6 weeks after the discontinuation of flutamide or bicalutamide.
66 Prostate Cancer
Guidelines for cytotoxic therapy in patients with CRPC

Patients with CRPC should be counselled, managed and treated in a multidisciplinary team. In non-metastatic CRPC, cytotoxic therapy should only be used in a clinical trial setting. In patients with a PSA rise only, two consecutive increases of PSA serum levels above a previous reference level should be documented. Prior to treatment, testosterone serum levels should be below 32 ng/dL. Prior to treatment, PSA serum levels should be > 2 ng/mL to assure correct interpretation of therapeutic efficacy. Potential benefits of cytotoxic therapy and expected side-effects should be discussed with each individual patient. In patients with metastatic CRPC who are candidates for cytotoxic therapy, docetaxel at 75 mg/m2 every 3 weeks is the drug of choice since it has shown a significant survival benefit. In patients with symptomatic osseous metastases due to CRPC, either docetaxel or mitoxantrone with prednisone or hydrocortisone are viable therapeutic options. If not contraindicated, docetaxel is the preferred agent based on the significant advantage in pain relief. In patients with relapse following first-line docetaxel chemotherapy, based on the results of prospective randomised clinical phase III trials, Cabazitaxel and Abiraterone are regarded as first-choice option for second-line treatment.
GR
B B
B B
Prostate Cancer 67
Second-line docetaxel may be considered in previously responding docetaxel-treated patients. Otherwise treatment is to be tailored to the individual patients. In case patients are not eligible for cabazitaxel or abiraterone, docetaxel is an option.
Guidelines for palliative management of patients with CRPC

Patients with symptomatic and extensive osseous metastases cannot benefit from medical treatment with regard to life prolongation. Management of these patients has to be directed at improving quality of life and providing pain reduction. Effective medical management with the highest efficacy and a low frequency of side-effects is the major goal of therapy. Bisphosphonates (e.g. zoledronic acid) should be offered to patients with skeletal masses to prevent osseous complications. However, the benefits must be balanced against the toxicity of these agents, in particular, jaw necrosis must be avoided. Palliative treatments, such as radionuclides, external beam radiotherapy and adequate use of analgesics, should be considered early on in the management of painful osseous metastases. Spinal surgery or decompressive radiotherapy are emergency surgeries which have to be considered for patients with neurological symptoms thought to be critical.
GR A
68 Prostate Cancer
summary
Prostate cancer is a complex disease, in which many aspects of the disease itself and the affected patient must be considered before decisions regarding diagnostic work-up, treatment and follow-up can be made.
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GUIDELINES ON RENAL CELL CARCINOMA

(Text update April 2010)
B. Ljungberg (Chairman), N. Cowan, D.C. Hanbury, M. Hora, M.A. Kuczyk, A.S. Merseburger, P.F.A. Mulders, J-J. Patard, I.C. Sinescu Eur Urol 2001 Sep;40(3):252-5 Eur Urol 2007 Jun;51(6):1502-10
Introduction
Renal cell carcinoma (RCC) represents 2-3% of all cancers, with the highest incidence occurring in Western countries. In Europe, until recently, there was a general annual increase of 2% in the incidence. However, incidence rates of RCC have now stabilised or declined in some countries (Sweden, Denmark), while other European countries are still showing an upward trend in the incidence of RCC. The use of imaging techniques such as ultrasound (US) and computed tomography (CT) has increased the detection of asymptomatic RCC. In addition, during the last 10 years, mortality rates have generally stabilised and declined prominently in some European countries. The peak incidence of RCC occurs between 60 and 70 years of age, with a 1.5:1 ratio of men to women. Aetiological factors include lifestyle factors, such as smoking, obesity, and hypertension. The 70 Renal Cell Carcinoma
most effective prophylaxis is to avoid cigarette smoking and obesity.
Diagnosis and classification

More than 50% of RCCs are diagnosed incidentally. Asymptomatic RCCs are generally smaller and of a lower stage than symptomatic RCCs. In their natural clinical course, RCCs remain asymptomatic and non-palpable until late. The classic triad of flank pain, gross haematuria and palpable abdominal mass is seldom found (6-10%). Clinical symptoms include macroscopic haematuria, palpable mass, arising varicocele, or bilateral lower extremity oedema; these symptoms should initiate radiological examinations. Paraneoplastic symptoms (e.g. hypertension, weight loss, pyrexia, neuromyopathy, anaemia, polycythaemia, amyloidosis, elevated erythrocyte sedimentation rate, and abnormal liver function) are found in approximately 20-30% of patients with RCC. About 20-30% of patients with symptoms present as a result of metastatic disease. Total renal function should always be evaluated. In patients with any sign of impaired renal function, a renal scan and total renal function evaluation should be undertaken to optimise the treatment decision.
Staging system
The current UICC 2009 TNM (Tumour Node Metastasis) classification is recommended for the staging of RCC.
Renal Cell Carcinoma
71
Table 1: The 2009 TNM classification for RCC

T - Primary tumour Primary tumour cannot be assessed TX No evidence of primary tumour T0 Tumour < 7 cm in greatest dimension, limited to the T1 kidney T1a Tumour < 4 cm in greatest dimension, limited to the kidney T1b Tumour > 4 cm but < 7 cm in greatest dimension Tumour > 7 cm in greatest dimension, limited to the T2 kidney T2a Tumour > 7 cm in greatest dimension but < 10 cm T2b Tumours > 10 cm limited to the kidney Tumour extends into major veins or perinephric tisT3 sues, but not into the ipsilateral adrenal gland and not beyond Gerotas fascia T3a Tumour grossly extends into the renal vein or its segmental (muscle-containing) branches, or tumour invades perirenal and/or renal sinus (peripelvic) fat but not beyond Gerotas fascia T3b Tumour grossly extends into the vena cava below diaphragm T3c Tumour grossly extends into vena cava or its wall above the diaphragm or invades the wall of the vena cava T4 Tumour invades beyond Gerotas fascia (including contiguous extension into the ipsilateral adrenal gland) 72 Renal Cell Carcinoma
N - Regional lymph nodes NX Regional lymph nodes cannot be assessed No regional lymph node metastasis N0 Metastasis in a single regional lymph node N1 Metastasis in more than one regional lymph node N2 M - Distant metastasis M0 No distant metastasis M1 Distant metastasis
Histopathological classification
Fuhrman nuclear grade is the most commonly used grading system. The most aggressive pattern observed defines the Fuhrman grade. RCC comprises four different subtypes with genetic and histological differences: clear cell RCC (cRCC, 80-90%), papillary RCC (pRCC, 10-15%), chromophobe RCC (chRCC, 4-5%), and collecting-duct carcinoma (1%). Generally, the RCC types have different clinical courses and responses to therapy. Fuhrman grading and RCC subtype classification are recommended. There are several integrated prognostic systems and nomograms that combine dependent prognostic factors, which can be useful for predicting survival and differentiating follow-up. Molecular markers and gene expression profiles appear promising for the prediction of survival, but cannot be recommended yet in routine practice.
Other renal tumours

The common RCC types account for 85-90% of all renal malignancies. The remaining 10-15% of renal tumours Renal Cell Carcinoma 73
include a variety of uncommon carcinomas, a group of unclassified carcinomas, and several benign kidney tumour masses. Except for angiomyolipomas, most of these less common renal tumours cannot be differentiated from RCC by radiological imaging and should therefore be treated in the same way as RCC. Renal cysts with a Bosniak classification > III should be surgically treated. In oncocytomas verified on biopsy, follow-up can be considered as an option. In angiomyolipomas, treatment (surgery, thermal ablation, and selective arterial embolisation) can be considered when the tumour > 4 cm. When possible, a nephronsparing procedure should be performed. A standardised oncological programme does not exist for advanced uncommon types of renal tumours.
Radiological investigations of RCC

Radiological investigations of RCC should include CT imaging, before and after intravenous contrast to verify the diagnosis and provide information on the function and morphology of the contralateral kidney and assess tumour extension, including extrarenal spread, venous involvement, and enlargement of lymph nodes and adrenals. Abdominal US and magnetic resonance imaging (MRI) are alternatives to CT. Contrast-enhanced US can be helpful in specific cases. Magnetic resonance imaging can be reserved for patients with possible venous involvement, or allergy to intravenous contrast. Chest CT is the most accurate chest staging; a routine chest x-ray should be done as a minimum. Renal masses 74 Renal Cell Carcinoma
may be classified as solid or cystic by imaging criteria. For evaluating solid renal masses, the presence of enhancement is the most important criteria for differentiating malignant lesions. For evaluating renal cystic masses, the Bosniak classification may be used. Other diagnostic procedures (bone scan, MRI, brain CT) should only be considered if indicated by clinical symptoms or laboratory results in selected cases. Renal arteriography and inferior venacavography have only a limited role in the work-up of selected patients with kidney tumours. The true value of positron emission tomography (PET) in the diagnosis and follow-up of RCC remains to be determined and is currently not standard. In patients with any sign of impaired renal function, an isotope renogram and total renal function evaluation should be considered to evaluate the need to preserve renal function. Renal biopsy There is an increasing indication for biopsy of renal tumours, as in ablative therapies and in patients being treated with surveillance or systemic therapy without previous histopathology. Core biopsy has demonstrated a high specificity and sensitivity for determining eventual malignancy, but about 20% of biopsies are non-conclusive. Percutaneous biopsy is rarely required for large renal masses scheduled for nephrectomy since it will not alter management. Fine-needle biopsy has only a limited role in the clinical work-up of patients with renal masses.
Renal Cell Carcinoma 75
Guidelines for the primary treatment of RCC

Until recently, the standard for curative therapy of RCC was radical nephrectomy with complete removal of the tumourbearing kidney with perirenal fat and Gerotas fascia. For localised RCCs, nephron-sparing surgery is recommended. Radical nephrectomy is recommended for patients with localised RCC, who are not suitable for nephron-sparing surgery due to locally advanced tumour growth, when partial resection is technically not feasible due to an unfavourable localisation of the tumour, or when the patients general health has significantly deteriorated. Complete resection of the primary RCC either by open or laparoscopic surgery offers a reasonable chance for cure. If pre-operative imaging is normal, routine adrenalectomy is not indicated. Lymphadenectomy should be restricted
Table 2: 2010 recommendations for primary surgical treatment of RCC according to T-stage
Stage T1 Surgery Nephron-sparing surgery Radical nephrectomy Open Laparoscopic Laparoscopic Open Laparoscopic Open Open Laparoscopic
T2
Radical nephrectomy Nephron-sparing surgery Radical nephrectomy
T3,T4
76 Renal Cell Carcinoma
to staging because extended lymphadenectomy does not improve survival. In patients who have RCCs with tumour thrombus and no metastatic spread, prognosis is improved after nephrectomy and complete thrombectomy. Embolisation of the primary tumour is indicated in patients with gross haematuria or local symptoms (e.g. pain), in patients unfit for surgical intervention, and before surgical resection of large skeletal metastases. No benefit is associated with tumour embolisation before routine radical nephrectomy. Nephron-sparing surgery Absolute indications for partial nephrectomy are anatomical or functional solitary kidney or bilateral RCC. Relative indications are a functioning opposite kidney affected by a condition that might impair renal function and hereditary
Recommendations Recommended standard Optional in experienced centres In patients not suitable for nephron-sparing surgery Optional in patients not suitable for nephron-sparing surgery Recommended standard Adequate and recommended, but carries a higher morbidity Feasible in selected patients in experienced centres Recommended standard Feasible in selected patients Renal Cell Carcinoma 77
forms of RCC with a high risk of developing a tumour in the contralateral kidney. Localised unilateral RCC with a healthy contralateral kidney is an indication for elective surgery. Nephron-sparing surgery is recommended for patients with localised RCC, as recurrence-free and long-term survival rates are similar to those for radical nephrectomy. Even in selected patients with a tumour diameter of up to 7 cm, nephron-sparing surgery has achieved results equivalent to those of a radical approach. If the tumour is completely resected, the thickness of the surgical margin (> 1 mm) does not correlate with the likelihood of local recurrence. If RCCs of larger size are treated with nephron-sparing surgery, follow-up should be intensified, as there is an increased risk of intrarenal recurrences. Laparoscopic radical and partial nephrectomy Laparoscopic radical nephrectomy has a lower morbidity compared with open surgery. It has become an established surgical procedure for RCC. Whether done retro- or transperitoneally, the laparoscopic approach must duplicate established, open surgical, oncological principles. Long-term outcome data indicate equivalent cancer-free survival rates versus open radical nephrectomy. Thus, laparoscopic radical nephrectomy is now considered the standard of care for patients with T1 and T2 RCCs, who are not treatable by nephron-sparing surgery. Laparoscopic radical nephrectomy should not be performed in patients with T1 tumours for whom partial resection is indicated. Laparoscopic nephrectomy is expected to become a widely available treatment option 78 Renal Cell Carcinoma
and should be promoted in centres treating RCC. In experienced hands, partial laparoscopic nephrectomy may be an alternative to open nephron-sparing surgery in selected patients. The optimal indication for laparoscopic nephronsparing surgery is a relatively small and peripheral tumour. Laparoscopic partial resection has a longer intra-operative ischaemia time than open partial nephrectomy and therefore carries a higher risk for reduced long-term renal function. It also has a higher surgical complication than open surgery. However, the oncological outcome seems comparable in available series. Robotic-assisted partial nephrectomy has been introduced, but requires further evaluation and more mature data before any conclusive recommendations can be made. Conclusion: Radical nephrectomy, preferably laparoscopic, is recommended for patients with localised RCC, who are not suitable for nephron-sparing surgery. Open partial nephronsparing surgery remains the standard of care. Laparoscopic partial nephrectomy should be limited to experienced centres. Minimally invasive alternative treatment Minimally invasive techniques, such as ablation with percutaneous radio-frequency, cryotherapy, microwave, and high-intensity focused US (HIFU), are suggested alternatives to surgery. Potential advantages of these techniques include reduced morbidity, outpatient therapy, and the ability to treat high-risk patients not fit for conventional surgery. These experimental treatments might be recommended for Renal Cell Carcinoma 79
selected patients with small, incidentally found, renal cortical lesions, elderly patients, patients with a genetic predisposition to multiple tumours, patients with a solitary kidney, or patients with bilateral tumours. The oncological efficacy remains to be determined for both cryotherapy and radiofrequency ablation (RFA), which are the most often used minimally invasive techniques. Current data suggest that cryoablation, when performed laparoscopically, results in fewer re-treatments and improved local tumour control compared with RFA. For both treatments, tumour recurrence rates are higher compared with nephron-sparing surgery. Further research is needed to determine the oncological success rate and complications associated with these procedures.
Adjuvant therapy
Adjuvant tumour vaccination may improve the duration of the progression-free survival (PFS), which is especially important in patients at high risk of metastases, e.g. T3 RCC. Cytokine therapy does not improve survival after nephrectomy. Although there is no current data supporting adjuvant therapy with targeting agents, three worldwide phase III randomised trials are ongoing. Outside controlled clinical trials, there is no indication for adjuvant therapy following surgery. Surgical treatment of metastatic RCC (mRCC) Nephrectomy of the primary tumour is curative only if surgery can excise all tumour deposits. For most patients with mRCC, nephrectomy is only palliative. In a meta-analysis of two randomised studies, comparing nephrectomy + immunotherapy versus immunotherapy alone, increased longterm survival was found in patients who underwent prior 80 Renal Cell Carcinoma
nephrectomy. In patients with a good performance status (PS), tumour nephrectomy + interferon-alpha (IFN-) can be recommended. For targeting agents, there is no current knowledge whether cytoreductive surgery is advocated before or after successful medical therapy. However, in the absence of available evidence data, cytoreductive nephrectomy is recommended when possible. Complete removal of metastases contributes to improved clinical prognosis. Metastasectomy should be carried out in patients with resectable disease and a good PS. It should also be considered in patients with residual and respectable metastatic lesions, who have previously responded to systemic therapy. Radiotherapy for metastases For selected patients with non-resectable brain or osseous lesions, radiotherapy can induce significant symptom relief.
Systemic therapy for mRCC

Chemotherapy Chemotherapy is considered ineffective in patients with RCC. Immunotherapy Available data show that immunotherapy with IFN- is beneficial in only a limited subset of patients; those with good PS, a PFS of > 1 year following initial diagnosis, and preferably the lung as the sole metastatic site. Randomised studies comparing targeting agents in a first-line setting to IFN- monotherapy have demonstrated superiority for either Renal Cell Carcinoma 81
sunitinib, bevacizumab + IFN-, or temsirolimus. IFN- monotherapy only remains an option in selected patients as first-line therapy for mRCC. High-dose bolus interleukin-2 (IL-2) gives durable complete responses in a limited number of patients; however, the toxicity associated with IL-2 is substantially higher than that with IFN-. To date, no superiority has been shown for treatment with either IFN- or IL-2 in mRCC patients. Only patients with cRCC benefit clinically from immunotherapy. A combination of cytokines, with or without additional chemotherapy, does not improve overall survival compared with monotherapy. The MSKCC (Motzer) prognostic criteria can be used for risk stratification including; Karnowsky performance status (< 80), time from diagnosis to treatment with IFN- (< 12 months), Haemoglobin (< normal), Lactate dehydrogenase (> 1.5 upper normal limit) and corrected serum calcium (> normal). Low risk, 0 risk factor; intermediate, 1-2 risk factors; high risk > 3 risk factors. Angiogenesis inhibitor drugs Recent advances in molecular biology have led to the development of several novel agents for the treatment of mRCC. In sporadic and VHL (von Hippel Lindau) cRCC, the accumulation of hypoxia inducible factor (HIF) due to a defective VHL protein results in over-expression of vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), promoting neo-angiogenesis. This process substantially contributes to the development and progression 82 Renal Cell Carcinoma
Table 3: Recommendations for first and second line systemic therapy in mRCC
Treatment First-line Risk or prior treatment Low- or intermediate-risk mRCC Recommended agent Sunitinib Bevacizumab + IFN- Pazopanib Temsirolimus Sorafenib Pazopanib Everolimus Clinical trials
Second-line
High-risk mRCC Prior cytokine therapy Prior VEGFR therapy Prior mTOR inhibitor therapy
of RCC. At present, four targeting drugs have been approved both in the USA and in Europe for mRCC, while other agents have shown significant efficacy in randomised controlled trials. Tyrosine kinase inhibitors (TKIs) Several TKIs have shown efficacy in cRCC with increased PFS as both first- and second-line treatments of mRCC. Sorafenib is an oral multikinase inhibitor with proven increased PFS as a second-line treatment after failure of systemic immunotherapy. Sunitinib is an oral TKI. In a phase III first-line study comparing sunitinib with IFN-, sunitinib achieved a longer PFS time (11 months vs. 5 months) in low- and intermediate-risk patients. In patients who did not receive Renal Cell Carcinoma 83
any post-study treatment, overall survival was longer in the sunitinib-only treated group than in the IFN- treated only group (28.1 months vs. 14.1 months, respectively). Pazopanib is an oral TKI targeting VEGF and PDGF receptors and c-Kit. In a prospective randomised trial of pazopanib versus placebo in treatment-naive mRCC patients and cytokine-treated patients, there was a significant improvement in PFS from 4.2 to 9.2 months and tumour response was observed. VEGF antibodies Bevacizumab is a humanised monoclonal antibody that binds VEGF. A double-blind phase III trial showed a median 31% overall response with bevacizumab + IFN- versus 13% in IFN- monotherapy. Median PFS increased significantly from 5.4 months with IFN- to 10.2 months for bevacizumab + IFN-, but was restricted to low- and intermediate-risk patients. Mammalian target of rapamycin (mTOR) inhibitors These inhibitors, which affect the mTOR pathway, show significant efficacy in mRCC, in other RCC types besides cRCC, and also in high-risk patients. Temsirolimus is a specific inhibitor of mammalian target of rapamycin. A phase III trial demonstrated increased overall survival in poor-risk patients with mRCC given temsirolimus monotherapy compared with IFN-. Everolimus is an oral mTOR inhibitor. A recent phase III study in patients who had failed previous anti-VEGF-R treatment showed a PFS of 4 months with everolimus versus 1.9 months with placebo. 84 Renal Cell Carcinoma
Clinical research continues into the use of these and several other new novel agents for the primary or secondary treatment of mRCC, including monotherapy, in combination with each other or with cytokines, or in the adjuvant setting. Only limited overall survival data are available for these new agents and their role is still under development. In the sunitinib randomised trial, patients crossed over from IFN- to sunitinib (n = 25), the median survival times were 20.0 versus 26.4 months for sunitinib, respectively (p = 0.03). In patients who did not receive any post-study sunitinib, the median overall survival was 14.1 months versus 28.1 months in the sunitinib group. To date, there has been no data on the curative effect of the new agents. These agents appear to promise to stabilise mRCC for a prolonged period of time. However, their clinical use has to be balanced against their toxicity profile and the patients quality of life.
Recommendations for systemic therapy

Tyrosine kinase inhibitors should be considered as first- or second-line treatment for mRCC patients as shown in Table 3. Interferon- monotherapy only remains as an option in selected patients as first-line therapy for mRCC.
Surveillance following surgery for RCC

Surveillance following surgery for RCC allows the urologist to monitor post-operative complications, renal function, local recurrence after partial nephrectomy or ablative treatment, recurrence in the contralateral kidney, and development of metastases. Renal Cell Carcinoma 85
The method and timing of investigation has been the subject of many publications. Using different scoring systems and algorithms, patients can be categorised as at low-, intermediate- or high-risk of developing metastases. Despite extensive research, there is no general recommendation for the method and timing of investigations for surveillance. In fact, there is no evidence for whether early versus later diagnosis of recurrence improves survival. However, follow-up remains important to increase knowledge of the disease and should be performed by the urologist, who should record the time elapsed to recurrence or metastatic development. Follow-up also allows metastases to be identified early. Early identification of metastases increases the possibility of surgical resection and efficacy of systemic treatment at a time when the tumour burden is as low as possible. This is particularly important with ablative therapies, such as cryotherapy and RFA, where the local recurrence rate is higher than conventional surgery and the patient may still be cured by repeat ablative therapy or radical nephrectomy. In metastatic disease, more extended tumour growth can reduce the possibility of surgical resection, which is considered the standard therapy in cases of resectable and preferably solitary lesions. In addition, within clinical trials, an early diagnosis of tumour recurrence might enhance the efficacy of a systemic treatment if the tumour burden is low. The urologist can therefore be selective in the use of imaging and the need for intensive surveillance. Although there is no evidence-based standard for the follow-up of patients with RCC, there are several scoring systems and nomograms for 86 Renal Cell Carcinoma
predicting tumour recurrence and metastases. Using these nomograms, several stage-based surveillance regimes have been proposed. However, none include ablative therapies. There is therefore a need for a surveillance algorithm that monitors patients after treatment for RCC that recognises not only the patients risk profile but also treatment efficacy. An example is given in Table 4; please note this is not an EAU recommendation. For patients with metastatic disease, an individual followup plan is required.
Table 4: Example of a proposed follow-up algorithm for surveillance after treatment for RCC with combined patient risk profile and treatment efficacy
(This is an example of a follow-up scheme; GR: C) Treatment Risk profile and schedule Low Intermediate High Treatment RN/PN only RN/PN/cryo/ RN/PN/cryo/ RFA RFA 6 months CXR and US CT CT 1 year CXR and US CXR and US CT 2 years CXR and US CT CT 3 years CXR and US CXR and US CT 4 years CXR and US CXR and US CT 5 years CXR and US CT CT > 5 yrs Discharge Yearly CXR CXR/CT in and US alternate years
Renal Cell Carcinoma 87
CT = computed tomography of chest and abdomen; cryo = cryotherapy; CXR = chest x-ray; PN = partial nephrectomy; RFA = radio-frequency ablation; RN = radical nephrectomy; US = ultrasound of kidneys and renal bed.
88 Renal Cell Carcinoma
GUIDELINES ON PENILE CANCER

G. Pizzocaro, F. Algaba, S. Horenblas, E. Solsona, S. Tana, H. Van Der Poel, N. Watkin Eur Urol 2010 Jun;57(6):1002-12
Introduction
Over recent years, the cure rate for penile cancer has risen to 80% because of improved knowledge of the disease, earlier diagnosis, technological advances, and specialist treatment in centres of excellence. In Western countries, primary malignant penile cancer is uncommon, with an overall incidence of less than 1.00 per 100,000 males in Europe and the United States of America (USA). Incidence also varies according to racial group, ethnicity, and geographical location. Social and cultural habits, hygienic and religious practices interfere significantly with risk factors. Since a few years, there has been a well-documented association between human papillomavirus (HPV) and squamous cell carcinoma (SCC). Vaccination is available for very young females against HPV strains responsible for most cases of cervical cancer. Vaccination will be considered in males according to the results in females.
Penile Cancer 89
Classification and pathology

The new, 2009, Tumor Node Metastasis (TNM) classification for penile cancer includes a change for the T1 category (Table 1). This classification needs a further update for the definition of the T2 category*.
Table 1: 2009 TNM staging classification

T - Primary tumour Primary tumour cannot be assessed TX No evidence of primary tumour T0 Carcinoma in situ Tis Non-invasive verrucous carcinoma, not associated Ta with destructive invasion Tumour invades subepithelial connective tissue T1 T1a without lymphovascular invasion and well or moderately differentiated (T1G1-2) T1b with lymphovascular invasion or poorly differentiated / undifferentiated (T1G3-4) T2* Tumour invades corpus spongiosum/corpora cavernosa Tumour invades urethra T3 Tumour invades other adjacent structures T4 N - Regional lymph nodes NX Regional lymph nodes cannot be assessed No palpable or visibly enlarged inguinal lymph node N0 Palpable mobile unilateral inguinal lymph node N1 Palpable mobile multiple or bilateral inguinal lymph N2 nodes Fixed inguinal nodal mass or pelvic lymphadenopaN3 thy, unilateral or bilateral 90 Penile Cancer
M - Distant metastasis M0 No distant metastasis M1 Distant metastasis TNM pathological classification The pT categories correspond to the T categories. The pN categories are based upon biopsy, or surgical excision.
Table 2: 2009 TNM pathological classification

pN - Regional lymph nodes pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Intranodal metastasis in a single inguinal lymph node pN2 Metastasis in multiple or bilateral inguinal lymph nodes pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis pM - Distant metastasis pM0 No distant metastasis pM1 Distant metastasis G - Histopathological grading Grade of differentiation cannot be assessed Gx Well differentiated G1 Moderately differentiated G2 G3-4 Poorly differentiated/undifferentiated Pathology Squamous cell carcinoma accounts for more than 95% of cases of malignant penile disease. Table 3 lists premalignant Penile Cancer 91
lesions and Table 4 lists the different types of penile SCC neoplasia.
Table 3: Premalignant lesions

Lesions sporadically associated with SCC of the penis Cutaneous horn of the penis Bowenoid papulosis of the penis Lesion at intermediate risk Balanitis xerotica obliterans (lichen sclerosus et atrophicus) Lesions at high risk of developing SCC of the penis (up to one-third transform to invasive SCC) Penile intraepithelial neoplasia (carcinoma in situ) Erythroplasia of Queyrat and Bowens disease
Table 4: Pathologic classification of SCC of the penis

Types of SCC Classic Basaloid Verrucous and its varieties: warty (condylomatous) carcinoma; verrucous carcinoma; papillary carcinoma; hybrid verrucous carcinoma; and mixed carcinomas (warty basaloid, adenobasaloid carcinoma) Sarcomatoid Adenosquamous Growth patterns of SCC Superficial spread Nodular or vertical-phase growth Verrucous 92 Penile Cancer
Differentiation grading systems for SCC Broders grading system Maiches system score
Diagnosis
Accurate histological diagnosis and staging of both the primary tumour and regional nodes are a prerequisite before making treatment decisions (Table 5). Biopsy The need for histological confirmation is dependent on: doubt about the exact nature of the lesion; treatment of the lymph nodes based on pre-operative histology. In these cases an adequate biopsy is advised. Although a punch biopsy may be sufficient for superficial lesions, but an excisional one is preferred. There is no need for biopsy if: there is no doubt about the diagnosis; treatment of the lymph nodes is postponed after treatment of the primary tumour and/or after histological examinations of the sentinel node(s). Physical examination The physical examination of suspected penile cancer must record: diameter of the penile lesion(s) or suspicious areas; location of lesion(s) on the penis; number of lesions; morphology of lesion(s): papillary, nodular, ulcerous or flat; relationship of lesion(s) to other structures, e.g. submuPenile Cancer 93
cosa, tunica albuginea, urethra, corpus spongiosum and corpus cavernosum; colour and boundaries of lesion(s); penile length. Imaging Physical examination is reliable in determining infiltration into the corpora. If doubt exists on depth of infiltration or proximal extension, magnetic resonance imaging (MRI) may be helpful on erect penis ( prostaglandin E1 injection).
Table 5: Guidelines for the diagnosis of penile cancer
GR Primary tumour C Physical examination, recording morphological and physical characteristics of the lesion. Cytological and/or histological diagnosis. C Inguinal lymph nodes Physical examination of both groins, recording nodal morphological and physical characteristics. If nodes are non-palpable, DSNB is indicated; if DSNB not available, ultrasound-guided FNAC/risk factors. If nodes are palpable, FNAC for cytological diagnosis. C Regional metastases (inguinal and pelvic nodes) A pelvic CT scan/PET-CT scan is indicated in patients with metastatic inguinal nodes.
94 Penile Cancer
C Distant metastases (beside inguinal and pelvic nodes) PET-CT scan also allows evidence of distant metastasis. If PET-CT is not available, abdominal CT scan and chest X-ray are advisable, and in symptomatic M1 patients a bone scan is also advisable. C Biological laboratory determinations for penile cancer are investigational and not for clinical use. CT = computed tomography; DNSB = dynamic sentinel node biopsy; GR = grade of recommendation; FNAC = fine-needle aspiration cytology; PET = positron emission tomography.
Treatment
The primary tumour and regional lymph nodes are usually treated separately (Table 6). Correct staging is crucial for accurate treatment. Lymphadenectomy (LAD) is mandatory for patients with evidence of inguinal lymph node metastases.
Table 6: Guidance on treatment strategies for penile cancer

Primary tumour Conservative treatment is to be considered whenever possible LE GR
Penile Cancer 95
Category Tis, Ta, T1a (G1, G2)
Categories: T1b (G3) and T2 (glans only) Category T2 (invasion of the corpora) Category T3 invasion of urethra Category T4 (other adj. structures) Local disease recurrence after conservative therapy Radiotherapy
CO2 or Nd:YAG laser surgery, wide local excision, glans resurfacing, or glans resection, depending on size and location of the tumour Mohs micrographic surgery or photodynamic therapy for well differentiated superficial lesions (Tis, G1, Ta) Glansectomy, with or without tips amputation or reconstruction Partial amputation
2b
2b
2b
Total amputation with perineal urethrostomy Eligible patients: neoadjuvant chemotherapy followed by surgery in responders. Alternative: external radiation Salvage surgery, consisting of penis-sparing treatment in small recurrences Larger recurrence: some form of amputation Organ-preserving treatment in selected patients with Tl-2 of glans or coronal sulcus, lesions < 4 cm
2b
2b 2b
B B
96 Penile Cancer
Neo adjuvant, before surgery 3 C Palliation in advanced or 3 C metastatic disease CO2 = carbon dioxide; Nd:YAG = neodymium:yttrium-aluminum-garnet.
Chemotherapy
Table 7: Guidance on treatment strategies for regional lymph nodes in penile cancer
Regional lymph nodes No palpable inguinal nodes Management of regional lymph nodes is fundamental Tis, Ta G1, T1G1: surveillance > T1G2: DSNB (NB: Inguinal LAD if histology is positive) If DSNB not available: risk factors / nomogram decisionmaking Ultrasound-guided FNAB (DSNB is unsuitable for palpable nodes) Negative biopsy: surveillance (repeat biopsy) Positive biopsy: inguinal LAD on positive side (NB: Modified LAD must include the central zone and both superior Daselers zones) LE 2a 2a GR B B
Palpable inguinal nodes
2a
Penile Cancer 97
Pelvic nodes
Adjuvant chemotherapy
Patients with fixed or relapsed inguinal nodes
Pelvic LAD if there is: extranodal metastasis; Cloquet node involved; > 2 inguinal node metastases Unilateral pelvic LAD if unilateral lymph node metastases with prolonged inguinal incision Bilateral pelvic LAD if bilateral inguinal metastases In patients with > 1 intranodal metastasis (pN2 pN3) after radical LAD, survival is improved by adjuvant chemotherapy (3 courses of cisplatin, fluorouracil [PF] chemotherapy) Neo-adjuvant chemotherapy is strongly recommended in patients with unresectable or recurrent lymph node metastases Taxanes seem to improve the efficacy of standard PF chemotherapy (or carboplatin)
2a
2b
2a 2b
B B
2a
98 Penile Cancer
Curative radiotherapy may be 2a B used for palliation in primary tumours of the glans penis and sulcus < 4 cm or 2a B Prophylactic radiotherapy in clinical N0 patients is not indicated LAD = lymphadenectomy; FNAB = fine-needle aspiration biopsy; DSNB = sentinel node biopsy. Radiotherapy
Follow-up
The aim of follow-up is to detect local and/or regional recurrences at an early curable stage. Metastases at distant sites are fatal. Risk stratification for recurrence is helpful. Traditional follow-up methods have been inspection and physical evaluation. Modern ultrasound or PET-CT imaging is a useful adjunct. The follow-up interval and strategies for patients with penile cancer are guided by the initial treatment of the primary lesion and regional lymph nodes (Table 7). About 92% of all recurrences occur within 5 years and they may be neo-occurrences. Follow-up can stop after 5 years in well educated and motivated patients able to perform self-examination.
Penile Cancer 99
Table 8: Follow-up schedule for penile cancer

Interval of follow-up Years 1 and 2 Years 3, 4 and 5 Recommendations for follow-up of the primary tumour Penile preserving treat- 3 months 6 months ment Amputation 6 months 1 year Recommendations for follow-up of the inguinal lymph nodes Wait-and-see 3 months 6 months pN0 6 months 1 year
pN+
3 months
6 months
Quality of life
As more people achieve long-term survival after cancer, sexual dysfunction and infertility are increasingly recognised as negative consequences. Penile-sparing surgery allows a better quality of life than penectomy and must be considered whenever feasible. Psychological support should be offered at a low threshold.
100 Penile Cancer
Examinations and investigations Regular physician or selfexamination Regular physician or selfexamination Regular physician or selfexamination Regular physician or selfexamination Ultrasound with FNAB Regular physician or selfexamination Ultrasound with FNAB
Maximum duration of follow-up 5 years 5 years
GR
C C
5 years 5 years
C C
5 years
Penile Cancer 101
Guidelines on TesTicular cancer

(Limited text update March 2011)
P. Albers (chairman), W. Albrecht, F. Algaba, C. Bokemeyer, G. Cohn-Cedermark, K. Fizazi, A. Horwich, M.P. Laguna Eur Urol 2008;53(3):478-96,497-513
introduction
Compared with other types of cancer, testicular cancer is relatively rare accounting for approximately 1-1.5% of all cancers in men. A steady increase in incidence has been seen over the past decades in the industrialised countries. The majority of these tumours are derived from germ cells (seminoma and nonseminoma germ cell testicular cancer) and more than 70% of patients are diagnosed with stage I disease. Epidemiological risk factors for testicular cancer as well as pathological and clinical risk factors in stage I and in metastatic disease are well established. Nowadays testicular tumours show excellent cure rates, mainly due to early diagnosis and their extreme chemo- and radiosensitivity.
Table 1: Prognostic risk factors for the development of tumours

Epidemiological risk factors History of cryptorchidism Klinefelters syndrome 102 Testicular Cancer
Familial history of testis cancer in first-grade relatives Presence of contralateral tumour Tin or infertility Pathological prognostic risk factors for occult metastatic disease (for stage I) For seminoma - Tumour size (> 4 cm) - Invasion of the rete testis For non-seminoma - Vascular/lymphatic invasion or peri-tumoural invasion - Proliferation rate (MIB-1) > 70% - Percentage embryonal carcinoma > 50% Clinical (for metastatic disease) Primary location Elevation of tumour marker levels Presence of non-pulmonary visceral metastasis
classification
Testicular epithelial cancer is classified into three categories: (a) germ cell tumours; (b) sex cord stromal tumours; (c) miscellaneous germ cell/sex cord stromal tumours. Germ cell tumours account for 90-95% of cases of testicular cancer according to the WHO classification system.
Testicular Cancer 103
Table 2: The recommended pathological classification

(modified World Health Organization 2004) 1. Germ cell tumours Intratubular germ cell neoplasia Seminoma (including cases with syncytiotrophoblastic cells) Spermatocytic seminoma (mention if there is a sarcomatous component) Embryonal carcinoma Yolk sac tumour Choriocarcinoma Teratoma (mature, immature, with malignant component) Tumours with more than one histological type (specify % of individual components) 2. Sex cord/gonadal stromal tumours Leydig cell tumour Malignant Leydig cell tumour Sertoli cell tumour (lipid-rich variant, sclerosing, large cell calcifying) Malignant Sertoli cell tumour Granulosa (adult and juvenile) Thecoma/fibroma group of tumours Other sex cord/gonadal stromal tumours (incompletely differentiated, mixed) Tumours containing germ cell and sex cord/gonadal stromal (gonadoblastoma) 3. Miscellaneous non-specific stromal tumours Ovarian epithelial tumours Tumours of the collecting ducts and rete testis 104 Testicular Cancer
Tumours (benign and malignant) of non-specific stroma
diagnosis of testicular cancer

The diagnosis of testicular cancer is based on: Clinical examination of the testis and general examination to rule out enlarged nodes or abdominal masses. Ultrasound of the testis to confirm testicular mass and always in a young man with a retroperitoneal mass or elevated tumour serum markers and without a palpable scrotal mass. Currently, testicular ultrasound should be performed even in the presence of clinically evident tumour. Serum tumour markers before orchiectomy (AFP and hCG) and LDH. The latter is mandatory in advanced tumours. Inguinal exploration and orchiectomy with en bloc removal of testis, tunica albuginea, and spermatic cord. If the diagnosis is not clear, a testicular biopsy (tumour enucleation) is to be taken for histopathological frozen section. Organ-sparing surgery can be attempted in special cases (bilateral tumour or solitary testes). Routine contralateral biopsy for diagnosis of carcinoma in situ should be discussed with the patient and is recommended in high risk patients (testicular volume < 12 mL, a history of cryptorchidism and age under 40 years).
diagnosis and treatment of Tin

Although the diagnosis of Tin remains controversial, a biopsy should be offered to patients with high risk for contralateral Tin (testicular volume < 12 mL, history of cryptorchidism or poor spermatogenesis). If performed, a double biopsy is preferred. In case of Tin, local radiotherapy is the treatment after counselling on impaired testosterone production and infertility.
staging of testicular tumours

For an accurate staging the following steps are necessary: Postorchiectomy half-life kinetics of serum tumour markers. The persistence of elevated serum tumour markers 3 weeks after orchiectomy may indicate the presence of disease, while its normalisation does not necessarily mean absence of tumour. Tumour markers should be assessed until they are normal, as long as they follow their half-life kinetics and no metastases are revealed. Assessment of retroperitoneal and mediastinal nodes and viscera. (Abdominopelvic CT scan and thoracic CT scan/X-ray Thorax) and supraclavicular nodes (physical examination). MRI is helpful only when the above are inconclusive or in patients with an allergy to contrast agents. Other examinations such as brain or spinal CT, bone scan or liver ultrasound should be performed if metastases are suspected. In patients diagnosed with testicular seminoma and a positive abdominopelvic CT scan, a chest CT scan is recommended. A chest CT scan should be routinely performed in patients 106 Testicular Cancer
diagnosed with non-seminomatous germ cell tumours (NSGCT) because in up to 10% of cases, small subpleural nodes may be present that are not visible radiologically.
staging system
The Tumour, Node, Metastasis (TNM 2009) staging system is endorsed.
Table 3: TnM classification for testicular cancer

pT - Primary tumour1 pTX Primary tumour cannot be assessed pT0 No evidence of primary tumour (e.g. histologic scar in testis) pTis Intratubular germ cell neoplasia (testicular intraepithelial neoplasia) pT1 Tumour limited to testis and epididymis without vascular/lymphatic invasion: tumour may invade tunica albuginea but not tunica vaginalis pT2 Tumour limited to testis and epididymis with vascular/lymphatic invasion, or tumour extending through tunica albuginea with involvement of tunica vaginalis pT3 Tumour invades spermatic cord with or without vascular/lymphatic invasion pT4 Tumour invades scrotum with or without vascular/ lymphatic invasion N - Regional lymph nodes clinical NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis
Metastasis with a lymph node mass < 2 cm in greatest dimension, or multiple lymph nodes, none > 2 cm in greatest dimension Metastasis with a lymph node mass > 2 cm but < 5 N2 cm in greatest dimension, or multiple lymph nodes, any one mass > 2 cm but < 5 cm in greatest dimension Metastasis with a lymph node mass > 5 cm in greatN3 est dimension pN - Pathological regional lymph nodes pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Metastasis with a lymph node mass < 2 cm in greatest dimension and 5 or fewer positive nodes, none > 2 cm in greatest dimension pN2 Metastasis with a lymph node mass > 2 cm but < 5 cm in greatest dimension; or > 5 nodes positive, none > 5 cm; or evidence of extranodal extension of tumour pN3 Metastasis with a lymph node mass > 5 cm in greatest dimension M - Distant metastasis MX Distant metastasis cannot be assessed M0 No distant metastasis M1 Distant metastasis M1a Non-regional lymph node(s) or lung M1b Other sites pM - Pathological distant metastasis The pM category corresponds to the M category N1
108 Testicular Cancer
S - Serum tumour markers Sx Serum markers studies not available or not performed Serum marker study levels within normal limits S0 S1 S2 S3
1
LDH (U/L) < 1.5 x N and 1.5-10 x N or > 10 x N or
hCG (mlU/ml) < 5,000 and 5,000-50,000 or > 50,000 or
AFP (ng/ml) < 1,000 1,000-10,000 > 10,000
Except for pTis and pT4, where radical orchiectomy is not always necessary for classification purposes, the extent of the primary tumour is classified after radical orchiectomy; see pT. In other circumstances, TX is used if no radical orchiectomy has been performed. The International Germ Cell Cancer Collaborative Group (IGCCCG) defined a prognostic factor-based staging system for metastatic germ cell cancer that includes good and intermediate prognosis seminoma and good, intermediate, and poor prognosis NSGCT.
Table 4: Prognostic-based staging system for metastatic germ cell cancer (iGcccG)
Good-prognosis group Non-seminoma (56% of cases) 5-year PFS 89% 5-year survival 92% All of the following criteria:
Testis/retroperitoneal primary No non-pulmonary visceral metastases AFP < 1,000 ng/mL hCG < 5,000 IU/L (1,000 ng/mL) LDH < 1.5 x ULN Seminoma (90% of cases) All of the following criteria: 5-year PFS 82% Any primary site 5-year survival 86% No non-pulmonary visceral metastases Normal AFP Any hCG Any LDH Intermediate-prognosis group Non-seminoma (28% of All of the following criteria: cases) 5-year PFS 75% Testis/retroperitoneal primary 5-year survival 80% No non-pulmonary visceral metastases AFP 1,000 - 10,000 ng/mL or hCG 5,000 - 50,000 IU/L or LDH 1.5 - 10 x ULN
Seminoma (10% of cases) Any of the following criteria: 5-year PFS 67% Any primary site 5-year survival 72% Non-pulmonary visceral metastases Normal AFP Any hCG Any LDH Poor-prognosis group Non-seminoma (16% of Any of the following criteria: cases) 5-year PFS 41% Mediastinal primary 5-year survival 48% Non-pulmonary visceral metastases AFP > 10,000 ng/mL or hCG > 50,000 IU/L (10,000 ng/mL) or LDH > 10 x ULN Seminoma No patients classified as poor prognosis PFS = progression-free survival; AFP = alpha-fetoprotein; hCG = beta-human chorionic gonadotrophin; LDH = lactate dehydrogenase; ULN = upper limit of normal range.
Guidelines for the diagnosis and staging of testicular cancer

Testicular ultrasound is mandatory. Orchidectomy and pathological examination of the testis is necessary to confirm the diagnosis and to define the local extension (pT category). In a lifethreatening situation due to extensive metastasis, chemotherapy has to be started before orchidectomy. Serum determination of tumour markers (AFP, hCG, and LDH) must be performed before and after orchidectomy for staging and prognostic reasons. The state of the retroperitoneal, mediastinal, and supraclavicular nodes and visceral state must be assessed in testicular cancer. AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase.
GR A A
Pathological examination of the testis

Following orchiectomy, the pathological examination of the testis should include a number of investigations. 1. Macroscopic features: side, testis size, maximum tumour size and macroscopic features of epididymis, spermatic cord and tunica vaginalis. 2. Sampling: 1 cm2 section for every centimetre of maximum tumour diameter, including normal macroscopic parenchyma (if present), albuginea and epididymis with selection of suspected areas. At least one proximal and one distal section of the spermatic cord plus any suspected area. 3. Microscopic features and diagnosis: histological type (specify individual components 112 Testicular Cancer
and estimate amount as a percentage); presence or absence of peri-tumoural venous and/ or lymphatic invasion; presence or absence of albuginea, tunica vaginalis, rete testis, epididymis or spermatic cord invasion, and; presence or absence of intratubular germinal neoplasia (Tin) in non-tumoural parenchyma intratubular germ cell neoplasia. 4. pT category according to TNM 2009. 5. Immunohistochemical studies: in seminoma and mixed germ cell tumour, AFP and hCG.
Guidelines for the treatment of testicular cancer

Seminoma stage I Surveillance is the recommended management option (if facilities available and patient compliant). Carboplatin-based chemotherapy (one course at AUC 7) can be recommended. Adjuvant treatment is not recommended for patients at low risk. Radiotherapy is not recommended as adjuvant treatment. GR A B A A
NSGCT stage I CS1 risk-adapted treatments based on vascular invasion or surveillance without using risk factors are recommended treatment options. Risk-adapted treatments for CS1 based on vascular invasion CS1A (pT1, no vascular invasion): low risk 1. If the patient is willing and able to comply with a surveillance policy, long-term (at least 5 years) close follow-up should be recommended. 2. In low-risk patients not willing (or suitable) to undergo surveillance, adjuvant chemotherapy or nerve-sparing RPLND are treatment options If RPLND reveals PN+ (nodal involvement) disease, chemotherapy with two courses of PEB should be considered. CS1B (pT2-pT4): high risk 1. Primary chemotherapy with two courses of PEB should be recommended (one course of PEB within a clinical trial or registry). 2. Surveillance or nerve-sparing RPLND in high-risk patients remain options for those not willing to undergo adjuvant chemotherapy. If pathological stage II is revealed at RPLND, further chemotherapy should be considered.
GR
Guidelines for the treatment of metastatic germ cell tumours

1. Low volume NSGCT stage IIA/B with elevated markers should be treated like good or intermediate prognosis advanced NSGCT, with three or four cycles of PEB. 2. In stage IIA/B without marker elevation, histology can be gained by RPLND or biopsy. A repeat staging can be performed after six weeks of surveillance before final decision on further treatment. 3. In metastatic NSGCT (> stage IIC) with a good prognosis, three courses of PEB is the primary treatment of choice. 4. In metastatic NSGCT with an intermediate or poor prognosis, the primary treatment of choice is four courses of standard PEB and inclusion in clinical trials is strongly recommended. 5. Surgical resection of residual masses after chemotherapy in NSGCT is indicated in the case of visible residual masses and when serum levels of tumour markers are normal or normalising. 6. Seminoma CS IIA/B can initially be treated with radiotherapy. When necessary, chemotherapy can be used as a salvage treatment with the same schedule as for the corresponding prognostic groups of NSGCT.
GR A
B 7. In seminoma stage CS IIB, chemotherapy (4 x EP or 3 x PEB, in good prognosis) is an alternative to radiotherapy. It appears that 4 x EP or 3 x PEB achieve a similar level of disease control. A 8. Seminoma stage IIC and higher should be treated with primary chemotherapy according to the same principles used for NSGCT. EP = eposide, cisplatin; NSGCT = non-seminomatous germ cell tumour; PEB = cisplatin, eposide, bleomycin; RPLND = retroperitoneal lymph node dissection.
relapse after chemotherapy

The treatment of relapsed GCT after chemotherapy is typically salvage chemotherapy. For patients at first relapse with good prognostic features (initial achievement of CR/PR M- and gonadal primary tumour) 4 cycles of standard dose salvage chemotherapy are proposed. For patients with poor prognostic factors (extragonadal primary and/or incomplete response to first line chemotherapy) and for all patients with subsequent (> first) relapse, high-dose chemotherapy with autologous stem cell support is recommended.
Follow-up of patients with testicular cancer

The aim of the follow-up is to detect relapse as early as possible and to monitor the contralateral testis. In the presence of a curative- or life prolongation therapy, the following principles should apply: (a) interval between examinations and duration of follow-up should be consistent with the time of maximal risk of recurrence, (b) tests should be directed at the most likely sites of recur116 Testicular Cancer
rence and have a good accuracy, (c) the increased risk of second malignancy, both in the primary site and in other tissues that may have been exposed to the same carcinogens, or in which there is epidemiological evidence of increased risk, should also guide the ordering tests, (d) non-malignant complications of therapy must also be considered.
Table 5: recommended minimum follow-up schedule in a surveillance policy: stage i non-seminoma

Procedure Physical examination Tumour markers Chest X-ray Abdominopelvic CT scan Year 1 4 times Year 2 Year 3-5 Year 6-10 4 times Once/yr. Once/yr.
4 times 4 times Once/yr. Once/yr. Twice Twice Twice. (at 3 and 12 mo) CT = computed tomography.
Table 6: recommended minimum follow-up schedule after rPlnd or adjuvant chemotherapy: stage i non-seminoma
Procedure Year 1 Physical exami- 4 times nation Tumour markers 4 times Chest X-ray Twice Abdominopelvic Once CT scan CT = computed tomography. Year 2 Year 3-5 Year 6-10 4 times Once/yr. Once/yr. 4 times Once/yr. Once/yr. Twice Once
Table 7: recommended minimum follow-up schedule for post orchidectomy surveillance, radiotherapy or chemotherapy: stage i seminoma
Procedure Year 1 Physical exami- 3 times nation Tumour markers 3 times Chest X-ray Twice Abdominopelvic Twice CT scan CT = computed tomography. Year 2 Year 3 Year 4-5 3 times Once/yr. Once/yr. 3 times Once/yr. Once/yr. Twice Twice
Table 8: recommended minimum follow-up in advanced nsGcT and seminoma

Procedure
Physical examination Tumour markers Chest X-ray Abdominopelvic CT scan* Chest CT scan Brain CT scan
Year 1
4 times 4 times 4 times Twice As indicated As indicated
Year 2
4 times 4 times 4 times Twice As indicated As indicated
Year 3-5
Twice/yr. Twice/yr. Twice/yr. As indicated As indicated As indicated
thereafter
Once/yr. Once/yr. Once/yr. As indicated As indicated As indicated
* Abdominal CT scanning must be performed at least annually if teratoma is found in the retroperitoneum. If the post-chemotherapy evaluation in a seminoma patient shows any mass > 3 cm, the appropriate CT scan should be repeated 2 and 4 months later to ensure that the mass is continuing to regress. If available, FDG-PET scanning can be performed. A chest CT scan is indicated if abnormality is detected on chest X-ray and after pulmonary resection. In patients with headaches, focal neurological findings, or any central nervous system symptoms. CT = computed tomography scan; FDG-PET = fluorodeoxyglucose-positron emission tomography.
Testicular stromal tumours

Testicular stromal tumours are rare, however, Leydig cell and Sertoli cell tumours are of clinical relevance. Testicular Cancer 119
leydig cell tumours

Leydig cell tumours constitute 1-3% of adult testicular tumours and 3% of testicular tumours in children. Only about 10% of them are malignant presenting the following features: Large size (> 5 cm) Cytologic atypia and DNA aneuploidy Increased mitotic activity and increased MIB -1 expression Necrosis Vascular invasion infiltrative margins Extension beyond the testicular parenchyma The tumour presents as a painless enlarged testis or as an incidental ultrasound finding accompanied in up to 80% of cases by hormonal disorders. Serum tumour markers are negative and approximately 30% of patients present with gynaecomastia. These tumours are often treated by inguinal orchiectomy because they are misinterpreted as germ cell tumours. Especially in patients with symptoms of gynaecomastia or hormonal disorders or typical imaging on ultrasound, until final histology is available, a partial orchiectomy (+ frozen section) should be considered. In case of histological signs of malignancy orchiectomy and RPLND are the treatment of choice.
sertoli cell tumours

They are even rarer than Leydig cell tumours, and they can be malignant in 10-22% of cases. Morphological signs of malignancy are: Large size (> 5 cm) 120 Testicular Cancer
Pleomorphic nuclei with nucleoli Increased mitotic activity Necrosis and vascular invasion They present either as an enlarged testis or as incidental ultrasound finding. Hormonal disorders are infrequent and serum tumour markers are negative. Ultrasonographically they generally appear as hypoechoic and cannot be safely distinguished from germ-cell tumour except for the subtype large cell calcifying form which is usually associated with genetic syndromes (Carneys complex, Peutz-Jeghers syndrome) Sertoli cell tumours are often interpreted as germ-cell tumours and an orchiectomy is performed. Organ-sparing surgery should be considered (with caution) but in case of histological signs of malignancy orchiectomy and RPLND are the treatment of choice.
conclusions
Most testis tumours derive from germ cells and are diagnosed at an early stage. Staging is the cornerstone and the 2009 TNM system is recommended for classification and staging purposes. The IGCCCG staging system is recommended for metastatic disease. Following orchiectomy, excellent cure rates are achieved for those early stages irrespective of the treatment policy adopted, although pattern and relapse rates are closely linked to the treatment modality chosen. In metastatic disease a multidisciplinary therapeutic approach offers an acceptable survival. Follow-up schedules should be tailored Testicular Cancer 121
to initial staging and treatment. Testicular stromal tumours are rare and usually benign. When suspected and pathologically confirmed they can be treated by organ sparing surgery. However, in case of malignancy (small percentage) orchiectomy and RPLND are the treatment of choice.
GUIDELINEs ON MaLE LOwEr UrINary TracT syMpTOMs (LUTs), INcLUDING BENIGN prOsTaTIc OBsTrUcTION (BpO)
M. Oelke (chairman), A. Bachmann, A. Descazeaud, M. Emberton, S. Gravas, M.C. Michel, J. NDow, J. Nordling, J.J. de la Rosette The EAU Guideline on Male LUTS is a symptom-orientated guideline that mainly reviews LUTS secondary to benign prostatic enlargement (BPE) or benign prostatic obstruction (BPO), detrusor overactivity or overactive bladder, and nocturia due to nocturnal polyuria in men aged 40 years or older. The multifactorial aetiology of LUTS is illustrated in Figure 1.
Male Lower Urinary Tract Symptoms 123
OAB detrusor overactivity
Benign Prostatic Obstruction (BPO)
And others ...
Nocturnal polyuria
Distral ureteral stone
Detrusor underactivity
LUTS
Bladder tumour
Neurogenic bladder dysfunction
Urethral stricture
Urinary tract infection
Prostatitis Foreign body
Figure 1: Causes of male lower urinary tract symptoms (LUTS)
assessment
Systematic diagnostic work-up is recommended (Figure 2). History, symptom and quality-of-life questionnaire, physical examination, urinalysis, blood analysis, ultrasound of the prostate, bladder and kidneys, as well as uroflowmetry and measurement of post-void residual urine are recommended in all patients. Optional tests are bladder diary in men with urinary frequency or nocturia; computer-urodynamic evaluation before surgical treatment should be performed in men who:
124 Male Lower Urinary Tract Symptoms
cannot void > 150 ml; have a maximum flow rate > 15 ml/s; are < 50 or > 80 years of age; can void but have post-void residual urine > 300 ml; are suspicious of having neurogenic bladder dysfunction; have bilateral hydronephrosis; had radical pelvic surgery or; had previous unsuccessful (invasive) treatment.
Note that only the diagnosis of nocturnal polyuria (> 33% of the 24-hour urine excretion over night) can be made by the bladder diary, whereas the diagnosis of all other forms of non-neurogenic benign forms of LUTS in men aged 40 years or older is mainly made by exclusion.
Questionnaire with QoL

(e.g. IPSS)
Treatment
Neurological diseases neurogenic bladder dysfunction, drug-induced LUTS, heart diseases with nocturnal polyuria, penile diseases (e.g. phimosis, meatal stenosis, lichen sclerosus, penile cancer), palbable prostate carcinoma ...
History, Physical Examination
Urinanalysis
(stix, sediment) Urinary tract infection, haematuria, diabetes mellitus
Blood Analysis
(Na+, serum-creatinine, PSA)
Deterioration of kidney function (e.g. due to distal ureter stone or transitional cell carcinoma), prostatitis
Ultrasound

Benign prostatic enlargement (BPE), prostate tumor/cyst, pelvic tumour, post-void residual urine, urinary retention, bladder stone, bladder tumour, bladder diverticulum, foreign body in bladder, distal ureter stone, hydronephrosis
(bladder, prostate, kidneys)
Uroflowmetry
Urethral stricture, dysfunctional voiding
Additional tests necessary according to abnormalities found during initial assessment
Bladder Diary
The level of evidence and the grade of recommendation (according to the Oxford classification system; 2001) for
Nocturnal polyuria, polydipsia-polyuria, diabetes insipidus In patients with negative findings after additional evaluation
Figure 2: Assessment algorithm of LUTS in men aged 40 years or older
(in cases of nocturia or polyuria)
Benign Conditions of Bladder and/or Prostate
with baseline values
each treatment option are summarised in Table 1.
conservative treatment
Watchful waiting (WW) is suitable for mild-to-moderate uncomplicated LUTS. It includes education, re-assurance, lifestyle advice, and periodic monitoring.
Drug treatment
Drugs used for the treatment of various forms of male LUTS are listed in Table 2.
Table 2: Key pharmacokinetic properties and standard doses of drugs licensed in Europe for the treatment of LUTs
tmax t Recommended [hours] [hours] daily dose 1-adrenoceptor antagonists (for treating symptoms of BPH) Alfuzosin IR 1.5 4-6 3 x 2.5 mg Alfuzosin SR 3 8 2 x 5 mg Alfuzosin XL 9 11 1 x 10 mg Doxazosin IR 2-3 20 1 x 2-8 mg Doxazosin 8-12 20 1 x 4-8 mg GITS Silodosin 2.5 11-18 1 x 4-8 mg Tamsulosin MR 6 10-13 1 x 0.4 mg Tamsulosin 4-6 14-15 1 x 0.4 mg OCAS Terazosin 1-2 8-14 1 x 5-10 mg Drug (class)
5-reductase inhibitors (for treating benign prostatic enlargement due to BPH) Dutasteride 1-3 3-5 weeks 1 x 0.5 mg Finasteride 2 6-8 1 x 5 mg Antimuscarinic drugs (for treating OAB/storage symptoms) Darifenacin 7 13 - 19 1 x 7.5-15 mg Fesoterodine 5 7 1 x 4-8 mg Oxybutynin IR 0.5 - 1 2-4 3-4 x 2.5-5 mg Oxybutynin ER 5 16 2-3 x 5 mg Propiverine 2.5 13 - 20 2-3 x 15 mg Propiverine ER 7 20 1 x 30 mg Solifenacin 4-6 45 - 68 1 x 5-10 mg Tolterodine IR 1 - 3 2-10 2 x 1-2 mg Tolterodine ER 4 6 - 10 1 x 4 mg Trospium chlo- 4 - 6 5 - 15 3 x 10-15 mg or 2 ride x 10-20 mg Antidiuretic (for treating nocturnal polyuria) Desmopressin 1-2 3 1 x 0.1-0.4 mg orally before sleeping Phosphodiesterase 5 Inhibitors (for treating erectile dysfunction male LUTS [experimental]) Sildenafil 1 (0.5-2) * 3-5 1 x 25-100 mg Tadalafil 2 (0.5-12) 17.5 1 x 2.5-20 mg Vardenafil 1 (0.5-2) * 4-5 2 x 10 mg ER: extended release; GITS: gastrointestinal therapeutic system; IR: immediate release; MR: modified release; OCAS: oral controlled absorption system; SR: sustained release; tmax: time to maximum plasma concentration; t: elimination half-life. 128 Male Lower Urinary Tract Symptoms
*dependent on food intake (i.e. slower resorption of the drug and an increase in tmax by approximately 1 hour after a fatty meal). 1-adrenoceptor antagonists (1-blockers) are often the first-line drug treatment of male LUTS because of their rapid onset of action and good efficacy. They are also used intermittently in LUTS of fluctuating symptom intensity. The main 1-blockers are alfuzosin, doxazosin, tamsulosin and terazosin. All 1-blockers have a similar efficacy in mild, moderate, or severe LUTS and in different age groups. Efficacy may be better with smaller prostates (< 40 ml). Some patients still require surgical treatment because 1-blockers do not reduce prostate size or prevent acute urinary retention. 1-blocker efficacy is maintained over at least 4 years. The commonest side effects of 1-blockers are asthenia, dizziness and (orthostatic) hypotension. 5-reductase inhibitors should only be considered in men with bothersome moderate-to-severe LUTS and enlarged prostates (prostate volume > 40 ml) or elevated PSA concentration (> 1.4-1.6 g/l). 5-reductase inhibitors are only suitable for long-term treatment (over many years) because of their slow onset of action. Dutasteride and finasteride are equally effective. Symptom reduction may not be better than placebo in patients with prostates < 40 ml. 5-reductase inhibitors reduce LUTS more slowly than 1-blockers and, in finasteride, less effectively. The greater the baseline prostate volume (or serum PSA concentration), the faster and more pronounced the symptomatic benefit of dutasteride. 5-reductase inhibitors, but not 1-blockers, reduce the long-term (> 1 year) risk of acute urinary retention or need Male Lower Urinary Tract Symptoms 129
for surgery. The most relevant side effects include reduced libido, erectile dysfunction and ejaculation disorders. About 1-2% of patients develop gynaecomastia (breast enlargement with breast or nipple tenderness). Muscarinic receptor antagonists may benefit men with smaller PSA levels (smaller prostates). Tolterodine significantly reduced urgency incontinence, daytime or 24-hour frequency, and urgency-related voiding compared to placebo. Nocturia, urgency and the International Prostate Symptom Score (IPSS) were also reduced, though without statistical significance. Although studies have been carried out with tolterodine or fesoterodine, other antimuscarinic agents are likely to show similar effects. Muscarinic receptor antagonists are generally well tolerated. Adverse effects include dry mouth, constipation, micturition difficulties, nasopharyngitis and dizziness. An increase in post-void residual (PVR) urine in men without BPO is minimal. Antimuscarinic drugs are not recommended in men with BPO because of a theoretical decrease in bladder strength, which might be associated with PVR or urinary retention. However, short-term treatment with antimuscarinic drugs in men with BPO is safe. There are no published long-term studies addressing efficacy. On this basis, antimuscarinic drugs, especially in men with BPO, should be prescribed with caution, and regular re-evaluations of IPSS and PVR are advised. Plant extracts (phytotherapy): no specific recommendations can be made about phytotherapy in male LUTS because of product heterogeneity, lack of regulatory framework, and research methodological problems. 130 Male Lower Urinary Tract Symptoms
Desmopressin is a synthetic analogue of the antidiuretic hormone, arginine vasopressin, which plays a key role in body water homoeostasis and urine production. Desmopressin is used to treat nocturia due to nocturnal polyuria in adults. The clinical effects (urine volume decrease, increase in urine osmolality) last about 8-12 hours. The most frequent adverse events are headache, nausea, diarrhoea, abdominal pain, dizziness, dry mouth, and hyponatremia (serum sodium concentration <130 mmol/l). Peripheral oedema and hypertension were reported with long-term treatment. Serum sodium concentration should be monitored regularly to detect hyponatremia. The risk of hyponatremia increases with age, lower serum sodium concentration at baseline, and higher basal 24-hour urine volume per bodyweight. Combination therapies 1-blocker + 5-reductase inhibitor are best prescribed long term (> 12 months) to men with moderate-to-severe LUTS at risk of disease progression (e.g. higher prostate volume, higher PSA concentration, advanced age). Combination treatment is better than monotherapy at reducing symptoms and improving Qmax, and better than 1-blockers at reducing the risk of acute urinary retention and the need for surgery. The 1-blocker may be discontinued after 6 months in men with moderate LUTS at baseline, but longer-term combination therapy is beneficial in severe LUTS (IPSS > 20). Adverse events of both drug classes have been reported. 1-blocker + muscarinic receptor antagonist are more efficacious in reducing voiding frequency, nocturia, or IPSS than 1-blockers or placebo alone. Furthermore, combination Male Lower Urinary Tract Symptoms 131
treatment significantly reduced urgency urinary incontinence episodes and urgency and increased quality of life. Persistent LUTS during 1-blocker treatment can be reduced by the addition of a muscarinic receptor antagonist (tolterodine) especially if there is detrusor overactivity. Adverse events of both drug classes are reported. PVR measurement is recommended during combination treatment to assess increased PVR or urinary retention. Phosphodiesterase (PDE) 5 inhibitors are still experimental and should not be used routinely.
summary conservative and/or medical treatment

Behavioural with or without medical treatments are usually the first choice of therapy. A flowchart illustrating conservative and medical treatment choices according to evidencebased medicine and patients profiles is provided in Figure 3.
Male LUTS
(without absolute indications for surgery)
symptom bother, IPSS > 7?
nocturnal polyuria only?
OAB storage symptoms only?
prostate volume > 40 ml?
Education + Lifestyle Advice

with or without
long-term treatment?
1-blocker
residual storage symptoms
Watchful Waiting
with or without
Education + Lifestyle Advice add Muscarinic Receptor Anagonist

with or without with or without

with or without

with or without
Figure 3: Treatment algorithm of male lower urinary tract symptoms (LUTS) using medical and/or conservative treatment options. Treatment decisions depend on results assessed during initial evaluation ().The absence (-) or presence of the condition (+) are indicated in circles (o).
Education + Lifestyle Advice 5-Reductase Inhibitor 1-blocker Muscarinic Receptor Antagonist
Desmopressin
surgical treatment
Prostate surgery is usually required when patients have experienced recurrent or refractory urinary retention, overflow incontinence, recurrent urinary tract infections, bladder stones or diverticula, treatment-resistant macroscopic hematuria due to BPH/BPE, or dilatation of the upper urinary tract due to BPO, with or without renal insufficiency (absolute operation indications, need for surgery). Additionally, surgery is usually needed when patients have had insufficient relief in LUTS or PVR after conservative or medical treatments (relative operation indications). Transurethral Resection (TURP) or Transurethral Incision of the Prostate (TUIP): TUIP reduces BPO by splitting the bladder outlet without tissue removal and TURP removes tissue from the prostatic transition zone to reduce BPO and, secondly LUTS. The choice between TURP and TUIP is based on prostate volume with prostates < 30 ml suitable for TUIP and prostates of 30-80 ml for TURP. Urinary tract infections should be treated prior to surgery. Bipolar TURP is an alternative to monopolar TURP in moderate-to-severe LUTS secondary to BPO. It has similar efficacy but lower morbidity. Open prostatectomy is the oldest surgical treatment modality for moderate-to-severe LUTS secondary to BPO. Removal of prostatic tissue resolves BPO and, secondarily, LUTS. Efficacy is maintained > 5 years. Perioperative complications include mortality and blood transfusion. Long-term complications are urinary incontinence and bladder neck stenosis or urethral stricture. Open prostatectomy is the most invasive, 134 Male Lower Urinary Tract Symptoms
but also the most effective and durable procedure for treating LUTS/BPO. Only Holmium enucleation (HoLEP) delivers similar results, but with less morbidity. In the absence of a Holmium laser, open prostatectomy is the surgical treatment of choice for men with prostates > 80 ml. Transurethral Microwave Therapy (TUMT) emits microwave radiation through an intra-urethral antenna to deliver heat into the prostate, which leads to tissue destruction, apoptosis, and denervation of -receptors reducing BPO and LUTS. Treatment is well tolerated, although most patients experience perineal discomfort and urinary urgency and require pain medication prior to or during therapy. TUMT is an outpatient procedure and an alternative for older patients with co-morbidities and those at risk for anaesthesia or otherwise unsuitable for invasive treatment. Baseline parameters predicting an unfavourable outcome include small prostates, mild-to-moderate BOO, and low energy delivered during treatment. Transurethral Needle Ablation (TUNA) of the prostate delivers low-level radiofrequency energy to the prostate via needles inserted transurethrally into the prostatic parenchyma. The energy induces coagulation necroses in the prostatic transition zone resulting in prostate volume reduction and resolution of BPO. TUNA is unsuitable for prostates > 75 ml or isolated bladder neck obstruction. TUNA can be performed as a day-case procedure and is associated with fewer side effects than TURP (e.g. bleeding, erectile dysfunction, urinary incontinence). Male Lower Urinary Tract Symptoms 135
Holmium Laser Enucleation (HoLEP) or Holmium Laser Resection of the Prostate (HoLRP): the holmium:yttriumaluminum-garnet (Ho:YAG) laser with a wavelength of 2140 nm is a pulsed, solid-state laser. Resection is usually performed in prostates < 60 ml, while enucleation is used for larger glands. Patients using anticoagulant medication and those with urinary retention can be treated safely. Dysuria is the most common peri-operative complication. Laser vaporisation of prostate (KTP, Greenlight) leads to immediate removal of prostatic tissue, relief of BPO and, secondarily, reduction of LUTS. Because no tissue for pathological examination can be harvested, screening for prostate cancer, if indicated, should be carried out before the laser operation. The treatment choice of tissue ablation depends on the availability of the armamentarium, patients choice, concomitant morbidity or drug use, and experience of the surgeon. Prostate stents are an alternative to catheterisation for men unfit for surgery. Stents require a functioning detrusor. Insertion is usually performed in an outpatient setting under local anaesthesia. Placement is confirmed by abdominal ultrasonography or cystoscopy. Antibiotic prophylaxis is only necessary with a positive urine culture. Ethanol or botulinum toxin injections into the prostate are still experimental.
summary surgical treatment

The choice of the surgical technique depends primarily on prostate size, co-morbidities of the patient, and the ability to have anaesthesia but also on patients preferences, willingness to accept surgery-associated side effects, availability of the surgical armamentarium, and experience of the surgeon with these operation techniques. A flowchart illustrating surgical treatment choices according to patients profiles is provided in Figure 4.
no
(with indications for surgery)
Male LUTS
surgical risk
yes
can stop anti-coagulation?
yes
< 30 ml
Figure 4: Treatment algorithm of bothersome lower urinary tract symptoms (LUTS) refractory to conservative/medical treatment or in cases of absolute operation indications. The flowchart was stratified by the patients ability to have anaesthesia, cardiovascular risk, and prostate size. 138 Male Lower Urinary Tract Symptoms
TUIP TURP
TURP TUMT TUNA KTP (Greenlight) HoLRP HoLEP
prostate volume
30 - 80 ml
low
Open prostatectomy HoLEP KTP (Greenlight)
> 80 ml
KTP (Greenlight) HoLEP HoLRP
can have surgery/general anaesthesia?
high
no
TUMT TUNA Stent
Follow-up
The below listed follow-up strategy is recommended: patients with Watchful Waiting should be reviewed at 6 months and then annually, provided symptoms do not deteriorate or absolute indications develop for surgical treatment. patients receiving 1-blockers, muscarinic receptor antagonists, or a combination of 1-blockers + 5-reductase inhibitors or muscarinic receptor antagonists should be reviewed 4-6 weeks after drug initiation. If patients gain symptomatic relief in the absence of troublesome adverse events, drug therapy may be continued. Patients should be reviewed at 6 months and then annually, provided symptoms do not deteriorate or absolute indications develop for surgical treatment. patients receiving 5-reductase inhibitor monotherapy should be reviewed after 12 weeks and 6 months to determine their response and adverse events. in patients receiving desmopressin, serum sodium concentration should be measured at day 3 and 7 as well as after 1 month and, if serum sodium concentration has remained normal, every 3 months subsequently; the follow-up sequence should be re-started after dose escalation. patients after prostate surgery should be reviewed 4-6 weeks after catheter removal to evaluate treatment response and adverse events. If patients have symptomatic relief and are without adverse events further re-assessment is not necessary.
Table 1: Level of Evidence (LE) and Grade of recommendation (Gr) of various treatments of male LUTs and follow-up
LE Conservative treatment Watchful Waiting Men with mild symptoms are suitable for watchful waiting. Men with LUTS should be offered lifestyle advice prior to or concurrent with treatment. Drug treatment 1. 1-blockers should be offered to men with moderate-to-severe LUTS. 2. 5-reductase inhibitors should be offered to men who have moderate-to-severe LUTS and an enlarged prostate (> 40 ml). 5-reductase inhibitors can prevent disease progression with regard to acute urinary retention and need for surgery. 3. Muscarinic receptor antagonists might be considered in men with moderate-tosevere LUTS who have predominantly bladder storage symptoms. Caution is advised in men with bladder outlet obstruction (BOO). 4. Desmopressin can be used for the treatment of nocturia due to nocturnal polyuria. 1b 1b GR A A
1a 1b
A A
1b
4 1b
C A
5.
6.
7.
Combination treatment with an 1-blocker together with a 5-reductase inhibitor should be offered to men with bothersome moderate-to-severe LUTS, enlarged prostates, and reduced Qmax (men likely to develop disease progression). Combination treatment is not recommended for short-term therapy (< 1 year). Combination treatment with an 1-blocker together with a muscarinic receptor antagonists might be considered in patients with bothersome moderateto-severe LUTS if symptom relief has been insufficient with the monotherapy of either drug. Combination treatment should cautiously be prescribed in men with suspected BOO. PDE5 inhibitors reduce moderate-tosevere male LUTS but are experimental and restricted to men with erectile dysfunction, pulmonary arterial hypertension, or to those who have bothersome LUTS in clinical trials.
1b
1b
2b 1b
B A
Surgical treatment 1. Monopolar TURP is the current surgical standard procedure for men with prostate sizes of 30-80 ml and bothersome moderate-to-severe LUTS secondary of BPO. Monopolar TURP provides subjective and objective improvement rates superior to medical or minimally invasive treatments. Bipolar TURP achieves short-term results comparable to monopolar TURP. TUIP is the surgical therapy of choice for men with prostate sizes < 30 ml, without a middle lobe, and bothersome moderateto-severe LUTS secondary to BPO. 2. Open prostatectomy is the first choice of surgical treatment in men with prostate sizes > 80 ml, bothersome moderateto-severe LUTS secondary to BPO, and LUTS refractory to drugs in the absence of a Holmium laser. Open prostatectomy is the most invasive surgical method with significant morbidity. 3. TUMT achieves symptom improvement comparable to TURP, but is associated with decreased morbidity and lower flow improvements. Durability is in favour of TURP with lower re-treatment rates compared to TUMT.
1a
1a 1a
A A
1b
1b
1a
1a
4.
5.
6.
7.
TUNA is an alternative to TURP for patients who wish to defer/avoid (complications of) TURP, but patients should be aware of significant re-treatment rates and less improvement in symptoms and quality of life. HoLEP and 532 nm laser vaporisation of the prostate are minimally invasive alternatives to TURP in men with moderate-to-severe LUTS due to BPO. Laser operations lead to immediate, objective and subjective improvements comparable to TURP. With regard to intra-operative safety, 532 nm laser vaporisation is superior to TURP and should be considered in patients receiving anticoagulant medication or with high cardiovascular risk. With regard to long-term complication rates, results are only available for HoLEP and are comparable to TURP. Prostatic stents are an alternative to catheterisation for men unfit for surgery. Stents may have a role in the temporary relief of LUTS/BPO after minimally invasive treatment. Intra-prostatic ethanol injections for men with moderate-to-severe LUTS secondary to BPO are still experimental and should be performed only in clinical trials.
1a
1b
1b
8.
Intra-prostatic BTX injections for men 3 with bothersome moderate-to-severe LUTS secondary to BPO or men in urinary retention are still experimental and should be performed only in clinical trials. Follow-up 3-4 Follow-up for all conservative, medical or operative treatment modalities is based on empirical data or theoretical considerations but not on evidence based studies.
GUIDELINES ON MALE SEXUAL DYSFUNCTION: Erectile Dysfunction and Premature Ejaculation

(Text update March 2009)
E. Wespes, E. Amar, I. Eardley, F. Giuliano, D. Hatzichristou, K. Hatzimouratidis, F. Montorsi, Y. Vardi Eur Urol 2002;41(1):1-5 Eur Urol 2006;49(5):806-15
ERECTILE DYSFUNCTION Definition, epidemiology and risk factors

Erectile dysfunction (ED) is the persistent inability to attain and maintain an erection sufficient to permit satisfactory sexual performance. Although ED is a benign disorder, it affects physical and psychosocial health and has a significant impact on the quality of life (QoL) of sufferers and their partners and families. Approximately 5-20% of men have moderate to severe ED. Erectile dysfunction shares common risk factors with cardiovascular disease including lack of exercise, obesity, smoking, hypercholesterolaemia, and the metabolic syndrome. The risk of ED may be reduced by modifying these risk factors, particularly taking exercise or losing weight. Another risk factor for ED is radical prostatectomy (RP) in any form (open, laparoscopic, or robotic) because of the risk of cavernosal nerve injury, poor oxygenation of the corpora cavernosa, Male Sexual Dysfunction 145
and vascular insufficiency. About 25-75% of men undergoing RP experience post-operative ED. Patients being considered for nerve-sparing radical prostatectomy (NSRP) should ideally be potent and the cavernosal nerves must be preserved to ensure erectile function recovery after RP.
Diagnosis and work-up

Basic work-up The basic work-up (minimal diagnostic evaluation) outlined in Figure 1 must be performed in every patient with ED. Due to the potential cardiac risks associated with sexual activity, the 2nd Princeton Consensus Conference stratified patients with ED wanting to initiate, or resume, sexual activity into three risk categories. The low-risk group includes asymptomatic patients with less than three risk factors for coronary artery disease (excluding male gender), mild or stable angina (evaluated and/or being treated), uncomplicated past myocardial infarction, left ventricular dysfunction or congestive heart failure (NYHA class I), post-successful coronary revascularisation, controlled hypertension, and mild valvular disease. All other patients are included in an intermediate- or high-risk category and require a cardiology consultation. Specific examinations and tests Although most patients with ED can be managed within the sexual care setting, some circumstances require specific diagnostic testing: Patients with primary erectile disorder (not caused by organic disease or psychogenic disorder). 146 Male Sexual Dysfunction
Young patients with a history of pelvic or perineal trauma who could benefit from potentially curative vascular surgery. Patients with penile deformities (e.g. Peyronies disease, congenital curvature) that might require surgical correction. Patients with complex psychiatric or psychosexual disorders. Patients with complex endocrine disorders. Specific tests may also be indicated at the request of the patient or his partner. For medico-legal reasons (e.g. penile prosthesis implant, sexual abuse). Specific diagnostic tests include: nocturnal penile tumescence and rigidity (NTPR) using Rigiscan; vascular studies: - intracavernous vasoactive drug injection; - duplex ultrasound of the cavernous arteries; - dynamic infusion cavernosometry/cavernosography (DICC); - internal pudendal arteriography; neurological studies (e.g. bulbocavernosus reflex latency, nerve conduction studies); endocrinological studies; specialised psychodiagnostic evaluation. The NPTR should take place for at least two nights. A functional erectile mechanism is indicated by an erectile event of at least 60% rigidity recorded on the tip of the penis, lasting for 10 min or longer. Male Sexual Dysfunction 147
The intracavernous injection test provides limited information about vascular status. However, Duplex ultrasound provides a simple way of assessing vascular status. Further vascular investigation is unnecessary if Duplex ultrasound is normal, as indicated by a peak systolic blood flow > 30 cm/s and a resistance index > 0.8. If ultrasound is abnormal, however, arteriography and DICC should be performed only in patients who are potential candidates for vascular reconstructive surgery.
Recommendations for the diagnostic work-up LE GR

Clinical use of a validated questionnaire related to ED may help assess all sexual function domains and the effect of a specific treatment modality. Physical examination is needed in the initial assessment of ED to identify underlying medical conditions associated with ED. Routine laboratory tests, including glucose-lipid profile and total testosterone, are required to identify and treat any reversible risk factors and modifiable lifestyle factors. Specific diagnostic tests are indicated by only a few conditions. ED = erectile dysfunction. 3 B
148 Male Sexual Dysfunction
Figure 1: Minimal diagnostic evaluation (basic work-up) in patients with erectile dysfunction Patient with erectile dysfunction (self-reported)
Medical and psychosexual history (use of validated instruments, e.g. IIEF) Identify sexual problems other than ED Identify common causes of ED Identify reversible risk factors for ED
Assess psychosocial status
Focused physical examination Signs of hypogonadism Cardiovascular and neurological status
Penile deformities
Prostatic disease
Laboratory tests
Glucose-lipid profile (if not assessed in the last 12 months)
Total testosterone (morning sample) If available: bio-available or free testosterone (instead of total)
IIEF = International Index for Erectile Function. Male Sexual Dysfunction 149
Treatment of ED
Only certain types of ED have the potential to be cured with specific treatments: Psychogenic ED: psychosexual therapy may be given either alone or with another therapeutic approach, but takes time and has had variable results. Post-traumatic arteriogenic ED in young patients: surgical penile revascularisation has a 60-70% long-term success rate. Hormonal causes of ED: testosterone replacement therapy is effective, but should only be used after other endocrinological causes for testicular failure have been excluded. Currently, it is contraindicated in men with a history of prostate carcinoma or with symptoms of prostatism. Close follow-up is necessary, including digital rectal examination (DRE), serum prostate-specific antigen (PSA) and haematocrit assessment, as well as monitoring the development of hepatic or prostatic disease. The use of pro-erectile drugs following RP is very important in achieving erectile function after surgery. Several trials have shown higher rates of recovery of post-RP erectile function in patients receiving any phosphodiesterase type 5 (PDE5) inhibitor or intracavernosal injections (therapeutic or prophylactic). Rehabilitation should start as soon as possible following RP. Most men with ED will be treated with treatment options that are not cause-specific. This approach requires a structured treatment strategy that depends on efficacy, safety, invasiveness, and cost, as well as patient and partner satisfac150 Male Sexual Dysfunction
tion. A treatment algorithm for ED is given in Figure 2.
First-line therapy
Oral pharmacotherapy Three potent, selective PDE5 inhibitors have been approved by the European Medicines Agency (EMA) for the treatment of ED. They are not initiators of erection and require sexual stimulation for an erection to occur. Efficacy is defined as rigidity sufficient for vaginal penetration. Sildenafil (Viagra) Sildenafil was the first PDE5 inhibitor available. It is effective after 30-60 min from administration. A heavy, fatty meal may reduce or prolong absorption. It is administered in 25, 50 and 100 mg doses. The recommended starting dose is 50 mg and adapted according to patient response and sideeffects. Efficacy may last for up to 12 h. Efficacy may last for up to 12 h. Efficacy rates (erections sufficient for successful intercourse) are 56%, 77% and 84% of men taking 25, 50 and 100 mg of sildenafil, respectively. The efficacy of sildenafil in almost every subgroup of patients with ED has been well established. Tadalafil (Cialis) Tadalafil is effective from 30 min after administration but its peak efficacy occurs after about 2 h. Efficacy is maintained for up to 36 h and is not affected by food. It is administered in 10 and 20 mg doses. The recommended starting dose is 10 mg and is adapted according to patient response and sideeffects. Efficacy rates are 67% and 81% of men taking 10 mg and 20 mg of tadalafil, respectively. Tadalafil also improves Male Sexual Dysfunction 151
erections in difficult-to-treat subgroups. Vardenafil (Levitra) Vardenafil is effective after 30 min from administration. A fatty meal > 57% in fat reduces its effect. It is administered in 5, 10 and 20 mg doses. The recommended starting dose is 10 mg and adapted according to the response and side-effects. In vitro, it is 10-fold more potent than sildenafil. However, this does not necessarily mean greater clinical efficacy. Efficacy rates are 66%, 76% and 80% of men taking 5 mg, 10 mg and 20 mg of vardenafil, respectively. Vardenafil also improves erections in difficult-to-treat subgroups. Choice of, or preference for, different PDE5 inhibitors The choice of a PDE5 inhibitor depends on the frequency of intercourse (occasional use or regular therapy, 3-4 times weekly) and the patients personal experience of the agent. Patients need to know whether a drug is short- or long-acting, possible disadvantages, and how to use it. On-demand or chronic use of PDE5 inhibitors Although PDE5 inhibitors were introduced as on-demand treatment, in 2008, tadalafil was also approved for continuous, everyday use in 2.5 and 5 mg doses. Daily dosing was well tolerated and significantly improved erectile function. Similar results have been found in diabetic patients. Daily tadalafil provides an alternative to on-demand dosing for couples that prefer spontaneous rather than scheduled sexual activity or who have frequent sexual activity.
Adverse events Common adverse events include headache, flushing, dizziness, dyspepsia, and nasal congestion. Sildenafil and vardenafil have been associated with visual abnormalities in less than 2% of patients, while tadalafil has been associated with back pain/myalgia in 6% of patients. However, adverse events are generally mild in nature, self-limited by continuous use, and the dropout rate due to adverse events is similar to placebo. Cardiovascular safety Clinical trials and post-marketing data of all PDE5 inhibitors have demonstrated no increase in myocardial infarction rates. No PDE5 inhibitor has adversely affected total exercise time or time to ischaemia during exercise testing in men with stable angina. In fact, they may improve exercise tests. Nitrates are totally contraindicated with all PDE5 inhibitors due to unpredictable hypotension. The duration of interaction between organic nitrates and PDE5 inhibitors varies according to the PDE5 inhibitor and nitrate. If a patient develops angina while using a PDE5 inhibitor, other antiangina agents may be used instead of nitroglycerine or until after the appropriate time has passed (24 h for sildenafil or vardenafil and 48 h for tadalafil). In general, the adverse event profile of the PDE5 inhibitor is not worsened, even when the patient is on multiple antihypertensive agents. Alpha-blocker interactions All PDE5 inhibitors appear to interact with alpha-blockers, Male Sexual Dysfunction 153
which under some conditions may result in orthostatic hypotension. The labelling for sildenafil currently includes a precaution advising that 50 or 100 mg (not 25 mg) of sildenafil should not be taken within 4 h of taking an alphablocker. The use of vardenafil with an alpha-blocker is not recommended. However, co-administration of vardenafil with tamsulosin is not associated with clinically significant hypotension. Tadalafil is contraindicated in patients taking alphablockers, except for tamsulosin. Dosage adjustments Lower doses of PDE5 inhibitors may be required in patients taking ketoconazole, itraconazole, erythromycin, clarithromycin, and HIV protease inhibitors (ritonavir, saquinavir). Higher doses of PDE5 inhibitors may be necessary in patients taking rifampicin, phenobarbital, phenytoin, or carbamazepine. Kidney or hepatic dysfunction may require dose adjustments. In patients with hypogonadism, androgen supplementation improves erectile response. Management of non-responders to PDE5 inhibitors Physicians should check that the patient is using a licensed medication and that the medication has been properly prescribed and correctly used (adequate sexual stimulation, dosage, and enough time between taking the medication and attempt at intercourse). Provided a patient is using a PDE5 inhibitor appropriately, there are several ways of improving efficacy. They include modification of associated risk factors, treatment of associated hypogonadism, changing to another PDE5 inhibitor, or 154 Male Sexual Dysfunction
continuous use of a PDE5 inhibitor. Vacuum constriction devices A vacuum constriction device (VCD) applies a negative pressure to the penis to draw venous blood into the penis, which is then retained by application of a visible constricting band at the base of the penis. This method is more acceptable to older patients. Efficacy, defined by an erection satisfactory for intercourse, is as high as 90%. Satisfaction rates range between 27% and 94%. Adverse events include penile pain, numbness, and delayed ejaculation and occur in less than 30% of patients.
Second-line therapy
Patients not responding to oral drugs may be offered intracavernous injections. Alprostadil (Caverject, Edex/Viridal) is the only drug approved for intracavernous treatment of ED. It is the most efficacious monotherapy for intracavernous treatment using 5-40 g doses. The patient should be enrolled in an office-based training programme (one or two visits) to learn the correct injection process. Efficacy rates are about 70% with reported sexual activity after 94% of injections and satisfaction rates of 87-93.5% in patients and 86-90.3% in partners. Dropout rates of 41-68% have been described, with most dropouts occurring within the first 2-3 months. Complications of intracavernous alprostadil include penile pain (50% of patients), prolonged erections (5%), priapism (1%), and fibrosis (2%). Drug combinations (mainly the three-drug combination of alprostadil + papaverine + phentolamine) may increase efficacy by up Male Sexual Dysfunction 155
to 90%. Fibrosis was found to be more common (5-10%) if papaverine was used (depending on total dose). After 4 h of erection, patients are advised to consult their doctor to avoid any damage to the intracavernous muscle, as this will result in permanent impotence. Blood aspiration and injection of phenylephrine are used to treat prolonged erections. If this problem occurs, the dosage of the next intracavernosal injection is usually reduced. Prostaglandin E1 may be administered intraurethrally as a semi-solid pellet (125-1000 g). A band placed at the base of the penis improves the resulting rigidity. The clinical success rate is lower than with intracavernosal injections, but about 70% of patients are satisfied or very satisfied with treatment. Side-effects include local pain (29-41%), dizziness (1.9-14%), and urethral bleeding (5%).
Third-line therapy (penile prostheses)

Surgical implantation of a penile prosthesis may be considered in patients who fail pharmacotherapy or who want a permanent solution. Prostheses are either malleable (semirigid) or inflatable (two- or three-piece). Most patients prefer the three-piece inflatable devices because erections are more natural, but these implants are much more expensive. Satisfaction rates of 70-87% are reported from patients after appropriate consultation. Complications include mechanical failure (less than 5% after 5-year follow-up with currently available three-piece prostheses) and infection. With antibiotic prophylaxis, the 156 Male Sexual Dysfunction
infection rate is 2-3% and may be further reduced by using an antibiotic-impregnated or hydrophilic-coated implant. Infection requires removing the prosthesis, antibiotic administration and re-implantation after 6-12 months. However, 82% success rates have been achieved using salvage therapy, involving removal and re-implantation immediately following copious irrigation of the corpora with a multi-antibiotic solution.
Recommendations for ED Treatment

Lifestyle changes and risk factor modification must precede or accompany ED treatment. Pro-erectile treatments have to be given at the earliest opportunity after radical prostatectomy. If a curable cause of ED is found, treat the cause first. PDE5 inhibitors are first-line therapy. Daily administration of PDE5 inhibitors may improve results and restore erectile function. Inadequate/incorrect prescription and poor patient education are the main causes of a lack of response to PDE5 inhibitors. Testosterone replacement restores efficacy in hypogonadic non-responders to PDE5 inhibitors. Apomorphine can be used in mild-to-moderate ED, psychogenic ED, or in patients with contraindications to PDE5 inhibitors. A vacuum constriction device can be used in patients with stable relationship. Intracavernous injection is second-line therapy. Penile implant is third-line therapy. PDE5 inhibitor = phosphodiesterase type 5 inhibitor.
LE 1b 1b 1b 1a 1b 3
GR A A B A A B
1b 1b
B B
4 1b 4
C B C
Male Sexual Dysfunction 157
Figure 2: Treatment algorithm for ED Treatment of erectile dysfunction

Identify and treat curable causes of ED Lifestyle changes and risk factor modification Provide education and counselling to patients and partners
Identify patient needs and expectations Shared decision-making Offer conjoint psychosocial and medical treatment
PDE5 inhibitors
Apomorphine SL Intracavernous injections Intraurethral alprostadil Vacuum devices
Assess therapeutic outcome: Erectile response Side-effects Satisfaction with treatment Inadequate treatment outcome Assess adequate use of treatment options Provide new instructions and counselling Re-trial Consider alternative or combination therapy Inadequate treatment outcome Consider penile prosthesis implantation
PDE5 inhibitor = phosphodiesterase type 5 inhibitor. 158 Male Sexual Dysfunction
PREMATURE EJACULATION Definition, epidemiology and risk factors

While defining premature ejaculation (PE) proves to be difficult, the International Society for Sexual Medicine (ISSM) has adopted a completely new definition of lifelong PE, which is the first evidence-based definition: Premature ejaculation is a male sexual dysfunction characterized by ejaculation which always or nearly always occurs prior to or within about one minute of vaginal penetration; and inability to delay ejaculation on all or nearly all vaginal penetrations; and negative personal consequences, such as distress, bother, frustration and/ or the avoidance of sexual intimacy. Thus, PE may be classified as lifelong (primary) or acquired (secondary). Lifelong PE is characterised by onset from the first sexual experience and remains a problem during life. Acquired PE is characterised by a gradual or sudden onset with ejaculation being normal before onset of the problem. Time to ejaculation is short, but not usually as fast as in lifelong PE. The prevalence of acquired PE is 20-30%; the prevalence of lifelong PE is 2-5%. The aetiology of PE is unknown, with little data to support suggested biological and psychological hypotheses, including anxiety, penile hypersensitivity, and serotonin receptor dysfunction. In contrast to ED, the prevalence of PE is not affected by age. Risk factors for PE are generally unknown. Premature ejaculation has a detrimental effect on self-confidence and relationship with the partner. It may cause mental Male Sexual Dysfunction 159
distress, anxiety, embarrassment, and depression. However, most men with PE do not seek help.
Diagnostic work-up
Diagnosis of PE is based on the patients medical and sexual history. The history should classify PE as lifelong or acquired and determine whether PE is situational (under specific circumstances or with a specific partner) or consistent. Special attention should be given to the length of time of ejaculation, degree of sexual stimulus, impact on sexual activity and QoL, and drug use or abuse. It is also important to distinguish PE from ED.
Recommendations for diagnosis of PE

Diagnosis and classification of PE is based on medical and sexual history. It should be multidimensional and assess IELT, perceived control, distress, and interpersonal difficulty due to the ejaculatory dysfunction. Clinical use of self-estimated IELT is adequate. Stopwatch-measured IELT is necessary in clinical trials. Patient-reported outcomes have the potential to identify men with PE. Further research is needed before they can be recommended for clinical use. Physical examination may be necessary in initial assessment of PE to identify underlying medical conditions associated with PE or other sexual dysfunctions particularly ED.
LE
GR
1a
2a
Routine laboratory or neurophysiological tests are not recommended. Additional tests should be directed by specific findings from history or physical examination. IELT = intravaginal ejaculatory latency time.
Treatment of PE
In many relationships, PE causes few if any problems. In such cases, treatment should be limited to psychosexual counselling. Before beginning treatment, it is essential to discuss patient expectations thoroughly. Erectile dysfunction or other sexual dysfunction or genitourinary infection (e.g. prostatitis) should be treated first or at the same time as PE. Various behavioural techniques have demonstrated benefit in treating PE. In lifelong PE, behavioural techniques are not recommended for first-line treatment. They are time-intensive, require the support of a partner, and can be difficult to do. Pharmacotherapy is the basis of treatment in lifelong PE but all medical treatments are off-label indications. Only chronic selective serotonin reuptake inhibitors (SSRIs) and on-demand topical anaesthetic agents have consistently shown efficacy in PE. A treatment algorithm for PE is presented in Figure 3. Psychological/behavioural strategies Behavioural strategies mainly include the stop-start programme developed by Semans and its modification, the squeeze technique, proposed by Masters and Johnson (several modifications exist). Masturbation before anticipation of sexual intercourse is another technique used by many Male Sexual Dysfunction 161
younger men. Overall, success rates of 50-60% have been reported short term. Improvements achieved with these techniques are generally not maintained long term. Topical anaesthetic agents Lidocaine-prilocaine cream (5%) is applied for 20-30 min prior to intercourse. A condom is required to avoid diffusion of the topical anaesthetic agent into the vaginal wall causing numbness in the partner. In two RCTs, lidocaine-prilocaine cream significantly increased the stopwatch-measured IELT compared to placebo. No significant side-effects have been reported. An aerosol formulation of lidocaine 7.5 mg plus prilocaine 2.5 mg (Topical Eutectic Mixture for Premature Ejaculation, TEMPE) is under evaluation and has shown similar results. SS-cream is a topical anaesthetic agent made from the extracts of nine herbs. It is applied to the glans penis 1 h before and washed off immediately prior to coitus. In a RCT, application of 0.2 g SS-cream significantly improved IELT and satisfaction compared to the placebo group. Mild local burning and mild pain were reported by 18.5% of patients. No adverse effects on sexual function or partner or systemic side-effects were observed. Selective serotonin reuptake inhibitors Commonly used selective serotonin reuptake inhibitors (SSRIs) include paroxetine (20-40 mg/day), sertraline (25200 mg/day), and fluoxetine (10-60 mg). 162 Male Sexual Dysfunction
Selective serotonin reuptake inhibitors were expected to increase the geometric mean IELT by 2.6-fold to 13.2-fold. Paroxetine was found to be superior to fluoxetine, clomipramine, and sertraline. Ejaculation delay may start a few days after drug intake, but it is more evident after 1-2 weeks and may be maintained for several years. Common side-effects of SSRIs include fatigue, drowsiness, yawning, nausea, vomiting, dry mouth, diarrhoea, and perspiration; they are usually mild and gradually improve after 2-3 weeks. Decreased libido, anorgasmia, anejaculation, and ED have been also reported. On-demand treatment is inferior to daily dosing, but may be combined with an initial trial of daily treatment or concomitant low-dose daily treatment to reduce adverse effects. Dapoxetine is a potent SSRI, which has been specially designed as an on-demand oral treatment for PE. An integrated analysis of two RCTs reported that dapoxetine, 30 and 60 mg, improved IELT significantly compared to placebo. Improved ejaculation control was reported by 51% and 58% of patients in the 30 mg and 60 mg dosage groups, respectively. Both dapoxetine doses were effective on the first dose. Common adverse events were nausea, diarrhoea, headache, and dizziness. Dapoxetine has been approved (December 2008) for the on-demand treatment of PE in seven European countries (Sweden, Austria, Finland, Germany, Spain, Italy, and Portugal). This is currently the first and only drug approved for such an indication. Phosphodiesterase type 5 inhibitors Several recent studies have supported the therapeutic role Male Sexual Dysfunction 163
of PDE5 inhibitors in PE. However, there is only one RCT comparing sildenafil to placebo. Although IELT was not significantly improved, sildenafil increased confidence, the perception of ejaculatory control and overall sexual satisfaction, reduced anxiety, and decreased the refractory time to achieve a second erection after ejaculation.
Recommendations for PE treatment

Erectile dysfunction, other sexual dysfunction, or genitourinary infection (e.g. prostatitis) should be treated first. Behavioural techniques can benefit PE. However, they are time intensive, require the support of a partner, and can be difficult to do. Pharmacotherapy is the basis of treatment in lifelong PE. Daily SSRIs are first-line, off-label, pharmacological treatment for PE. The pharmacokinetic profile of currently available SSRIs is not amenable to on-demand dosing. Dapoxetine, a short-acting SSRI, has already been approved for the on-demand treatment of PE in seven European countries. Topical anaesthetic agents provide viable alternatives to SSRIs (off-label). A trial of PDE5 inhibitors may be attempted. Recurrence is likely after treatment cessation. Behavioural therapy may augment pharmacotherapy to enhance prevention of relapse. SSRI = selective serotonin reuptake inhibitor. 164 Male Sexual Dysfunction
LE 2a
GR B
1a 1a
A A
1a
1b 2B 1b 3
A C A C
Figure 3: Management of PE
Clinical diagnosis of premature ejaculation based on patient/partner history Time to ejaculation (IELT) Perceived degree of ejaculatory control Degree of bother/distress Onset and duration of PE Psychosocial/Relationship issues Medical history
Treatment of premature ejaculation Patient counselling Discussion of treatment options If PE is secondary to ED, treat ED first or concomitantly
Lifelong PE
Lifelong PE
Pharmacotherapy Relationship counselling Behavioural therapy Combination treatment
Behavioural therapy Pharmacotherapy Relationship counselling Combination treatment
Attempt graduated withdrawal of Drug therapy after 6-8 weeks Behavioural therapy includes stop/start technique, squeeze and sensate focus Pharmacotherapy (off label) includes SSRIs (daily use) and topical anaesthetics; it is recommended as first-line treatment option in lifelong PE Consider dapoxetine for on-demand use (the only approved drug for PE)
PE = premature ejaculation; IELT = intravaginal ejaculatory latency time; ED = erectile dysfunction; SSRI = selective serotonin receptor inhibitor. Adapted from Lue et al. Summary of the recommendations on sexual dysfunctions in men. J Sex Med 2004;1:6-23. Male Sexual Dysfunction 165
GUIDELINES ON pENILE cUrvatUrE

E. Wespes (chairman), K. Hatzimouratidis (vice-chair), I. Eardley, F. Giuliano, D. Hatzichristou, I. Moncada, A. Salonia, Y. Vardi
congenital penile curvature

Congenital penile curvature has an unknown cause and a prevalence rate of 4-10% in the absence of urethral abnormalities. It is diagnosed from the medical and sexual history. Physical examination during erection helps to document curvature and exclude other pathologies. Erectile function is normal, but can be compromised by excessive curvature. Congenital penile curvature can only be treated surgically, using the same principles as in Peyronies disease (see below), except surgery can be performed at any time in adults. Surgery is almost exclusively plication, resulting in high curvature correction rates of 67-97%.
peyronies disease
Epidemiology, physiopathology and natural history The cause of Peyronies disease is unknown, but the most widely accepted hypothesis is trauma to the tunica albuginea. The most commonly associated comorbidities and risk factors are diabetes, hypertension, lipid abnormalities, ischaemic cardiopathy, erectile dysfunction, smoking and excessive alcohol consumption. It has a prevalence rate of 0.4-9%. Dupuytrens contracture is more common in Penile Curvature 167
Peyronies disease (9-39%), while Peyronies disease occurs in 4% of patients with Dupuytrens contracture. However, it is unclear if these factors contribute to the pathophysiology of Peyronies disease. Two phases of the disease can be distinguished. The first is the acute inflammatory phase, which may be associated with pain. The second is the fibrotic phase, identified by formation of hard palpable plaques that can be calcified, which results in disease stabilisation. With time, penile curvature is expected to worsen in 30-50% of patients or stabilise in 47-67% of patients. Spontaneous improvement has been reported by only 3-13% of patients and is more likely early in the disease. Pain tends to resolve with time in 90% of men, usually during the first 12 months after disease onset. Patient evaluation Particular attention should be given to whether the disease is still active, as this will influence medical treatment or the timing of surgery. Patients most likely to have active disease are those with short symptom duration, pain during erection, or a recent change in penile curvature. Resolution of pain and stability of the curvature for at least 3 months are well-accepted criteria for disease stabilisation and referral for surgical intervention. A palpable node or plaque is usually identified on a routine genitourinary assessment. However, there is no correlation between plaque size and degree of curvature. The measurement of length during erection is important because it impacts directly on treatment decisions. An objective 168 Penile Curvature
assessment of penile curvature with an erection is mandatory. This can be obtained by a home (self) photograph of a (preferably) natural erection, a vacuum-assisted erection, or an intracavernosal injection using vasoactive agents. Erectile dysfunction is common (> 50%) due to penile vascular disease. The presence of erectile dysfunction may impact on treatment strategy. Sonographic measurement of the plaques size is inaccurate and operator-dependent and is not recommended in everyday clinical practice. Duplex ultrasonography may be necessary to assess vascular parameters. Non-operative treatment Conservative treatment of Peyronies disease is primarily focused on patients in the early stages of disease. Several options have been suggested, including oral pharmacotherapy (vitamin E, potassium para-aminobenzoate, tamoxifen, colchicine, acetyl esters of carnitine, pentoxifylline), intralesional injection therapy (steroids, verapamil, clostridial collagenase, interferon) and other topical treatments (verapamil, iontophoresis, extracorporeal shock wave therapy, traction devices, vacuum devices). The role of conservative treatment in men with stable/ chronic disease has not yet been adequately defined. No single drug has been approved by the European Medical Association for the treatment of Peyronies disease. The results of the studies on conservative treatment for Peyronies disease are often contradictory because of several Penile Curvature 169
methodological problems that make it difficult to provide recommendations in everyday real life.
recommendations on non-operative treatment for peyronies disease

Conservative treatment for Peyronies disease is primarily aimed at treating patients in the early stages of disease. It is an option in patients not fit for surgery or when surgery is not acceptable to the patient. Oral treatment with potassium para-aminobenzoate may result in a significant reduction in penile plaque size and penile pain and an increase in penile curvature stabilisation. Intralesional treatment with verapamil may result in a significant reduction in penile curvature and plaque volume. Intralesional treatment with clostridial collagenase showed significant decreases in the deviation angle, plaque width and plaque length. Intralesional treatment with interferon may improve penile curvature, plaque size and density, and pain. Topical verapamil gel 15% may improve penile curvature and plaque size. Iontophoresis with verapamil 5 mg and dexamethasone 8 mg may improve penile curvature and plaque size.
LE 3
GR C
1b
1b
2b
1b
1b 1b
B B
170 Penile Curvature
Extracorporeal shock-wave treatment fails to improve penile curvature and plaque size, and should not be used to reduce plaque size. However, it may help improve penile pain. Penile traction devices and vacuum devices may reduce penile deformity and increase penile length. Recommendations AGAINST Intralesional treatment with steroids do not reduce penile curvature, plaque size or penile pain and are not recommended. Oral treatment with vitamin E and tamoxifen is not recommended. Other oral treatments (acetyl esters of carnitine, pentoxifylline) are not recommended.
1b
1b
2b 3
B C
Surgical treatment Although conservative treatment for Peyronies disease should resolve painful erections in most men, only a small percentage experience any significant straightening of the penis. The aim of surgery is to correct curvature and allow satisfactory intercourse. Surgery is indicated only in patients with stable disease for at least 3 months, although a 6-12 month period has also been suggested. Two major types of repair may be considered for both congenital penile curvature and Peyronies disease: penile shortening and penile lengthening procedures. Penile shortening procedures include the Nesbit wedge resection and the plication techniques performed on the convex side of the penis. Penile lengthening procedures are performed on the concave side of the penis and require the use of a graft. They are used Penile Curvature 171
to minimise penile shortening caused by Nesbit resection or plication of the tunica albuginea or to correct complex deformities. Several types of grafts include autologous grafts (dermis, vein grafts, tunica albuginea, tunica vaginalis, temporalis fascia, buccal mucosa), allografts (cadaveric pericardium, cadaveric fascia lata, cadaveric dura matter, cadaveric dermis), xenografts (porcine small intestine submucosa, bovine pericardium, porcine dermis) and synthetic grafts (Gore-Tex, Dacron). Finally, in patients with Peyronies disease and erectile dysfunction not responding to medical treatments, surgical correction of the curvature with concomitant penile prosthesis implantation should be considered. The decision on the most appropriate surgical procedure to correct penile curvature is based on pre-operative assessment of penile length, the degree of the curvature, and erectile function status. The results of the different surgical approaches are presented in Table 1. It must be emphasised that there are no randomised controlled trials available addressing surgery in Peyronies disease. The treatment algorithm is presented in Figure 1.
Guidelines recommendations on surgical treatment for penile curvature
LE
GR C
Surgery is indicated when Peyronies disease 3 is stable for at least 3 months (without pain or deformity deterioration), which usually occurs after 12 months from the onset of symptoms, and intercourse is compromised by the deformity.
Penile length, curvature severity, erectile function (including response to pharmacotherapy in case of erectile dysfunction) and patient expectations must be assessed prior to surgery. Tunical shortening procedures, especially plication techniques are the first treatment options for congenital penile curvature and for Peyronies disease with adequate penile length, curvature < 60 and absence of special deformities (hour-glass, hinge). Grafting techniques are the preferred treatment option for patients with Peyronies disease with no adequate penile length, curvature > 60 and presence of special deformities (hour-glass, hinge). Penile prosthesis implantation, with or without any additional procedure (modelling, plication or grafting), is recommended in Peyronies disease patients with erectile dysfunction not responding to pharmacotherapy.
2b
2b
2b
This short booklet text is based on the more comprehensive EAU guidelines (978-90-79754-83-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
Penile Curvature 173
table 1: results of surgical treatments for peyronies disease (data from different, non-comparable studies)
Tunical lengthening procedures Nesbit Plication Grafts 4.7-30.8% 41-90% 0-40% 79-100% 58-100% 74-100% 4-26.9% 7.7-10.6% 0-16.7% 0-13% 2-21% 1 0-22.9% 0-21.4% At least 3 0-15% 0-16.7% Many types of grafts and techniques used Tunical shortening procedures
Penile shortening Penile straightening Persistent or recurrent curvature Post-operative erectile dysfunction Penile hypoesthesia Technical modifications
Figure 1: Treatment algorithm for Peyronies disease

Treatment of Peyronies disease
Discuss natural history of the disease Reassure patient that Peyronies is a benign disease Discuss current treatment modalities Shared decision-making
Active disease (pain, deformity deterioration, no calcification on ultrasound)
Stable disease (no pain, no deformity deterioration, calcification plaques on ultrasound)
Conservative treatment
Surgicaltreatment
No ED
ED
Yes Adequate penis length Curvature < 60 Absence of special deformities (hour-glass, hinge) Short penis Curvature > 60 Presence of special deformities (hour-glass, hinge)
Response to treatment
No
Nesbit or plication procedures
Tunica lengthening procedures
Penile prosthesis (remodelling, plaque)
Penile Curvature 175
GUIDELINES FOR THE INVESTIGATION AND TREATMENT OF MALE INFERTILITY

A. Jungwirth, T. Diemer, G.R. Dohle, A. Giwercman, Z. Kopa, C. Krausz, H. Tournaye Eur Urol 2002 Oct;42(4):313-22 Eur Urol 2004 Nov;46(5):555-8 Eur Urol 2012 Jan;61(1):159-63
Definition
Infertility is the inability of a sexually active, non-contracepting couple to achieve spontaneous pregnancy in one year. (WHO, 1995). About 15% of couples do not achieve pregnancy within 1 year and seek medical treatment for infertility. Eventually, less than 5% remain unwillingly childless.
Prognostic factors
The main factors influencing the prognosis in infertility are: duration of infertility; primary or secondary infertility; results of semen analysis; age and fertility status of the female partner. As a urogenital expert, the urologist should examine any male with fertility problems for urogenital abnormalities, so 176 Male Infertility
that appropriate treatment can be given.
Diagnosis
The diagnosis of male fertility must focus on a number of prevalent disorders (Table 1). Simultaneous assessment of the female partner is preferable, even if abnormalities are found in the male, since WHO data show that both male and female partners have pathological findings in 1 out of 4 couples who consult with fertility problems.
Table 1: Reasons for a reduction in male infertility

Congenital factors (cryptorchidism and testicular dysgenesis, congenital absence of the vas deferens) Acquired urogenital abnormalities (obstructions, testicular torsion, testicular tumour, orchitis) Urogenital tract infections Increased scrotal temperature (e.g. due to varicocele) Endocrine disturbances Genetic abnormalities Immunological factors (autoimmune diseases) Systemic diseases (diabetes, renal and liver insufficiency, cancer, hemochromatosis) Exogenous factors (medications, toxins, irradiation) Lifestyle factors (obesity, smoking, drugs, anabolic steroids) Idiopathic (4050% of cases) Semen analysis Semen analysis forms the basis of important decisions concerning appropriate treatment. Semen analysis should be performed in a laboratory adhering to national quality control standards (Table 2). Male Infertility 177
Table 2: Lower reference limits (5th centiles and 95% confidence intervals) for semen characteristics*
Lower reference limit (95% CI) Semen volume (mL) 1.5 (1.4-1.7) Total sperm number (106 per ejaculate) 39 (33-46) 15 (12-16) Sperm concentration (106 per mL) Total motility (PR+NP, %) 40 (38-42) Progressive motility (PR, %) 32 (31-34) Vitality (live spermatozoa, %) 58 (55-63) Sperm morphology (normal forms, %) 4 (3.0-4.0) Other consensus threshold values > 7.2 pH Peroxidase-positive leukocytes < 1.0 (106 per mL) MAR test (motile spermatozoa with < 50 bound particles, %) Immunobead test (motile spermatozoa < 50 with bound beads, %) > 2.4 Seminal zinc (mol/ejaculate) > 13 Seminal fructose (mol/ejaculate) > 20 Seminal neutral glucosidase (mU/ejaculate) *WHO Manual for Semen Analysis, 5th edn, 2010. Frequency of semen analyses If values are normal according to WHO criteria, one test should suffice. If the results are abnormal, semen analysis should be repeated. It is important to distinguish between oligozoospermia (< 15 million spermatozoa/mL), astheno178 Male Infertility Parameter
zoospermia (< 40% motile spermatozoa) and teratozoospermia (< 4% normal forms). Quite often, all three pathologies occur at the same time, i.e. as oligo-astheno-teratozoospermia (OAT) syndrome. In extreme cases of OAT syndrome (< 1 million spermatozoa/mL), just as with azoospermia, there is an increased incidence of genetic abnormalities and/or obstruction of the male genital tract. Hormonal investigation Endocrine malfunctions are more prevalent in infertile men than in the general population, but are still quite uncommon. Hormonal screening can be limited to determining the levels of follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone in cases of abnormal semen parameters. In men diagnosed with azoospermia or extreme OAT, it is important to distinguish between obstructive and nonobstructive causes. Criteria with a reasonable predictive value for non-obstruction are a normal FSH with bilaterally normal testicular volume. However, 29% of infertile men with a normal FSH appear to have defective spermatogenesis. Hypergonadotrophic hypogonadism (elevated FSH/LH) Impaired spermatogenesis associated with elevated levels of gonadotrophins is a common problem and is due to primary testicular failure. Causes include: Congenital Klinefelters syndrome, anorchia, cryptorchidism, testicular dysgenesis, Y chromosome microdeletions Acquired after orchitis, testicular torsion, testicular tumour, systemic illness, cytotoxic therapy. Male Infertility 179
Hypogonadotrophic hypogonadism (deficient FSH/LH) Low levels of gonadotrophins due to dysfunction of the pituitary gland or hypothalamus are rare and may occur as a result of: Congenital anomalies isolated hypogonadotrophic hypogonadism (iHH), syndromic KK, Kallmanns syndrome, Prader-Willi syndrome Acquired anomalies acquired hypothalamic/pituitary gland diseases (malignant CNS tumours, pituitary adenoma, hyperprolactionaemia, granulomatous illness, hemochromatosis) Exogenous factors drugs (anabolic steroids, obesity, irradiation). If unexplained hypogonadotrophic hypogonadism is present, the medical examination should include magnetic resonance imaging (MRI) of the pituitary gland. Microbiological assessment Indications for microbiological assessment include abnormal urine samples, urinary tract infections, male accessory gland infections (MAGI) and sexually transmitted diseases (STDs). The clinical implications of white blood cells detected in a semen sample are as yet undetermined. However, in combination with a small ejaculate volume, this may point to a (partial) obstruction of the ejaculatory ducts caused by a (chronic) infection of the prostate or seminal vesicles. Genital infections may instigate the production of spermatotoxic free oxygen radicals. Neisseria gonorrhoea and Chlamydia trachomatis infections can also cause obstruction of the genital tract. Although antibiotic procedures for MAGI 180 Male Infertility
might provide improvement in sperm quality, therapy does not necessarily increase the probability of conception. Genetic evaluation A substantial number of andrological fertility disorders that used to be described as idiopathic male infertility have a genetic origin. An extensive family history and karyotype and Y chromosome deletion analysis will detect a number of these disorders, not only providing a diagnosis, but also enabling appropriate genetic counselling. The latter may be very important with the advent of intracytoplasmic sperm injection (ICSI), because genetic defects may be transferred and a balanced translocation of the infertile father may become unbalanced in the offspring. Chromosomal abnormalities are more common in men with OAT and with azoospermia, and karyotyping is recommended in these men both for diagnosis purposes and for genetic counselling. The most common sex chromosome abnormality is Klinefelters syndrome (47, XXY), which affects around 14% of men diagnosed with azoospermia. Klinefelters syndrome is characterized by hypergonadotrophic hypogonadism which may be associated with eunuchoid features and/or gynaecomastia. Both testicles are very small due to extensive tubular sclerosis. In around 60% of all patients, testosterone levels decrease with age requiring androgen replacement. Furthermore, chromosome translocations and deletions can be found, which may be hereditary and cause habitual abortion and congenital malformations in the offspring. In cases of azoospermia or severe OAT, there may be deletions in the Male Infertility 181
azoospermic factor (AZF) region of the Y chromosome and testing is advised. The prevalence of Y deletions is considerable (around 5%) in this group of patients. The presence of a Y deletion means that the defect will be passed to sons, who will then also be be affected by spermatogenic disturbances or failure. When performing ICSI with surgically retrieved sperm or ejaculated spermatozoa, based on a diagnosis of congenital bilateral/unilateral absence of the vas deferens (CAVD), both the male and the female partner should be tested for mutations in the cystic fibrosis transmembrane regulator (CFTR) gene. Apart from causing cystic fibrosis (CF), this gene is also associated with CAVD; 85% of all males diagnosed with CAVD also test positive for two CFTR-gene mutations when the entire gene is sequenced. In cases where the partner is a carrier of a CFTR mutation, depending on the mutation involved, there is a 25% chance of a child with CF or CAVD. Genetic counselling is mandatory in these cases. Ultrasonography Ultrasonography is a useful tool for locating intrascrotal defects. Colour Doppler ultrasound of the scrotum can detect a varicocele in around 30% of subfertile males. Testicular tumours can be found in 0.5%, and testicular microcalcifications (a potentially premalignant condition) are detected in around 25% of subfertile males, especially patients diagnosed with a history of cryptorchidism. Transrectal ultrasonography (TRUS) is indicated in men with a low volume of ejaculate (<1.5 mL) to exclude obstruction of the ejaculatory 182 Male Infertility
ducts caused by a midline prostatic cyst or stenosis of the ejaculatory ducts. Testicular biopsy Testicular biopsy is usually performed as part of a therapeutic process in azoospermic patients (testicular sperm retrieval) who decide to undergo ICSI. Indications for performing a diagnostic testicular biopsy could be azoospermia or extreme OAT, in the presence of a normal testicular volume and normal FSH levels. The biopsy is aimed at differentiating between testicular insufficiency and obstruction of the male genital tract. It is advised that, during the procedure, tissue that contains spermatozoa is cryopreserved for future ICSI attempts. In addition, testicular biopsies are performed to detect carcinoma in situ of the testis in infertile men with testicular microcalcifications and risk factors for testicular cancer (i.e. male infertility, cryptorchidism, history of a testicular tumour, testicular atrophy). Pathological classifications are: Absence of seminiferous tubules (tubular sclerosis) Presence of sertoli cells only (sertoli cell only syndrome) Maturation arrest spermatogenesis arrested at different stages (spermatogonia, spermatocytes or spermatides) Hypospermatogenesis all cell types up to spermatozo are present, but there is a distinct decline in the number of reproducing spermatogonia.
Male Infertility 183
Treatment
Counselling Lifestyle factors can impair semen quality, e.g. heavy smoking, alcohol abuse, use of anabolic steroids, extreme sports (marathon training, excessive strength sports), and an increase in scrotal temperature through thermal underwear, sauna or hot tub use, or occupational exposure to heat sources. A considerable number of drugs can affect spermatogenesis. Medical (hormonal) treatment Antioxidant treatment (folic acid, vitamin E, zinc, selenium) have a positive influence on semen quality and some improvement of spontaneous pregnancy rates. No studies have confirmed that hormonal therapies, such as human menopausal gonadotrophin (HMG)/human chorionic gonadotrophin (HCG), androgen, anti-oestrogens (clomiphene and tamoxifen), prolactin inhibitors (bromocriptine) and steroids, have improved pregnancy rates in men with idiopathic OAT. However, some primarily endocrinological pathologies can be treated medically, including: Low testosterone: clomiphene citrate 50 mg/day or tamoxifen 20 mg/day Hypogonadotrophic hypogonadism: start HCG 1500 IU subcutaneously 3 times per week, and add HMG or FSH 75150 IU intramuscularly 3 times per week, until spermatogenesis occurs Hyperprolactinaemia: dopamine agonists. In patients with sperm autoantibodies, high-dose corticos184 Male Infertility
teroids, although effective, are not recommended because of serious side-effects. Surgical treatment Varicocele The treatment of varicocele is a controversial subject, mainly based on whether there is an actual need to treat varicocele in infertile men. There is evidence of improved semen parameters after successful varicocele treatment. Current information supports the hypothesis that in some men, the presence of varicocele is associated with progressive testicular damage from adolescence onwards and consequent reduction in fertility. Although treatment of varicocele in adolescents may be effective, there is a significant risk of over-treatment. In cases of normal semen analysis and in men with a subclinical varicocele, there appears to be no benefit from treatment compared with observation. Varicocele repair, however, seems effective in couples in whom the men hasoligozoospermia, a clinical varicocele and otherwise unexplained infertility. Microsurgery/vasovasostomy and epididymovasostomy Only urologists with experience in microsurgery should undertake these procedures using an operating microscope. The likelihood of initiating pregnancy is inversely proportional to the obstruction interval and becomes less than 50% after 8 years. Other important prognostic factors are the quality of the semen after the procedure and the partners age. In approximately 15% of men who have undergone a successful vasovasostomy, sperm quality deteriorates to the level of azoospermia or extreme oligospermia within 1 year. Male Infertility 185
Sometimes an epididymal obstruction coexists, especially in men with a long interval between vasectomy and vasovasostomy. In these men a vaso-epididymostomy is indicated. Considering that a vaso-epididymostomy has a limited effect on pregnancy rates (2030%), it is advisable to combine this procedure with microsurgical epididymal sperm aspiration (MESA), and cryopreserve the harvested spermatozoa for ICSI. The indications for vaso-epididymostomy include obstructions at the level of the epididymis in the presence of a normal spermatogenesis (testicular biopsy). Poor sperm quality and sometimes sperm antibodies after successful vasectomy repair may prevent spontaneous pregnancy and assisted reproduction is indicated. MESA/TESE MESA in combination with ICSI is indicated in men with obstructive azoospermia when reconstruction (vasovasostomy, vaso-epididymostomy) cannot be performed or is unsuccessful. An alternative would be percutaneous aspiration of spermatozoa from the caput epididymis (PESA). If a MESA or PESA procedure does not produce spermatozoa, testicular sperm extraction (TESE) can be applied. In about 5060% of men with non-obstructive azoospermia (NOA), spermatozoa can be found in the testis. Some authors recommend taking several testicular samples, while others advocate microsurgical harvesting of spermatozoa. So far, no clinical or laboratory parameter has been shown to be useful in predicting sperm harvesting in men with NOA. In case of AZFa and AZFb microdeletions, no spermatozoa can be retrieved.
186 Male Infertility
Transurethral incision of ejaculatory ducts or midline prostatic cyst Distal obstructions of the genital tract are commonly caused by infections of the prostatic urethra and the accessory glands or by a cyst in the midline of the prostate. Treatment of the obstruction by transurethral incision of the cyst or the ejaculatory ducts (TURED) may lead to an increase in semen quality and, occasionally, spontaneous pregnancy. Long-term results, however, are disappointing. Disorders of ejaculation Retrograde ejaculation and anejaculation can occur: In neurological diseases, e.g. multiple sclerosis, diabetes mellitus (neuropathy) and spinal cord injuries Following prostate surgery, bladder neck surgery, sympathectomy and retroperitoneal surgery, e.g. lymph node dissections for testicular tumours During antidepressant therapy. Often, no cause for retrograde ejaculation can be found. The diagnosis is based on the medical history and laboratory microscopic assessment of the post-ejaculate urine. Retrograde ejaculation should also be suspected if the ejaculate volume is very low (partial retrograde ejaculation). Treatment of retrograde ejaculation is basically aimed at removing the cause of the disorder or harvesting spermatozoa from the urine after orgasm. Anejaculation can be treated by vibrostimulation or electroejaculation techniques. It is possible to induce ejaculation in around 90% of patients with spinal cord injuries. However, Male Infertility 187
the semen quality is often poor with a low number of motile spermatozoa and increased rates of DNA fragmentation. This accounts for the disappointing results of assisted reproduction techniques in these men. Testicular sperm extraction (TESE), in-vitro fertiliation and ICSI are often required.
This short booklet text is based on the more comprehensive EAU guidelines (978-90-79754-83-0), available to all members of the European Association of Urology at their website - http://www.uroweb.org.
188 Male Infertility
GUIDELINES ON MaLE HypOGONaDISM

G.R. Dohle, S. Arver, C. Bettocchi, S. Kliesch, M. Punab, W. de Ronde
Introduction
Male hypogonadism is a clinical syndrome caused by androgen deficiency. It may adversely affect multiple organ functions and quality of life. Androgens play a crucial role in the development and maintenance of male reproductive and sexual functions. Low levels of circulating androgens can cause disturbances in male sexual development, resulting in congenital abnormalities of the male reproductive tract. Later in life, this may cause reduced fertility, sexual dysfunction, decreased muscle formation and bone mineralisation, disturbances of fat metabolism, and cognitive dysfunction. Testosterone levels decrease as a process of ageing: signs and symptoms caused by this decline can be considered a normal part of ageing. However, low testosterone levels are also associated with several chronic diseases, and symptomatic patients may benefit from testosterone treatment. Androgen deficiency increases with age; an annual decline in circulating testosterone of 0.4-2.0% has been reported. In middle-aged men, the incidence was found to be 6%. It is more prevalent in older men, in men with obesity, those with co-morbidities, and in men with a poor health status.
Male Hypogonadism 189
aetiology and forms

Male hypogonadism can be classified in 4 forms: 1. Primary forms caused by testicular insufficiency; 2. Secondary forms caused by hypothalamic-pituitary dysfunction; 3. Late onset hypogonadism; 4. Male hypogonadism due to androgen receptor insensitivity. The main causes of these different forms of hypogonadism are highlighted in Table 1. The type of hypogonadism has to be differentiated, as this has implications for patient evaluation and treatment and enables identification of patients with associated health problems.
Table 1: Different forms of male hypogonadism and main causes

Primary forms (testicular insufficiency) Congenital forms Main causes Klinefelter syndrome Testicular dysgenesis (cryptorchidism) Congenital anorchia Testicular malignancy Orchitis Medications (chemotherapy) Systemic diseases Acuired anorchia
Acuired forms
190 Male Hypogonadism
Secondary forms (hypothalamic-pituitary dysfunctions) Congenital forms
Main causes
Acuired forms
Late onset hypogonadism (Combined testicular and hypothalamic pituitary insucfficiency) Androgen receptor insensitivity
Kallmann syndrome Idiopathic hypogonadotrophic hypogonadism (IHH) Pituitary tumour (prolactinoma) Drugs Systemic disease (renal failure, hemochromatosis, hypothyroidism, trauma, infections) Abuse of anabolic steroids Morbid obesity Radiotherapy Ageing Obesity Chronic diseases Poor health status Partial androgen insensitivity syndrome (PAIS)
Diagnosis
The diagnosis of male hypogonadism is based on clinical symptoms and signs of androgen deficiency (Table 2 and 3), together with consistently low serum testosterone levels.
Table 2: Signs and symptoms suggesting prepubertalonset hypogonadism

Small testes Cryptorchidism Gynaecomastia High voice Unclosed epiphyses Linear growth into adulthood Eunuchoid habitus Sparse body/facial hair Infertility Low bone mass Sarcopenia Reduced sexual desire/activity
Table 3: Signs and symptoms associated with lateonset hypogonadism

Loss of libido Erectile dysfunction Sarcopenia Low bone mass Depressive thoughts Changes in mood, fatigue and anger Sleep disturbances Loss of body hair Hot flushes Loss of vigour Insulin resistance Metabolic syndrome 192 Male Hypogonadism
Visceral obesity Gynaecomastia Diminished cognitive functions Routine screening for testosterone deficiency is not indicated. However, testosterone assessment should be done in men with: Pituitary mass, following radiation involving the sellar region and other diseases in the hypothalamic and sellar region; End-stage renal disease receiving haemodialysis; Treatment with medications that cause suppression of testosterone levels e.g. corticosteroids and opiates; Moderate to severe chronic obstructive lung disease; Infertility; Osteoporosis or low-trauma fractures; Human immunodeficiency virus (HIV) infection with sarcopenia; Type 2 diabetes. Acquired hypogonadotropic hypogonadism (secondary forms) can be caused by some drugs, hormones, anabolic steroids and by tumours of the pituitary gland. Imaging (CT scan or MRI) of the sellar region and complete endocrine work-up is requested when a pituitary tumour is suspected.
Recommendations for screening
GR Screening for testosterone deficiency is only recomC mended in adult men with consistent and preferably multiple signs and symptoms, listed in Tables 2 and 3. Male Hypogonadism 193
Adult men with established severe hypogonadism B should be screened for concomitant osteoporosis. Total testosterone assessment should be repeated at A least on two occasions with a reliable method. - In men with total testosterone levels close to the lower normal range (8-12 nmol/l), the free testosterone level should be measured to strengthen the laboratory assessment. - In men with suspected or known abnormal sex hormone-binding globulin (SHBG) levels, free testosterone should also be included.
Treatment
The aim of treatment is to restore testosterone levels to the physiological range and thereby improve the patients quality of life. Indications and contraindications are listed in Tables 4 and 5.
Table 4: Indications for testosterone treatment

Adult men with consistent and preferably multiple signs and symptoms of hypogonadism (listed in Tables 2 and 3) and low testosterone Delayed puberty (idiopathic, Kallmann syndrome) Klinefelter syndrome with hypogonadism Sexual dysfunction and low testosterone Low muscle strength and bone mass in hypogonadism Hypopituitarism Testicular insufficiency and symptomatic hypogonadism
Table 5: Contraindications against testosterone treatment

Prostate cancer Prostate-specific antigen (PSA) > 4 ng/mL Male breast cancer Severe sleep apnoea Male infertility Haematocrit > 50% Severe lower urinary tract symptoms due to benign prostatic enlargement
Choice of treatment
Testosterone replacement therapy (TRT) is safe and effective and the agents are available as oral preparations, intramuscular injections, and transdermal gel or patches (Table 6).
Table 6: Testosterone preparations for replacement therapy

Formulation Testosterone undecanoate Administration Advantages Oral; 2-6 cps Absorbed every 6 h through the lymphatic system, with consequent reduction of liver involvement Disadvantages Variable levels of testosterone above and below the mid-range. Need for several doses per day with intake of fatty food
Testosterone cypionate
Intramuscular; one injection every 2-3 weeks
Testosterone enanthate
Testosterone undecanoate
Short-acting preparation that allows drug withdrawal in case of onset of side effects Short-acting preparation that allows drug withdrawal in case of onset of side effects Steady-state testosterone levels without fluctuation
Possible fluctuation of testosterone levels
Possible fluctuation of testosterone levels
Transdermal testosterone
Gel or skin patches; daily application
Steady-state testosterone level without fluctuation
Sublingual testosterone
Sublingual; daily doses
Rapid absorption and achievement of physiological serum level of testosterone
Long-acting preparation that cannot allow drug withdrawal in case of onset of side effects Skin irritation at the site of application and risk of interpersonal transfer Local irritation
Buccal testosterone
Buccal tablet; two doses per day
Subdermal depots
Subdermal implant every 5-7 months
Rapid absorption and achievement of physiological serum level of testosterone Long duration and constant serum testosterone level
Irritation and pain at the site of application
Risk of infection and extrusion of the implants
In patients with secondary hypogonadism, anti-oestrogens or hormonal stimulation with hCG and FSH or alternatively GnRH can restore testosterone production.
Recommendations
GR The patient should be fully informed about expected A benefits and side effects of each treatment option. The selection of the preparation should be a joint decision by an informed patient and the physician. Short-acting preparations may initially be preferred to B long-acting depot administration when starting treatment. Patients can switch to a long-acting depot if preferred and side effects are absent or minimal. Human chorionic gonadotrophin (hCG) treatment B can only be recommended for hypogonadal patients who are receiving simultaneous fertility treatment.
Risk factors in testosterone treatment

Case reports and small cohort studies point to a possible correlation between TRT and the onset of breast cancer, Male Hypogonadism 197
but there is as yet a lack of strong evidence for this relationship. Randomised controlled trials support the hypothesis that TRT does not result in changes in prostatic histology. However, there are not yet data available that show longterm prostatic safety of TRT. Testosterone therapy is not related to the development of de novo cardiovascular events. However, patients with severe cardiovascular diseases should be screened first by a cardiologist before TRT is initiated.
Recommendations for initiation of treatment

Haematological, cardiovascular, breast and prostatic assessment should be performed before the start of treatment. Men with severe cardiovascular co-morbidity should be assessed by a cardiologist before TRT is initiated and there should be close cardiovascular monitoring during TRT. Prostate health should be assessed by digital rectal examination (DRE) and PSA before the start of TRT. In patients treated for localised prostate cancer and without signs of prostate cancer recurrence, testosterone therapy should not start before at least 1 year of follow-up.
GR A
A C
Recommendations for monitoring
GR C The response to treatment (symptoms and testosterone serum levels) should be assessed 3, 6 and 12 months after the onset of treatment, and thereafter annually.
In men with an abnormal bone mineral density (BMD), BMD measurements should be repeated 6 and 12 months after the start of TRT and thereafter annually. Haematocrit should be monitored at 3, 6 and 12 months and thereafter annually. The testosterone dosage should be decreased, or therapy discontinued if the haematocrit increases above normal levels. Prostate health should be monitored by PSA testing at 3, 6 and 12 months and thereafter annually. Routine screening of potential cardiovascular side effects is not indicated in men receiving TRT.
C A
This short booklet text is based on the more comprehensive EAU guidelines (978-90-79754-83-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
GUIDELINEs ON URINARY INCONTINENCE

(Complete text update February 2012)
M.G. Lucas (chairman), J.L.H.R. Bosch, F. Cruz, D.J.M.K. de Ridder, T.B. Madden, A. Nambiar, A. Neisius, R.S. Pickard, A. Tubaro, W.H. Turner This pocket version aims to synthesise the important clinical messages described in the full text and is presented as a series of evidence summaries and graded action based recommendations, which follow the standard for levels of evidence used by the EAU (see Introduction chapter). The grades of recommendation aim to make it clear what the clinician should or should not do in clinical practice, not merely to comment on what they might do. Recommendations have been deliberately written as actionbased sentences. The following words or phrases are used consistently throughout the Guidelines, as follows. Consider an action. This word is used when there is not enough evidence to say whether the action causes benefit or risk to the patient. However, in the opinion of the Panel, the action may be justified in some circumstances. Action is optional. Offer an action. This word is used when there is good evidence to suggest that the action is effective, or that, in the 200 Urinary Incontinence
opinion of the Panel, it is the best action. Action is advisable. Carry out (perform) an action. Do something. This phrase is used when there is strong evidence that this is the only best action in a certain clinical situation. Action is mandatory. Avoid an action. This phrase is used when there is highlevel evidence that the action is either ineffective or is harmful to the patient. Action is contraindicated. The Panel has tried to avoid extensive narrative text. Instead, algorithms are presented for both initial and specialised management of men and women with non-neurogenic UI. Each decision node of these algorithms is clearly linked back to the relevant evidence and recommendations.
AssEssMENT AND DIAGNOsIs History and Physical Examination

Although there is no evidence to support this, there is absolute consensus of expert opinion that this is an essential step.
Recommendations 1
Take a history to include the following; Type of incontinence (stress, urge or mixed) Timing and severity Any associated urinary symptoms Obstetric and gynaecological history Any comorbidities Medication review
GR A*
Urinary Incontinence 201
A* Do a physical examination to include: Abdominal exam to detect bladder enlargement or abdominal/pelvic mass Perineal examination Digital vaginal or rectal examination Assess oestrogen status of woman Assess voluntary pelvic floor contraction A* Consider early referral to specialist if: UI associated with pain Haematuria History of recurrent UTI Previous pelvic surgery or radiotherapy Constant leak suspicious of fistula Any voiding difficulty Suspicion of neurological disease * Given Grade A because, despite an absence of evidence, expert opinion assigns absolute importance to these steps
Questionnaires Recommendations 2
GR Healthcare professionals should be aware that the use C of questionnaires and PROMs has not been shown to influence patient outcome in UI due to the lack of specific research in this area
202 Urinary Incontinence
Voiding diaries Recommendations 3

Voiding diaries should be used in urinary incontinence to evaluate co-existing storage and voiding dysfunction in clinical practice and in research A diary duration of between 3 and 7 days is recommended
GR A
Urinalysis and UTI Recommendations 4

Do urinalysis as a part of the initial assessment of a patient with urinary incontinence In a patient with urinary incontinence, treat a symptomatic urinary tract infection appropriately (see EAU Guidelines on Urological Infections) Do not treat asymptomatic bacteriuria in elderly patients to improve urinary incontinence
GR A A
Post-voiding residual volume Recommendations 5

Post-voiding residual should be measured by ultrasound Measure post-voiding residual in patients with urinary incontinence who have voiding dysfunction Measure post-voiding residual when assessing patients with complicated urinary incontinence Post-voiding residual should be monitored in patients receiving treatments that may cause or worsen voiding dysfunction
GR A B C B
Urodynamics Recommendations 6
(NB: These refer only to neurologically intact adults with urinary incontinence) Clinicians carrying out urodynamics in patients with urinary incontinence should: Ensure that the test replicates patients symptoms Interpret results in context of the clinical problem Check recordings for quality control Remember there may be physiological variability within the same individual Advise patients that the results of urodynamics may be useful in discussing treatment options, although there is limited evidence that performing urodynamics will alter the outcome of treatment for urinary incontinence Do not routinely carry out urodynamics when offering conservative treatment for urinary incontinence Perform urodynamics if the findings may change the choice of surgical treatment Perform urodynamics prior to surgery for urinary incontinence if there are either symptoms of overactive bladder, a history of previous surgery or a suspicion of voiding difficulty Do not routinely carry out urethral pressure profilometry
GR
B C C
Pad testing
A well-designed continence pad will contain any urine leaked within a period of time and this has therefore been used as a way of quantifying leakage. Although the International Continence Society has attempted to standardize pad testing, 204 Urinary Incontinence
there remain differences in the way patients are instructed to undertake activity during the test.
Recommendations 7
GR Use a pad test when quantification of urinary inconti- C nence is required Use repeat pad test if objective treatment outcome C measure is required
Imaging Recommendation 8
GR Do not routinely carry out imaging of the upper A or lower urinary tract as part of the assessment of uncomplicated stress urinary incontinence in women
CONsERVATIVE TREATMENT
Conventional medical practice encourages the use of simple, relatively harmless, interventions before resort to those associated with higher risks.
simple Medical interventions

Correction of Underlying disease/cognitive impairment Numerous conditions exacerbate UI or make it more likely to occur, whether or not they play any part in the pathophysiology of leakage. These conditions include: cardiac failure chronic renal failure diabetes chronic obstructive pulmonary disease neurological disorders stroke Urinary Incontinence 205
dementia multiple sclerosis general cognitive impairment sleep disturbances e.g. sleep apnoea.
Adjustment of medication
There is very little evidence of benefit from the adjustment of medication. There is also a theoretical risk, at least, that stopping or altering medication may bring with it more harm than good.
Recommendations 9
GR Take a drug history from all patients with urinary A incontinence Inform women with urinary incontinence that begins A or worsens after starting systemic oestrogen replacement therapy that it may cause urinary incontinence Review any new medication associated with the C development or worsening of urinary incontinence
Constipation
Several studies have shown strong associations between constipation, urinary incontinence and overactive bladder. Constipation can be improved by behavioural and medical treatments.
Recommendations 10
For adults with urinary incontinence, treat co-existing constipation
GR C
Containment (pads etc) Recommendations 11

Offer pads when containment of urinary incontinence is needed Adapt the choice of pad to the type and severity of urinary incontinence and the patients needs Offer catheterisation to manage urinary incontinence when no other treatments can be considered Offer condom catheters to men with urinary incontinence without significant residual urine Offer to teach intermittent catheterisation to manage urinary incontinence associated with retention of urine Do not routinely offer intravaginal devices as treatment for incontinence Do not use penile clamps for control of urinary incontinence in men
GR B A B A A
B A
Lifestyle Changes
Examples of lifestyle factors that may be associated with incontinence include obesity, smoking, level of physical activity and diet. It may therefore be possible to improve urinary incontinence by beginning lifestyle interventions, such as weight loss, fluid restriction, reduction of caffeine or alcohol intake, limiting heavy activity and stopping smoking.
Recommendations 12
Encourage obese women suffering from any urinary incontinence to lose weight (> 5%) Advise adults with urinary incontinence that reducing caffeine intake may improve symptoms of urgency and frequency but not incontinence Patients with abnormally high or abnormally low fluid intake should be advised to modify their fluid intake appropriately Counsel female athletes experiencing urinary incontinence with intense physical activity that it will not predispose to urinary incontinence in later life Patients with urinary incontinence who smoke should be given smoking cessation advice in line with good medical practice although there is no definite effect on urinary incontinence
GR A B
Behavioural and physical therapies Recommendations 13

Offer supervised pelvic floor muscle training lasting at least 3 months, as a first-line therapy to women with stress or mixed urinary incontinence Pelvic floor muscle training programmes should be as intensive as possible Consider using biofeedback as an adjunct in women with stress urinary incontinence Offer supervised pelvic floor muscle training to continent women in their first pregnancy to help prevent incontinence in the postnatal period
GR A
A A A
Offer instruction on pelvic floor exercises to men undergoing radical prostatectomy to speed recovery of urinary incontinence Offer bladder training as a first-line therapy to adults with urgency urinary incontinence or mixed urinary incontinence Offer timed voiding to adults with urinary incontinence, who are cognitively impaired Do not offer electrical stimulation with surface electrodes (skin, vaginal, anal) alone for the treatment of urinary incontinence Do not offer magnetic stimulation for the treatment of urinary incontinence or overactive bladder in adult women Offer posterior tibial nerve stimulation to women with urgency urinary incontinence who cannot tolerate anticholinergic medication
A A
DRUG TREATMENT OF URINARY INCONTINENCE Antimuscarinics Recommendations 14
GR Offer instant release or extended release formulations A of antimuscarinic drugs as initial drug therapy for adults with urgency urinary incontinence If instant release formulations of antimuscarinic A drugs are unsuccessful for adults with urgency urinary incontinence, offer extended release formulations or longer-acting antimuscarinic agents Consider using transdermal oxybutynin if oral B antimuscarinic agents cannot be tolerated due to dry mouth Urinary Incontinence 209
Offer and encourage early review (of efficacy and side effects) of patients on antimuscarinic medication for urgency urinary incontinence (< 30 days) When prescribing antimuscarinic drugs to elderly patients, be aware of the risk of cognitive side effects, especially in those receiving cholinesterase inhibitors Avoid using oxybutynin instant release in patients who are at risk of cognitive dysfunction Consider use of trospium chloride in patients known to have cognitive dysfunction Use solifenacin, tolterodine and darifenacin with caution in patients with cognitive dysfunction Do an objective assessment of mental function before treating patients whose cognitive function may be at risk Check mental function in patients on antimuscarinic medication if they are at risk of cognitive dysfunction
A B B C
Duloxetine Recommendations 15
Duloxetine should not be offered to women or men who are seeking a cure for their incontinence Duloxetine can be offered to women or men who are seeking temporary improvement in incontinence symptoms Duloxetine should be initiated using dose titration because of high adverse effect rates
GR A A
Intravaginal Oestrogen Recommendations 16
GR Women using systemic oestrogen should be counA selled that they have an increased risk for developing urinary incontinence or worsening of their existing incontinence Offer post-menopausal women with urinary inconA tinence local oestrogen therapy, although the ideal duration of therapy and best delivery method are unknown Advise post-menopausal women who are taking oral B oestrogens that they have an increased risk for developing urinary incontinence or worsening of their existing urinary incontinence
Desmopressin Recommendations 17
GR Offer desmopressin to patients requiring occasional B short-term relief from urinary incontinence, inform them that this drug is not licensed for this indication Do not use desmopressin for long-term control of A urinary incontinence
sURGICAL TREATMENT
Generic principles of surgery: Always discuss the purpose of surgery and the likely benefits and risks, with the patient and/or carers Explain alternative approaches even if they are not available locally Surgeons should be properly trained to do these proceUrinary Incontinence 211
dures and perform adequate numbers to maintain expertise Surgeons should be able to report their own outcomes for any operation they offer and share this information with their patient
Recommendations 18
(Surgery for women with uncomplicated stress urinary incontinence) Offer the mid-urethral sling to women with uncomplicated stress urinary incontinence as the preferred surgical intervention whenever available Offer colposuspension (open or laparoscopic) or autologous fascial sling to women with stress urinary incontinence if mid-urethral sling cannot be considered Warn women who are being offered a retropubic insertion synthetic sling about the relatively higher risk of peri-operative complications compared to transobturator insertion Warn women who are being offered transobturator insertion of mid-urethral sling about the higher risk of pain and dyspareunia in the longer term Warn women undergoing autologous fascial sling that there is a high risk of voiding difficulty and the need to perform clean intermittent self-catheterisation; ensure they are willing and able to do so. Do a cystoscopy as part of retropubic insertion of a mid-urethral sling, or if difficulty is encountered during transobturator sling insertion, or if there is a significant cystocoele
GR
Women being offered a single-incision sling device for which an evidence base exists, should be warned that short-term efficacy is inferior to standard midurethral slings and that long-term efficacy remains uncertain Only offer single-incision sling devices, for which there is no level 1 evidence base, as part of a structured research programme Only offer adjustable mid-urethral sling as a primary surgical treatment for stress urinary incontinence as part of a structured research programme Do not offer bulking agents to women who are seeking a permanent cure for stress urinary incontinence
Complicated stress UI in women Recommendations 19
GR (Surgery for complicated stress urinary incontinence in women) The choice of surgery for recurrent stress urinary C incontinence should be based on careful evaluation of the individual patient Women should be warned that the outcome of secC ond-line surgical procedures is likely to be inferior to first-line treatment, both in terms of reduced benefit and increased risk of harm C Offer implantation of AUS or ACT as an option for women with complicated stress urinary incontinence if they are available and appropriate monitoring of outcome is in place
Warn women receiving AUS or ACT that there is a high risk of mechanical failure or a need for explantation AUS = Artificial Urinary Sphincter; ACT = Adjustable Compression Therapy
Men with stress UI Recommendations 20

(Surgical treatment of men with stress urinary incontinence) Only offer bulking agents to men with mild postprostatectomy incontinence who desire temporary relief of UI symptoms Do not offer bulking agents to men with severe postprostatectomy incontinence Offer fixed slings to men with mild-to-moderate postprostatectomy incontinence Warn men that severe incontinence, prior pelvic radiotherapy or urethral stricture surgery, may worsen the outcome of fixed male sling surgery Offer AUS to men with persistent (more than 6 months) moderate-to-severe post-prostatectomy incontinence that has not responded to conservative management Warn about the long-term risk of failure and need for revision when counselling men for insertion of AUS Only offer the non-circumferential compression device (ProACT) for men with post-prostatectomy incontinence if arrangements for monitoring of outcome are in place
GR
C B C
C C
Warn men considering a non-circumferential comC pression device (ProACT) that there is a high risk of failure and subsequent explantation Do not offer non-circumferential compression device C (ProACT) to men who have had pelvic radiotherapy AUS = Artifical urinary sphincter
surgical interventions for Refractory Detrusor Overactivity Intravesical Botulinum Toxin injection Recommendations 21
GR Offer botulinum toxin A intravesical injections to A patients with urgency urinary incontinence refractory to antimuscarinic therapy Warn patients of the possible need to self-catheterise A and the associated risk of urinary tract infection; ensure that they are willing and able to do so Patients should also be warned of the licensing status A of botulinum toxin A, and that the long-term effects remain unknown
sacral nerve stimulation (neuromodulation) Recommendation 22
GR If available, offer patients with urgency urinary A incontinence that is refractory to conservative therapy, the opportunity to be treated by sacral nerve neuromodulation before bladder augmentation or urinary diversion is considered Urinary Incontinence 215
Augmentation Cystoplasty / Urinary Diversion Recommendations 23

Only offer augmentation cystoplasty to patients with detrusor overactivity incontinence who have failed conservative therapy, in whom the possibility of botulinum toxin and sacral nerve stimulation has been discussed Warn patients undergoing augmentation cystoplasty of the high risk of having to perform clean intermittent self-catheterisation; ensure they are willing and able to do so Do not offer detrusor myectomy as a treatment for urinary incontinence Only offer urinary diversion to patients who have failed less invasive therapies for the treatment of urinary incontinence and who will accept a stoma Warn patients undergoing augmentation cystoplasty or urinary diversion of the high risk of short-term and long-term complications, and the possible small risk of malignancy Life-long follow-up is recommended for patients who have undergone augmentation cystoplasty or urinary diversion
GR C
C C
Treatment of Mixed Urinary Incontinence Recommendations 24

Treat the most bothersome symptom first in patients with mixed urinary incontinence Warn patients with mixed urinary incontinence that the chance of success of pelvic floor muscle training is less satisfactory than for stress urinary incontinence alone Offer antimuscarinic drugs to patients with urgepredominant mixed urinary incontinence Warn patients with mixed urinary incontinence that surgery is less likely to be successful than surgery in patients with stress urinary incontinence alone
GR C B
A A
This short text is based on the more comprehensive EAU guidelines (ISBN 978-90-79754-09-0), available to all members of the European Association of Urology at their website - http://www.uroweb.org.

Female presenting with Urinary Incontinence
GA GA GC GB GA GB GC rec 7 rec 5 Haematuria Pain Recurrent UTI Grade 3 or symptomatic prolapse Previous pelvic radiotherapy Previous surgery for UI (go to bottom of pathway) Pelvic mass Suspicion of fistula rec 1 rec 1 rec 2 rec 3 rec 4
Initial assessment History Physical examiniation Questionnaire optional Voiding diary Urinalysis Post void residual if voiding difficulty Pad test if quantification of leakage is desired
Reasons for specialist Referral (rec 1)
continued on page 205
Female Discuss management
Stress Incontinence
Mixed Incontinence Rec 24 Urgency Incontinence
Advise on bowels, drugs, co-morbidity, fluid intake Advise on weight loss Consider intervention related to cognitive impairment (scheduled voiding) Offer pads if needed Consider reducing caffeine intake Consider topical oestrogen for post-menopausal women
GC recs 9, 10, 12 GA rec 12 GC GB rec 11 GB rec 12 GA rec 16
Supervised, intensive PFMT +/- Biofeedback GA rec 13 +/- Bladder training GB recs 13&24
Bladder training GB rec 13
Anti-muscarinics GA recs 14 + 24
Consider PTNS GB rec 13
Male Discuss management

Mixed Incontinence Rec 24 Urgency Incontinence GC recs 9, 10, 12 GA rec 12 GC GB rec 11 GB rec 12 Bladder training GB rec 13 Anti-muscarinics GA recs 14 + 24 Consider PTNS GB rec 13
Stress Incontinence
Advise on bowels, drugs, co-morbidity, fluid intake Advise on weight loss Consider intervention related to cognitive impairment (scheduled voiding) Offer pads if needed Consider reducing caffeine intake
Provide information on pelvic floor excersie GB rec 13
Male presenting with Urinary Incontinence
GA GA GC GB GA GB GC rec 7 rec 5
Initial assessment History Physical examiniation Questionnaire optional Voiding diary Urinalysis Post void residual if voiding difficulty Pad test if quantification of leakage is desired rec 1 rec 1 rec 2 rec 3 rec 4
Reasons for specialist Referral
See rec 1 Haematuria Pain Recurrent UTI Previous pelvic radiotherapy Abnormal DRE Findings suspicious of voiding dysfunction
Female Failed initial management
Consider urodynamics
GA rec 6

Mixed Incontinence See Rec 24 Urgency Incontinence
Urgency predominant Stress predominant
Stress Incontinence
Offer MUS GA recs 18 + 24 Consider peri-urethral injections for temporary Offer Botulinum toxin A or the opportunity for SNS GA rec 21
Offer the opportunity for SNS GA rec 22
Offer fascial sling or colposuspension if MUS unavailable GA recs 18 + 24 Failure
Discuss bladder augmentation on urinary diversion GA rec 23
Re-evaluate patient and consider second-line surgery GC rec 19
Re-evaluate and re-enter algorithm at appropriate stage
Male Failed initial management

Re-evaluate, perform urodynamics and cystoscopy, and consider imaging of lower UT GB rec 6
Stress Incontinence
Mixed Incontinence Rec 24 Urgency Incontinence
Consider peri-urethral injection for temporary relief, and minimally invasive compressione devices GC rec 20
Offer Botulinum toxin A GA rec 21
Offer the opportunity for treatment with SNS GA rec 22
Consider fixed slings for men with PRPI GC rec 20
Discuss bladder augmentation or urinary diversion GC rec 23
Offer AUS to men with persistent moderate to severe PPI GB rec 13
GUIDELINES ON UROLOGICAL INFECTIONS

M. Grabe (chairman), T.E. Bjerklund-Johansen, H. Botto, M. ek, K.G. Naber, R.S. Pickard, P. Tenke, F. Wagenlehner, B. Wullt
Introduction
Infections of the urinary tract (UTIs) pose a serious health problem for patients at high cost for society. UTIs are also the most frequent healthcare associated infections. E. coli is the predominating pathogen in uncomplicated UTIs while other Enterobacteriaceae and Enterococcus spp are isolated in higher frequency in patients with urological diseases. The present state of microbial resistance development is alarming and the rates of resistance are related to the amount of antibiotics used in the different countries. Particularly worrisome is the increasing resistance to broad spectrum antibiotics. It is thus essential to limit the use of antibiotics in general and fluoroquinolones and cephalosporins in particular, especially in uncomplicated infections and asymptomatic bacteriuria.
Classification and definitions

For practical clinical reasons, urinary tract infections (UTIs) and male genital tract infections are classified into entities defined by the predominant clinical symptoms (Table 1). 224 Urological Infections
Table 1: Classification of urinary and male genital tract infections

Uncomplicated lower UTI (cystitis) Uncomplicated pyelonephritis Complicated UTI with or without pyelonephritis Urosepsis Urethritis Prostatitis, epididymitis, orchitis The definitions of bacteriuria and pyuria are listed in Table 2.
Table 2: Significant bacteriuria in adults

1. > 103 uropathogens/mL of midstream urine in acute uncomplicated cystitis in female. 2. > 104 uropathogens/mL of midstream urine in acute uncomplicated pyelonephritis in female. 3. > 105 uropathogens/mL in midstream urine of women or 104 uropathogens/mL of midstream urine in men (or in straight catheter urine in women) with complicated UTI. 4. In a suprapubic bladder puncture specimen, any count of bacteria is relevant. Asymptomatic bacteriuria Asymptomatic bacteriuria is defined as two positive urine cultures taken more than 24 hours apart containing 105 uropathogens/mL of the same bacterial strain (usually only the species can be detected). Pyuria The diagnostic requirement for pyuria is 10 white blood cells per high-power field (HPF) (x400) in the resuspended sediUrological Infections 225
ment of a centrifuged aliquot of urine or per mm3 in unspun urine. For routine investigation, a dipstick method can also be used, including a leukocyte esterase test and the assessment of haemoglobin and of nitrites. Urethritis Symptomatic urethritis is characterised by alguria and purulent discharge. Classification of prostatitis/chronic pelvic pain syndrome (CPPS) It is recommended that the classification according to NIDDK/NIH is used (Table 3).
Table 3: Classification of prostatitis according to NIDDK/NIH

I II III Acute bacterial prostatitis (ABP) Chronic bacterial prostatitis (CBP) Chronic pelvic pain syndrome (CPPS) A. Inflammatory CPPS: WBC in EPS/voided bladder urine-3 (VB3)/semen B. Non-inflammatory CPPS: no WBC/EPS/VB3/semen Asymptomatic inflammatory prostatitis (histological prostatitis)
IV
Epididymitis, orchitis Most cases of epididymitis, with or without orchitis, are caused by common urinary pathogens. Bladder outlet obstruction and urogenital malformations are risk factors for this type of infection. Consider Chlamydia trachomatis infection in the younger male population. 226 Urological Infections
Diagnosis
UTI (general) A disease history, physical examination and dipstick urinalysis, including white and red blood cells and nitrite reaction, is recommended for routine diagnosis. Except in isolated episodes of uncomplicated lower UTI (cystitis) in premenopausal, healthy women, a urine culture is recommended in all other types of UTI before treatment, so allowing antimicrobial therapy to be adjusted if necessary. Pyelonephritis In cases of suspected pyelonephritis, it may be necessary to evaluate the upper urinary tract to rule out upper urinary tract obstruction or stone disease. Urethritis Pyogenic urethritis is indicated by a Gram stain of secretion or urethral smear that shows more than five leukocytes per HPF (x1,000) and in case of gonorrhoea gonococci are located intracellularly as Gram-negative diplococci. A positive leukocyte esterase test or more than 10 leukocytes per HPF (x400) in the first voiding urine specimen is diagnostic. Prostatitis/CPPS In patients with prostatitis-like symptoms, an attempt should be made to differentiate between bacterial prostatitis and CPPS. This is best done by the four glass test according to Mearse & Stamey, if acute UTI and STD can be ruled out.
Urological Infections 227
Table 4: Recommendations for antimicrobial therapy in urology

Diagnosis Cystitis acute, uncomplicated Most frequent pathogen/species E. coli Klebsiella Proteus Staphylococci E. coli Proteus Klebsiella Other enterobacteria Staphylococci E. coli Enterococci Pseudomonas Staphylococci Klebsiella Proteus Enterobacter Other enterobacteria (Candida)
Pyelonephritis acute, uncomplicated
UTI with complicating factors Nosocomial UTI Pyelonephritis acute, complicated
228 Urological Infections
Initial, empirical antimicrobial therapy TMP-SMX1 Nitrofurantoin Fosfomycin trometamol Pivmecillinam Fluoroquinolone (altern.)2, 3 Fluoroquinolone2 Cephalosporin (group 3a) Alternatives: Aminopenicillin/BLI Aminoglycoside Fluoroquinolone2 Aminopenicillin/BLI Cephalosporin (group 2) Cephalosporin (group 3a) Aminoglycoside In case of failure of initial therapy within 1-3 days or in clinically severe cases: Anti-Pseudomonas active: Fluoroquinolone, if not used initially Acylaminopenicillin/BLI Cephalosporin (group 3b) Carbapenem Aminoglycoside In case of Candida: Fluconazole Amphotericin B
Therapy duration 3 days (5-)7 days 1 day (3-)5 days (1-)3 days 7-10 days
3-5 days after defeverescence or control/elimination of complicating factor
E. coli Other enterobacteria Pseudomonas Epididymitis Enterococci acute Staphylococci Chlamydia Ureaplasma Urosepsis E. coli Other enterobacteria After urological interventions - multiresistant pathogens: Pseudomonas Proteus Serratia Enterobacter 1Only in areas with resistance rate < 20% (for E. coli). 2Fluoroquinolone with mainly renal excretion (see text). 3Avoid Fluoroquinolones in uncomplicated cystitis whenever possible. BLI = beta-lactamase inhibitor; UTI = urinary tract infection.
Prostatitis acute, chronic
Treatment and Prophylaxis

Treatment of UTI depends on a variety of factors. Table 4 provides an overview of the most common pathogens, antimicrobial agents and duration of treatment for different conditions. Prophylactic treatment may be recommended for patients with recurrent UTI. The regimens shown in Table 5 have a documented effect in preventing recurrent UTI in women.
Fluoroquinolone2 Alternative in acute bacterial prostatitis: Cephalosporin (group 3a/b) In case of Chlamydia or Ureaplasma: Doxycycline Macrolide Cephalosporin (group 3a/b) Fluoroquinolone2 Anti-Pseudomonas active acylaminopenicillin/BLI Carbapenem Aminoglycoside
Acute: 2-4 weeks Chronic: 4-6 weeks or longer
3-5 days after defeverescence or control/elimination of complicating factor
Special situations UTI in pregnancy Asymptomatic bacteriuria is treated with a 7-day course based on sensitivity testing. For recurrent infections (symptomatic or asymptomatic), either cephalexin, 125-250 mg/day, or nitrofurantoin, 50 mg/day, may be used for prophylaxis. UTI in postmenopausal women In women with recurrent infection, intravaginal oestriol is recommended. If this is not effective, antibiotic prophylaxis could be considered. Urological Infections 231
UTI in children Treatment periods should be extended to 7-10 days. Tetracyclines and fluoroquinolones should not be used because of adverse effects on teeth and cartilage. Acute uncomplicated UTI in young men Treatment should last at least 7 days. Complicated UTI due to urological disorders The underlying disorder must be managed if a permanent cure is to be achieved. Whenever possible, treatment should be guided by urine culture to avoid inducing resistant strains. Sepsis in urology (urosepsis) Patients with UTI may develop sepsis. Early signs of systemic inflammatory response (fever or hypothermia, tachycardia, tachypnoea, hypotension, oliguria, leukopenia) should be recognized as the first signs of possible multi-organ failure. As well as appropriate antibiotic therapy, life-support therapy in collaboration with an intensive care specialist may be necessary. Any obstruction in the urinary tract must be drained.
Table 5: Recommendations for antimicrobial prophylaxis of recurrent uncomplicated UTI

Agent1 Standard regimen Nitrofurantoin Nitrofurantoin macrocrystals TMP-SMX Dose 50 mg/day 100 mg/day 40/200 mg/day or three times weekly 100 mg/day 3 g/10 day
TMP Fosfomycin trometamol Breakthrough infections Ciprofloxacin 125 mg/day Norfloxacin 200-400 mg/day Pefloxacin 800 mg/week During pregnancy Cephalexin 125 mg/day Cefaclor 250 mg/day 1Taken at bedtime. TMP = trimethoprim-sulphamethoxazole.
Follow-up of patients with UTI For routine follow-up after uncomplicated UTI and pyelonephritis in women, dipstick urinanalysis is sufficient. In women with a recurrence of UTI within 2 weeks, repeated urinary culture with antimicrobial testing and urinary tract evaluation is recommended. In the elderly, newly developed recurrent UTI may warrant a full evaluation of the urinary tract. In men with UTI, an urological evaluation should be Urological Infections 233
performed in adolescent patients, cases of recurrent infection and all cases of pyelonephritis. This recommendation should also be followed in patients with prostatitis, epididymitis and orchitis. In children, investigations are indicated after two episodes of UTI in girls and one episode in boys. Recommended investigations are ultrasonography of the urinary tract supplemented by voiding cystourethrography. Urethritis The following guidelines for therapy comply with the recommendations of the Center for Disease Control and Prevention (2002). For the treatment of gonorrhoea, the following antimicrobials can be recommended: First choice Cefixime 400 mg orally as a single dose Ceftriaxone 1g im as a single dose (im with local anaesthetic) Second choice Ciprofloxacin 500 mg orally or Ofloxacin 400 mg orally or Levofloxacin 250 mg orally as a single dose
As gonorrhoea is often accompanied by chlamydial infection, an antichlamydial active therapy should be added. The following treatment has been successfully applied in Chlamydia trachomatis infections:
First choice Azithromycin 1 g (= 4 caps @ 250 mg) orally as single dose Doxycycline 2 times daily 100 mg orally for 7 days
Second choice Erythromycin 4 times daily 500 mg orally for 7 days Ofloxacin 2 times daily 300 mg orally or Levofloxacin once daily 500 mg orally for 7 days
If therapy fails, infections with Trichomonas vaginalis and/or Mycoplasma spp. should be considered. These can be treated with a combination of metronidazole (2 g orally as a single dose) and erythromycin (500 mg orally, 4 times daily, for 7 days). Prostatitis Acute bacterial prostatitis can be a serious infection. The parenteral administration of high doses of bactericidal antibiotics, such as an aminoglycoside and a penicillin derivative or a third-generation cephalosporin, is required until defervescence occurs and infection parameters return to normal. In less severe cases, a fluoroquinolone may be given orally for at least 10 days. In chronic bacterial prostatitis and inflammatory CPPS, a fluoroquinolone or trimethoprim should be given orally for 2 weeks after the initial diagnosis. The patient should then be reassessed and antibiotics only continued if the pretreatment cultures were positive or if the patient has reported positive effects from the treatment. A total treatment period of 4-6 weeks is recommended. Urological Infections 235
Table 6:
Procedure
Recommendations for peri-operative antibacterial

Pathogens (expected) Enterobacteriaceae (Anaerobes) Prophylaxis (standard) All patients
Diagnostic procedures Transrectal biopsy of the prostate Cystoscopy Urodynamic study
Enterobacteriaceae Enterococci Staphylococci Ureteroscopy Enterobacteriaceae Enterococci Staphylococci Endourological surgery and ESWL ESWL Enterobacteriaceae Enterococci
No
No
No
Ureteroscopy for uncomplicated distal stone
Enterobacteriaceae Enterococci Staphylococci
No
Ureteroscopy of proximal or impacted stone and percutaneous stone extraction TUR of the prostate
Enterobacteriaceae Enterococci Staphylococci
All patients
Enterobacteriaceae Enterococci
All patients
prophylaxis in urology
Antibiotics Remarks
Fluoroquinolones TMP SMX Metronidazole1 TMP SMX Cephalosporin 2nd generation TMP SMX Cephalosporin 2nd generation TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI2 TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI Fluoroquinolones TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI Fluoroquinolones TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI
Single dose effective in low risk. Consider prolonged course in risk patients Consider in risk patients
No studies
In patients with stent or nephrostomy tube or other risk factor Consider in risk patients
Short course, Length to be determined Intravenous suggested at operation Low-risk patients and small-size prostate require no prophylaxis
TUR of bladder tumour
Enterobacteriaceae Enterococci
No
Open or laparoscopic urological surgery3 Clean operations Skin-related pathogens, e.g. staphylococci Catheterassociated uropathogens Clean-contaminated Enterobacteriaceae (opening of urinary tract) Enterococci Staphylococci
No
Recommended
Clean-contaminated/ Enterobacteriaceae contaminated (use of bowel Enterococci segments): Anaerobes Skin-related bacteria Implant of prosthetic Skin-related devices bacteria, e.g. staphylococci
All patients
All patients
BLI=beta-lactamase inhibitor; TMP SMX = trimethoprim with or resection. 1No evidence for the use of mettronidazole in prostate core biopsies. 2Gram-negative bacteria excluding Pseudomonas aeruginosa. 3Classifications of surgical field contamination (CDC).
TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI
Consider in risk patients and large tumours
Consider in high-risk patients. Short post-operative catheter requires no treatment TMP SMX Cephalosporin 2nd or 3rd generation Aminopenicillin/BLI Cephalosporin 2nd or 3rd generation Metronidazole Single peri-operative course
As for colonic surgery
Cephalosporin 2nd or 3rd generation Penicillin (penicillinase stable)

without sulphamethoxale (co-trimoxazole); TUR = transurethral
Combination therapy with antibiotics and -blockers: Urodynamic studies have shown increased urethral closing pressure in patients with chronic prostatitis. Combination treatment with -blockers and antibiotics has been reported to have a higher cure rate than antibiotics alone in inflammatory CPPS. This treatment option is favoured by many urologists. Surgery: Generally, surgery should be avoided in the treatment of prostatitis, except for the drainage of prostatic abscesses. Epididymitis, orchitis Prior to antimicrobial therapy, a urethral swab and midstream urine sample should be obtained for microbiological investigation. The first choice of drug therapy should be fluoroquinolones, preferably those agents that react well against C. trachomatis (e.g. ofloxacin, levofloxacin), because of their broad antibacterial spectra and favourable penetration into urogenital tract tissues. In cases caused by C. trachomatis, treatment may also be continued with doxycycline, 200 mg/day, for a total treatment period of at least 2 weeks. Macrolides are alternative agents. In cases of C. trachomatis infection, the sexual partner should also be treated.
Perioperative antibacterial prophylaxis in urological surgery

The main aim of antimicrobial prophylaxis in urology is to prevent symptomatic or febrile genitourinary infections, such as acute pyelonephritis, prostatitis, epididymitis and urosep240 Urological Infections
sis, as well as serious wound infections. The recommendations for short-term peri-operative antibacterial prophylaxis in standard urological interventions are listed in table 6.
This short booklet is based on the more comprehensive EAU guidelines (ISBN 978-90-79754-70-0), available to all members of the European Association of Urology at their website, http://www.uroweb.org.
GUIDELINES ON NEUROGENIC LOWER URINARY TRACT DYSFUNCTION

M. Sthrer (chairman), B. Blok, D. Castro-Diaz, E. ChartierKastler, P. Denys, G. Kramer, J. Pannek, G. del Popolo, P. Radziszewski, J-J. Wyndaele
Introduction
Before the 1980s, considerable morbidity was associated with renal failure in patients with neurogenic lower urinary tract dysfunction (NLUTD). Most patients with NLUTD require life-long care to maintain their quality of life (QoL) and maximise life-expectancy. Significant technological developments that have occurred over the last 30 years have helped to achieve these goals.
Methodology
Where possible, the Panel has used a three-tier system (A-C) to grade treatment recommendations and thus assist clinicians in determining the validity of a recommendation.
Terminology
The terminology used and the diagnostic procedures outlined follow the recommendations for the investigation of the lower urinary tract (LUT) published by the International Continence Society (ICS). 242 Neurogenic Lower Urinary Tract Dysfunction
Risk factors and epidemiology

All central and peripheral neurological disorders carry a high risk of causing functional disturbances of the urinary tract.
Classification
Several classification systems have been proposed for NLUTD. The panel recommends a functional classification for motor function based on urodynamic and clinical findings (Figure 1). Fig. 1: The EAU-Madersbacher classification system Detrusor Overactive Overactive Overactive Underactive
Overactive
Underactive Normo-active Urethral sphincter Detrusor
Overactive
Underactive
Underactive
Normoactive
Normoactive
Underactive
Normo-active Overactive Urethral sphincter
Underactive
Adapted from Madersbacher et al. Neurogenic Lower Urinary Tract Dysfunction 243
Timing of diagnosis and treatment

In both congenital and acquired NLUTD, early diagnosis and treatment are essential, as irreversible changes within the LUT may occur, even when the related neuropathological signs are normal. Also, remember that NLUTD can, by itself, be the presenting feature of neurological pathology.
Diagnosis
Patient assessment Diagnosis of NLUTD should be based on a comprehensive assessment of neurological and non-neurological conditions. Initial assessment should include a detailed history, physical examination, and urinalysis. History An extensive general and specific history is mandatory and should concentrate on past and present symptoms and disorders of the urinary tract, bowel, and sexual and neurological function. Special attention should be paid to possible warning signs and symptoms (e.g. pain, infection, haematuria, fever) that warrant further investigation. Physical examination The neurological status should be described as completely as possible. All sensations and reflexes in the urogenital area must be tested, including detailed testing of the anal sphincter and pelvic floor functions (Figure 2). Availability of this clinical information is essential for the reliable interpretation of subsequent diagnostic investigations.
244 Neurogenic Lower Urinary Tract Dysfunction
Fig. 2: The neurological status of a patient with NLUTD must be described as completely as possible (a - dermatomes, b - associated reflexes)
Fig. 2a - Dermatomes of spinal cord levels L2-S4.
Fig. 2b - Urogenital and other reflexes in lower spinal cord. Neurogenic Lower Urinary Tract Dysfunction 245
Urodynamic tests A bladder diary should be recorded for at least 2-3 days. Uroflowmetry and ultrasound assessment of post-void residual should be repeated at least 2 or 3 times in patients able to void. Invasive urodynamic studies comprise mandatory assessment tools to determine the exact type of NLUTD (Table 1).
Table 1: Guidelines for urodynamics and uro-neurophysiology tests in NLUTD

Urodynamic investigation is necessary to document the (dys-)function of the LUT. The recording of a bladder diary is advisable. Non-invasive testing is mandatory before invasive urodynamics is planned. Video-urodynamics is currently the preferred method for invasive urodynamics in patients with NLUTD. If this is not available, then a filling cystometry continuing into a pressure flow study should be performed. For standard urodynamic testing, a physiological filling rate (see Table 1, e.g. not faster than 20 mL/min) and body-warm fluid must be used. Specific uro-neurophysiological tests and provocative manoeuvres (e.g. fast filling cystometry with cooled saline [the ice water test], coughing, tapping, anal stretch) are elective procedures.
GR A B A A
Filling cystometry is the only procedure that quantifies the filling function of the bladder. However, when filling cystometry is used alone, the results have limited significance. Measurement of detrusor leak point pressure (DLPP) has limited diagnostic value; it is not recommended as a stand alone test. Pressure flow studies: the function of the LUT must also be recorded during the voiding phase. Video-urodynamics combines filling cystometry and pressure flow studies with radiological imaging. Currently, video-urodynamics is considered to provide the most comprehensive information evaluating NLUTD. Electromyography (EMG) is a semi-quantitative measure of pelvic floor activity, which can be used to detect detrusor/ sphincter dyssynergia (DSD) and pelvic floor relaxation disorders.
Table 2: Characteristic findings in NLUTD*

Filling phase Increased, decreased, or absent bladder sensation Vegetative non-specific sensations Low bladder compliance High capacity bladder Detrusor overactivity, spontaneous or provoked Incompetent urethral closure mechanism Voiding phase Acontractile or underactive detrusor Neurogenic Lower Urinary Tract Dysfunction 247
Bladder outlet obstruction DSD Non-relaxing urethral sphincter obstruction These signs warrant further neurological evaluation, as LUTD may be the presenting symptom of a neurological disease. *modified from ICS publication.
Treatment
Introduction Treatment of NLUTD aims to protect the upper urinary tract, and improve continence, QoL and, whenever possible, LUT function. In patients with a high detrusor pressure in the filling phase, the principal aim of treatment is conversion of an overactive, high-pressure bladder into a low-pressure reservoir; even if this should result in a high post-void residual. The patients QoL is a prime consideration when making any treatment decision. Conservative treatment Drug treatment for neurogenic detrusor overactivity (NDO) Antimuscarinic agents are currently the most widely used treatment, although most of the available drugs have not been registered for the treatment of this patient population. Antimuscarinic agents can also be given intravesically. Drug treatment for neurogenic detrusor underactivity There is no evidence of effective drug treatment for detrusor underactivity. 248 Neurogenic Lower Urinary Tract Dysfunction
Drug treatment to decrease bladder outlet resistance Selective and non-selective alpha-blockers have been partially successful in decreasing bladder outlet resistance, residual urine and autonomic dysreflexia. Catheterisation Intermittent, self- or third-party, catheterisation (IC) is the gold standard for the management of NLUTD. Compared to clean IC, aseptic IC provides significant benefit in reducing the potential for contamination. On average, IC, using a 12-14 Fr catheter, is needed 4-6 times per day. Indwelling transurethral IC and, to a lesser extent, suprapubic cystostomy should be avoided as they are risk factors for UTI and significant long-term complications. If indwelling catheters must be used, empirical evidence and expert opinion suggests silicone catheters provide advantages over latex catheters. Assisted bladder emptying Triggered reflex voiding is not recommended as there is a risk of pathologically elevated bladder pressures. Only in the case of absence, or surgically reduced, outlet obstruction it may be an option. Bladder compression techniques to expel urine (Crede) and voiding by abdominal straining (Valsalva manoeuvre) create high pressures and are potentially hazardous, and their use should be discouraged.
Neurogenic Lower Urinary Tract Dysfunction 249
Rehabilitation In selected patients, pelvic floor muscle exercises, pelvic floor electro-stimulation, and biofeedback might be beneficial. External appliances Social continence for the incontinent patient can be achieved using an appropriate method of urine collection.
Minimally invasive treatment

Botulinum toxin A injections in the bladder Botulinum toxin A causes a long-lasting (approximately 9 months), reversible, chemical denervation. Intravesical vanilloid treatment Resiniferatoxin and capsaicin have limited clinical efficacy compared to botulinum toxin A injected in the detrusor. Bladder neck and urethral procedures Reduction of the bladder outlet resistance, to protect the upper urinary tract, can be achieved by sphincterotomy or chemical denervation of the sphincter using botulinum toxin A. Insertion of urethral stents is not recommended. Increasing bladder outlet resistance using bulking agents or urethral inserts, or alternative appliances is not recommended for long-term treatment.
NDO and reflux

Vesico-ureteral reflux should be managed by lowering intravesical pressure. If reflux is persistent, intervention using bulking agents or ureteral re-implantation can be considered. 250 Neurogenic Lower Urinary Tract Dysfunction
Surgical treatment
Overactive detrusor Bladder augmentation/clam cystoplasty is indicated for an overactive detrusor, when less invasive procedures have failed. Alternative options include: auto-augmentation (myomectomy), dorsal rhizotomy, with or without sacral anterior root stimulation (SARS) (complete lesions), and neuromodulation (incomplete lesions). Substitution, with either continent or incontinent diversion, is indicated for the small contracted non-compliant bladder. Fig. 3: Surgery for neurogenic detrusor overactivity
Surgery for neurogenic detrusor overactivity
All lesions Botulinum Toxin A Incomplete lesion Neuromodulation Complete lesion Deafferentation
Auto-Augmentation (optional) Neurostimulation Clam Cystoplasty Enterocystoplasty
Underactive detrusor Sacral anterior root stimulation (complete lesions) and sacral neuromodulation (incomplete lesions) are effective in selected patients. Sphincter insufficiency (underactive urethra) The artificial urinary sphincter is the preferred tried and tested treatment. Neurogenic Lower Urinary Tract Dysfunction 251
Procedures to treat sphincter incompetence are suitable only when the detrusor activity is, or can be, controlled and there is no significant associated vesico-ureteral reflux.
Quality of life
QoL represents a very important aspect in the global management of the patient who has NLUTD. Restoration and maintenance of the patients QoL it as much as possible, should be one of the major aims of treatment. QoL should be integral to the evaluation of lower urinary tract symptoms in patients with NLUTD and also, when considering any type of treatment for neurogenic bladder dysfunction.
Follow-up
Meticulous follow-up and regular checks are essential. Individualised patient follow-up is imperative to safeguard QoL and life expectancy. The underlying pathology and the state of the urinary tract dictate the frequency of follow-up required.
Table 3: Minimum follow-up required in patients with NLUTD*

Investigation Urinalysis Ultrasound of the upper urinary tract, bladder status, post void residual Physical examination, blood biochemistry, and urine microbiology Frequency At least once every 6 months Every 6 months GR A A
Annually
A (Video-) urodynamic inves- Every 2 years tigations in patients without detrusor overactivity and with normal bladder compliance A (Video-) urodynamic inves- At least once a year tigations in patients with detrusor overactivity, and/or low bladder compliance The need for detailed special investigations must be determined on the basis of the patients risk profile (see above), but should, where indicated, include a video-urodynamic study, which should be carried out in an institution with neuro-urological expertise. *Grades of recommendation assigned on basis of panel consensus.
Summary
NLUTD is a multi-faceted pathology. Extensive investigation and a precise diagnosis are required before the clinician can initiate individualised therapy. Treatment must take into account the patients medical and physical condition and expectations with regard to his/her future social, physical, and medical situation.
Neurogenic Lower Urinary Tract Dysfunction 253
GUIDELINES ON UROLOGICAL TRAUMA

N. Djakovic, Th. Lynch, L. Martnez-Pieiro, Y. Mor, E. Plas, E. Serafetinides, L. Turkeri, R.A. Santucci, M. Hohenfellner Eur Urol 2005;47(1):1-15
Renal Trauma
Background Renal injuries account for 1-5% of all traumas.
Table 1: Injury severity scale for the kidney*#

Grade Description Contusion or non-expanding subcapsular haemato1 ma, no laceration Non-expanding perirenal haematoma, cortical lac2 eration < 1 cm deep without extravasation Cortical laceration > 1 cm without urinary 3 extravasation Laceration: through corticomedullary junction 4 into collecting system or vascular: segmental renal artery or vein injury with contained haematoma 5 Laceration: shattered kidney or vascular: renal pedicle injury or avulsion * Adapted from the American Association for the Surgery of Trauma (AAST). # Advance one grade for multiple injuries up to grade 3. 254 Urological Trauma
Diagnosis History: time and setting of incident, past renal surgery, known renal abnormalities. Exam: for non-genitourinary injuries: Lab: gross hematuria, dipstick urine analysis, serial haematocrit, baseline serum creatinine. Patient selection: blunt trauma with macroscopic or microscopic haematuria and hypotension, a history of rapid deceleration injury and/or significant associated injuries should undergo radiographic evaluation. Any degree of haematuria after penetrating abdominal or thoracic injury requires urgent imaging. Imaging: computed tomography (CT) scan with and without intravenous contrast material in haemodynamically stable patients. Patients requiring exploration should undergo an intraoperative one-shot intravenous pyelography (IVP) with bolus intravenous injection of 2 mL/kg contrast. Ultrasonography may be helpful during the primary evaluation or follow-up of recuperating patients. Formal IVP, magnetic resonance imaging (MRI) and radiographic scintigraphy are secondline methods of imaging. Angiography can be used for diagnosis and simultaneous selective embolisation of bleeding vessels if necessary. Treatment Indications for surgical management include haemodynamic instability, expanding or pulsatile perirenal haematoma, and main renal artery avulsion or thrombosis in a single kidney (Figures 1 and 2). Urological Trauma 255
Figure 1: Evaluation of blunt renal trauma in adults

Suspected adult blunt renal trauma*
Determine haemodynamic stability
Stable
Unstable
Gross haematuria
Renal imaging**
Rapid deceleration injury or major associated injuries
Microscopic haematuria
Emergency laparotomy One-shot IVP
Grade 3-4
Grade 1-2
Observation
Normal IVP
Stable
Retroperitoneal haematoma
Observation Bed rest, Serial Ht, Antibiotics
Grade 5 Associated injuries requiring laparotomy Renal exploration***
Pulsatile or expanding
Abnormal IVP
Suspected renal trauma results from reported mechanism of injury and physical examination. ** Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable patients. In settings where the method is not available, the urologist should rely on other imaging modalities (IVP, angiography, radiographic scintigraphy, MRI). *** Renal exploration: although renal salvage is a primary goal for the urologist, decisions concerning the viability of the organ and the type of reconstruction are made during the operation.
Post-operative care, follow-up, and complications The role of repeat imaging is unknown. Some experts recommend repeat imaging within 2-4 days of injury. Nuclear scintigraphy may be useful for documenting functional recovery. Patient follow-up: physical examination, urinalysis, individualised radiological investigation, serial blood pressure 256 Urological Trauma
Figure 2: Evaluation of penetrating renal trauma in adults

Suspected adult penetrating renal trauma*
Determine haemodynamic stability
Stable
Unstable
Renal imaging**
Emergency laparotomy One-shot IVP
Grade 3
Grade 5
Grade 1-2
Observation
Normal IVP
Stable
Retroperitoneal haematoma
Observation Bed rest, Serial Ht, Antibiotics
Associated injuries requiring laparotomy
Pulsatile or expanding Renal exploration*** Abnormal IVP
Suspected renal trauma results from reported mechanism of injury and physical examination. ** Renal imaging: CT scans are the gold standard for evaluating blunt and penetrating renal injuries in stable patients. In settings where the method is not available, the urologist should rely on other imaging modalities (IVP, angiography, radiographic scintigraphy, MRI). *** Renal exploration: although renal salvage is a primary goal for the urologist, decisions concerning the viability of the organ and the type of reconstruction are made during the operation.
measurement, and serum determination of renal function. Long-term follow-up should include monitoring for renovascular hypertension. Complications (bleeding, infection, perinephric abscess, sepsis, urinary fistula, hypertension, urinary extravasation, urinoma, hydronephrosis, calculus formation, chronic pyeloneUrological Trauma 257
phritis, arteriovenous fistula, and pseudoaneurysms) require a thorough radiographic evaluation. Medical management and minimally invasive techniques should be the first choice, while renal salvage should be attempted when exploration is necessary. Nephrectomy may be required.
Ureteral Trauma
Background External trauma to the ureter is rare. Seventy-five percent of ureteral injuries are iatrogenic, 18% from blunt trauma, and 7% from penetrating trauma. The most common site of injury is the lower third (74%).
Table 2: Injury severity scale for the ureter*

Grade 1 2 3 4 5 Description Haematoma only Laceration < 50% of circumference Laceration > 50% of circumference Complete tear < 2 cm of devascularisation Complete tear > 2 cm of devascularisation
* Adapted from the AAST.
Diagnosis The sine qua non is extravasation of radiological contrast material. The diagnosis is most often made with intraoperative one-shot IVP and CT. If the CT scan is non-diagnostic, then do IVP or retrograde pyelography. Treatment Minimal injury can be managed with ureteral stenting or by placement of a nephrostomy tube. Ureteral injury complicat258 Urological Trauma
ing vascular graft procedures are controversial: best evidence is to save the kidney by judicious ureteral repair but older citations suggest immediate nephrectomy. In complete injuries the type of reconstructive repair procedure depends on the nature and site of the injury. The options are: 1. Upper third: uretero-ureterostomy. 2. Middle third: uretero-ureterostomy or Boari flap and reimplantation (staged, do not do acutely). 3. Lower third: direct reimplantation or psoas hitch or Blandy cystoplasty. 4. Complete ureteral loss: ileal interposition (delayed) or autotransplantation (delayed). Damage control first: tie off ureter, place percutaneous nephrostomy.
Bladder Trauma
Background Blunt trauma accounts for 67-86% of bladder ruptures, is primarily caused by motor vehicle accidents, and may be classified as extraperitoneal or intraperitoneal.
Table 3: Injury severity scale for the bladder*

Grade Description Haematoma 1 Laceration Laceration 2 3 Laceration - Contusion, intramural haematoma - Partial thickness - Extraperitoneal bladder wall laceration < 2 cm - Extraperitoneal (> 2 cm) or intraperi-toneal (< 2 cm) bladder wall laceration Urological Trauma 259
4 5
Laceration Laceration
- Intraperitoneal bladder wall laceration > 2 cm - Intraperitoneal or extraperitoneal bladder wall laceration extending into the bladder neck or ureteral orifice (trigone)
* Adapted from the AAST.
Diagnosis The most common signs and symptoms are: Gross haematuria, abdominal tenderness, inability to void, suprapubic bruising, and abdominal distension. Extravasation of urine may result in swelling in the perineum, scrotum and/or anterior abdominal wall. The combination of pelvic fracture and gross haematuria constitutes an indication for cystography. In patients with pelvic fracture and microhaematuria, imaging should be reserved for those with anterior rami fractures (straddle fracture) or Malgaigne type severe ring disruption (Figure 3). Retrograde cystography is the standard diagnostic procedure. The bladder must be distended by the instillation of 350 mL of contrast media. A post-drainage film must be obtained. CT cystography is an excellent alternative. Routine cystoscopy is recommended after major gynecological operations and/or incontinence surgery. Treatment Extraperitoneal ruptures can be managed by catheter drainage only. Bladder neck involvement, the presence of bone fragments 260 Urological Trauma
in the bladder wall, or entrapment of the bladder wall necessitates open repair. Intraperitoneal ruptures are managed by surgical repair.
Urethral Trauma
Background Injuries to the posterior urethra (PU) occur with pelvic fractures, mostly as a result of motor vehicle accidents. The male PU is injured in 4-19% of pelvic fractures, and the female urethra in 0-6% of all pelvic fractures. The combination of straddle fractures with diastasis of the sacroiliac joint has the highest risk of urethral injury. Injuries can vary from simple stretching to partial rupture to complete disruptions. Urethral injuries in women are rare. For children, urethral injuries tend to follow the same mechanism of injury as in adults, although injuries to the prostate and bladder neck may be more common. Injuries to the anterior urethra (AU) are caused by intercourse (penile fracture), penetrating trauma, and placement of penile constriction bands.
Table 4: Injury severity scale for the urethra*

Grade Description Contusion - Blood at the urethral meatus; normal 1 urethrogram Stretch - Elongation of the urethra without 2 injury extravasation on urethrography Partial - Extravasation of contrast at injury 3 disruption site with contrast visualised in the bladder Urological Trauma 261
Complete - Extravasation of contrast at injury disruption site without visualisation in the bladder; < 2 cm of urethral separation Complete - Complete transection with > 2 cm 5 disruption urethral separation, or extension into * Adapted from the AAST. the prostate or vagina 4 Diagnosis In the absence of blood at the meatus or penile haematoma, urethral injury is less common. Exclude by catheterisation. Blood at the meatus is present in 37-93% of patients with PU injury, and in at least 75% of patients with AU injury. A high-riding prostate is an unreliable finding. Avoid urethral instrumentation until the urethra is imaged. In an unstable patient, alternatively, an attempt can be made to pass a urethral catheter, but if there is any difficulty a suprapubic catheter is inserted and a retrograde urethrogram performed later. Blood at the vaginal introitus is present in more than 80% of female patients with pelvic fractures and co-existing urethral injuries. Although non-specific, haematuria on a first voided specimen may indicate urethral injury. The amount of urethral bleeding correlates poorly with the severity of injury. Pain on urination or inability to void suggests urethral disruption. Retrograde urethrography is the gold standard for evaluating urethral injury. If delayed primary repair is contemplated, and when the proximal urethra in a simultaneous cystogram and urethrogram is not visualised, either MRI of the PU or endos262 Urological Trauma
copy through the suprapubic tract can be used to define the anatomy of the PU. In females, urethroscopy may be an important adjunct for the identification and staging of urethral injuries. Treatment While intervention should be guided by the clinical circumstances, the following algorithms are suggested for the treatment of urethral injuries in males and females (Figures 3-5). Iatrogenic urethral trauma The most common form of iatrogenic urethral trauma is that caused by instruments. Most of the relevant urethral lesions caused by iatrogenic trauma are strictures. These strictures are of variable location and severity. They often require different management strategies. Symptoms of iatrogenic urethral injury The symptoms of urethral injury caused by improper catheterisation or use of instruments are: penile and/or perineal pain (100%) urethral bleeding (86%).
Urological Trauma 263
Figure 3: Management of posterior urethral injuries in men

Suspected Urethral Injury Retrograde Urethrogram Normal
Prostatomembranous Disruption
Urethral contusion Treat with suprapubic or transurethral catheter
Complete Rupture
Partial Rupture
Penetrating
Blunt
Blunt
Penetrating
Primary open repair. If patient unstable or important associated nonurological injuries, suprapubic cystostomy No
Assess for Acute Surgical Indications: Bladder neck injury, rectal tear, pie-inthe-sky bladder
Suprapubic Cystostomy
Primary open repair. If patient unstable or important associated nonurological injuries, suprapubic cystostomy
Yes Suprapubic Tube + Endoscopic realignment. Open if rectal or bladder injury. or Stricture
Suprapubic Cystostomy
Stricture
No stricture
Urethrotomy
Option: Endoscopic realignment if patient is stable (< day 14)
or
Delayed urethroplasty
Stricture
Stricture
No stricture
Follow-up
if stricture is short (< 1cm) and flimsy
if stricture is long or denser
Delayed endoscopic optical incision
Salvage urethroplasty in referal centre
264 Urological Trauma
Recommendations for treatment: algorithms (Figures 4-6) Figure 4: Flow diagram of treatment for iatrogenic urethral injury caused by improper insertion of a catheter
Suspected iatrogenic urethral injury (improper catheter insertion)
Urethroscopy
False passage
Pre-existing stenosis
Endoscopic guide wire placement and catheter insertion
Suprapubic drainage
No stricture
Stricture
If stricture is short and flimsy
If stricture is longer or denser
Follow-up
Endoscopic optical incision
If failure
Urethral reconstruction
Figure 5: Flow diagram of treatment for stricture after radical prostatectomy

Iatrogenic urethral stricture Anastomotic stricture after radical prostatectomy
Dilatation
Endoscopic optical bladder neck incision
Endoscopic bladder neck incision
If failure
Open surgery (reanastomosis)
Urinary diversion
Figure 6: Flow diagram for treatment for stricture after major abdominal surgery or radiotherapy
Urethral injury due to major abdominal surgery or radiotherapy
Conservative treatment Urinary drainage
Urinary diversion
Major reconstruction
Figure 7: Management of anterior urethral injuries in men

Suspected urethral injury
Retrograde urethrogram
Extravasation
No extravasation
Complete disruption
Partial disruption
Urethral contusion
Penetrating
Blunt
Penetrating
If associated with penile rupture
Primary urethral repair
Suprapubic cystostomy
Primary urethral repair
Suprapubic cystostomy or transurethral Foley catheter
Stricture
No stricture
Follow-up
If stricture is short (< 1 cm) and flimsy
If stricture is long or denser
Endoscopic optical incision
If failure
Formal urethral reconstruction
Figure 8: Management of urethral injuries in women

Haematuria or blood at the vaginal introitus or labial swelling
Suspect urethral injury
Urethroscopy
Injured bladder neck or urethra
No lesions of bladder-urethra
Patient unstable
Patient stable Evaluation of upper urinary tract
Suprapubic cystostomy
Delayed primary reconstruction
Injury of bladder neck or proximal urethra
Injury of distal urethra
Retropubic repair of urethra, bladder and pelvic floor
Transvaginal repair of urethra and pelvic floor
Complications The risk of impotence caused by delayed urethroplasty is about 5% and the rate of incontinence is about 4%.
Genital Trauma
Background A direct blow to the erect penis may cause penile fracture. Blunt trauma to the scrotum can cause testicular dislocation, Urological Trauma 267
testicular rupture and/or subcutaneous scrotal haematoma. Traumatic dislocation of the testicle occurs mostly in victims of car or motorcycle accidents, or in pedestrians run over by a vehicle. Testicular rupture is found in approximately 50% of direct blunt traumas to the scrotum. In females, blunt trauma to the vulva is rare. Penetrating trauma to the external genitalia is frequently associated with injuries to other organs. Diagnosis Information about the accident should include: involved persons, animals, vehicles, and weapons. Trauma to external genitalia may be due to abusive assault. In suspicious cases, a sexual assault forensic exam is necessary (photodocumentation). Presence or macro- and or microhaematuria requires a retrograde urethrogram; in females cystoscopy is recommended. In women with genital injuries and blood at the vaginal introitus, gynaecologic investigation is indicated. Patients with penile fracture report a sudden cracking or popping sound associated with local pain and immediate detumescence.
Table 5: Injury severity scale for the penis*

Grade Description Cutaneous laceration/contusion 1 Bucks fascia (cavernosum) laceration without 2 tissue loss Cutaneous avulsion/laceration through 3 glans/meatus/cavernosal or urethral defect < 2 cm Cavernosal or urethral defect > 2 cm/partial 4 penectomy Total penectomy 5 * Adapted from the AAST.
Table 6: Injury severity scale for the scrotum*

Grade Description Contusion 1 Laceration < 25% of scrotal diameter 2 Laceration > 25% of scrotal diameter 3 Avulsion < 50% 4 Avulsion > 50% 5 * Adapted from the AAST.
Table 7: Injury severity scale for the testis*#

Grade 1 2 3 4 Description Contusion or haematoma Subclinical laceration of tunica albuginea Laceration of tunica albuginea with < 50% parenchymal loss Major laceration of tunica albuginea with > 50% parenchymal loss
Total testicular destruction or avulsion 5 * Adapted from the AAST. # Advance one grade for bilateral lesions up to grade 5.
Table 8: Injury severity scale for the vulva*#

Description Contusion or haematoma Laceration, superficial (skin only) Laceration, deep into fat, or muscle Avulsion; skin, fat or muscle Injury into adjacent organs (anus, rectum, urethra, bladder) * Adapted from the AAST. # Advance one grade for bilateral lesions up to grade 5. Grade 1 2 3 4 5
Table 9: Injury severity scale for the vagina*#

Description Contusion or haematoma Laceration, superficial (mucosa only) Laceration, deep into fat or muscle Laceration, complex, into cervix or peritoneum Injury into adjacent organs (anus, rectum, urethra, bladder) * Adapted from the AAST. # Advance one grade for bilateral lesions up to grade 5. Treatment Penile trauma Subcutaneous haematoma, without rupture of the cavernosal tunica albuginea and no immediate detumescence of the erect penis can be managed with non-steroidal analgesics and ice-packs. 270 Urological Trauma Grade 1 2 3 4 5
Penile fracture: immediate surgical intervention with closure of the tunica albuginea. Penetrating penile trauma: surgical exploration and conservative debridement of necrotic tissue is recommended with primary closure in most cases. Scrotal trauma Blunt trauma with subcutaneous haematoma: conservative management. Large haematocele or testicular rupture: surgical exploration with excision of necrotic tubules and closure of the tunica albuginea. Traumatic dislocation of the testis: can be manually replaced but secondary orchidopexy is recommended. (If manual reposition cannot be performed, in situ orchidopexy is indicated). Extended laceration of scrotal skin: surgical closure. Penetrating injuries to the scrotum: surgical exploration with conservative debridement of non-viable tissue. Extensive destruction of the tunica albuginea: tunica vaginalis flap can be mobilised for testicular closure. Complete disruption of the spermatic cord: realignment without vaso-vasostomy. Female genital trauma (see Figure 9) Blunt trauma to the vulva commonly presents as haematomas: non-steroidal antirheumatics and cold packs relieve pain. Extended vulvar haematoma or haemodynamically unstable patients: surgical intervention may be indicated. Vulvar laceration: repair after conservative debridement. Urological Trauma 271
Vaginal lesion: abdominal CT scan for exclusion of additional injuries.
Mass casualty events, triage, and damage control

Definition A mass casualty event is one in which the number of injured people is significantly higher than the number of healthcare providers available. Causes of mass casualty events Potential mass casualty events include: the collapse of buildings or bridges; earthquakes; floods; tsunamis; train collisions; aircraft catastrophes; civilian terrorism. Triage divides patients into four groups: 1. Patients with life-threatening injuries that require immediate intervention, presenting with Airway compromise, Breathing failure and/or Circulatory compromise from ongoing external haemorrhage. 2. Patients with severe but non-life-threatening injuries, in whom treatment can be acceptably delayed: major fractures, vascular injuries of the limbs and large soft tissue wounds. 3. Walking wounded with minimal injuries. 4. Patients who are so severely injured that treatment would require allocation of resources and time that would deny 272 Urological Trauma
other, more salvageable patients, timely care. These patients are given minimal or no treatment, and reevaluated when resources become available. There is no absolute definition for this group because triage is individualised according to the number and severity of casualties related to the available resources. Principles urological consultations during a mass casualty scenario: Rule out under-triage by the surgeon in charge, and perform a rapid primary survey of every patient. Avoid unnecessary imaging procedures such as CT scans and retrograde urethrography. These procedures are performed later, after mass casualty protocols have been suspended. Treat unstable patients who are to have surgery using damage control principles. Stable patients with suspected renal injuries should be transferred to the surgical ward without imaging procedures. Re-evaluate if there is any change in their haemodynamic status, or when possible as dictated by the constraints of the mass casualty event. Patients managed in this delayed fashion should be treated according to traditional trauma management protocols. Minimal acceptable procedures should be performed in order to transfer patients to the surgical wards, e.g. suprapubic drainage of the bladder when bladder or urethral injuries are suspected, clamping and ligation of bleeding vessels from wounds to the external genitalia, etc. Urological Trauma 273
Figure 9: Female genitourinary trauma

Female genitourinary trauma
consider sperm swab if indicated

Blunt Penetrating History Urine analysis Blood analysis History Urine analysis Blood analysis Blood at vulvar introitus Haematuria Blood at vulvar introitus Vaginal inspection Cystoscopy Vaginal inspection No vaginal injury Abdominal CT + cystography Conservative Labial haematoma Surgery Asssociated injuries Minor Major Conservative Blood analysis catheter Stable haematocrit Unstable haematocrit Conservative Abdominal CT + bloodtransfusion drainage
Vaginal injury
Abdominal CT
No associated injuries
Primary closure
Surgery (laparotomy, etc.)
Figure 10: Male genitourinary trama 1

Male genitourinary trauma - 1
History Urine analysis Examination
Blunt
Haematuria
Urethral trauma evaluation Testis
Penis
Sonography, possibly MRI Contusion Rupture Dislocation
Haematoma
Penile fracture
Sonography possibly scrotal MRI
Sonography possibly scrotal MRI
Sonography possibly abdominal CT
Conservative
Surgery
A minor intratesticular haematoma A major intratesticular haematoma
Surgery
Conservative surgical repositioning

Conservative
Surgery (drainage)
Figure 11: Male genitourinary trauma 2
Mal
Patient stable
Abdominal CT
Urethrogra
No associated injuries
Associated injuries
No extravasation
Conservative debridement
Bladder drainage Debridement and reconstruction of genitourinary and associated injuries
Transurethral catheter
Primary closure
ale genitourinary trauma - 2
History Urinalysis Examination Vaccination (i.e. tetanus, rabies) if indicated
Penetrating
Patient unstable
ography
Stabilize
Not stabilisable
Extravasation
CT scan
Immediate surgery Reconstruction if necessary
See guidelines for urethral trauma
Associated injuries
Bladder drainage Debridement and reconstruction of genitourinary and associated injuries
GUIDELINES ON PAIN MANAGEMENT IN UROLOGY

P. Bader (chair), D. Echtle, V. Fonteyne, K. Livadas, G. De Meerleer, A. Paez Borda, E.G. Papaioannou, J.H. Vranken
General principles of cancer pain management

The therapeutic strategy depends on the four goals of care: 1. Prolonging survival 2. Optimising comfort 3. Optimising function 4. Relieving pain.
Table 1: Hierarchy of general principles of cancer pain management

Individualised treatment for each patient. Causal therapy to be preferred over symptomatic therapy. 3. Local therapy to be preferred over systemic therapy. 4. Systemic therapy with increasing invasiveness: World Health Organization (WHO) ladder. 5. Compliance with palliative guidelines. 6. Both psychological counselling and physical therapy from the very beginning. Systemic analgesic pharmacotherapy: the analgesic ladder Analgesic pharmacotherapy is the mainstay of cancer pain management. Although concurrent use of other interventions is valuable in many patients, and essential in some, analgesic 278 Pain Management in Urology 1. 2.
drugs are needed in almost every case. Analgesic drugs can be separated into three groups: non-opioid analgesics; opioid analgesics; adjuvant analgesics. Adjuvant analgesics are drugs with other primary indications that can be effective analgesics in specific circumstances. There are three groups: corticosteroids; neuroleptics; benzodiazepines. The WHO has proposed a useful approach to drug selection for cancer pain, known as the analgesic ladder. When combined with appropriate dosing guidelines, this approach is capable of providing adequate relief to 70-90% of patients (Figure 1) (LE: 1a). Figure 1: The World Health Organizations analgesic ladder Step 3 Non-opioid analgesics + strong opioids + adjuvant analgesics Step 2 Non-opioid analgesics + weak opioids + adjuvant analgesics Step 1 Non-opioid analgesics + adjuvant analgesics Pain Management in Urology 279
Table 2: Treatment of neuropathic pain

Drug Amitriptyline (nortiptyline) Gabapentin Pregabalin Tramadol Dosage 25-75 mg 600-1200 mg 75-300 mg 50-100 mg Frequency (maximum) Once per day Three times daily Twice daily Four times daily
GR Amitriptyline and nortriptyline are first-line treatment A for neuropathic pain; nortriptyline has fewer sideeffects. Tricyclic antidepressants (TCA) must be used cauA tiously in patients with a history of cardiovascular disorders, glaucoma, and urine retention. Gabapentin and pregabalin are first-line treatments A for neuropathic pain, especially if TCAs are contraindicated. GR = grade of recommendation.
Recommendations
Pain management in urological cancers Table 3: Docetaxel-based chemotherapy versus mitoxantrone-based regimens in prostate cancer
Chemotherapy agent Docetaxel Plus additional therapy Prednisone Frequency Response rate Pain QoL (%) (%) Every 3 35 22 weeks
280 Pain Management in Urology
Docetaxel Mitoxantrone
Prednisone Prednisone
Weekly Every 3 weeks
31 22
23 13
Recommendation: Anticancer treatment
LE GR Hormonal therapy (orchiectomy, LHRH ana1a A logues, diethylstilboestrol equivalent) Total androgen blockade: flare prevention, sec2b B ond line Intermittent androgen suppression: experimental 3 B Monotherapy with anti-androgen: currently not 1b A recommended First-line treatment controls disease for 12-18 1b A months; second line individualised Supportive care Low-dose glucocorticoids 1b A Chemotherapy Mitoxantrone plus prednisolone 1b B Estramustine + vinblastine or etoposide or pacli- 2b B taxel Docetaxel 1b A Abiratereone 1b A Cabazitaxel 1b A Pain management Pain assessment (localisation, type, severity, B overall distress) Pain due to painful and stable bone metastases (single lesions) External beam irradiation 1b A Pain due to painful bony metastases (widespread) Primary hormonal therapy 1a A Pain Management in Urology 281
Radioisotopes (strontium-89 or samarium-153) Bisphosphonates Systemic pain management World Health Organization analgesic ladder step 1: NSAID or paracetamol Opioid administration Dose titration Access to breakthrough analgesia Tricyclic antidepressant and/or anticonvulsant in case of neuropathic pain NSAID = non-steroidal anti-inflammatory drug.
2 1b 1a
B A A
2 1b 1a
B A A
External beam radiation Single-fraction radiotherapy is an excellent palliative treatment for symptomatic bone metastases, resulting in complete or partial pain relief in 20-50% and in 50-80% of patients, respectively. Metastatic epidural spinal cord compression is a severe complication requiring urgent treatment. Direct decompressive surgery is superior to radiotherapy alone. Primary radiotherapy is recommended for patients who are not suited for surgery. For impending pathological fractures, a prophylactic orthopaedic procedure should be considered.
Table 4: Criteria for selecting patients for primary therapy for spinal cord compression
Absolute criteria Operability Duration of paraplegia Life expectancy Radiosensitivity Relative criteria Diagnosis of primary tumour Bone fragments with compression Number of foci of compression Surgery Radiotherapy Medically operable Medically inoperable > 48 hours < 48 hours > 3 months < 3 months Highly sensitive Known Absent > 1 foci
Unknown Present 1 focus
Radioisotopes The most important radiopharmaceuticals are: 89Sr (strontium-89 chloride); 153Sm (samarium-153 lexidronam); and, to a lesser extent, 186Re (renium-186 etidronate). There is no clear difference in treatment response between 89Sr, 153Sm and 186Re. However, there is a difference in onset of response, duration of response and toxicity. For 153Sm and 186Re, the onset of response is rapid, but duration is shorter than 89Sr.
89Sr
and 153Sm lexidronam are indicated for treatment of bone pain, resulting from skeletal metastases involving more Pain Management in Urology 283
than one site and associated with an osteoblastic response on bone scan but without spinal cord compression (LE: 2, GR: B). Overall, the response rate is 60-80%. However, pain reduction is unlikely to occur within the first week, and can occur as late as 1 month after injection. Analgesics should therefore continue to be prescribed to patients until bone pain improves. If the pain responds to the initial treatment, administration of 153Sm lexidronam can be repeated at intervals of 8-12 weeks in the presence of recurrent pain (LE: 2, GR: B). Radiopharmaceuticals should not be administered if the glomerular filtration rate is < 30 mL/min in patients who are pregnant or who are breast feeding. Because of myelosuppression, a white blood cell count > 3500/L and a platelet count > 100,000/L are desirable.
Post-operative pain management Recommendations

Post-operative pain should be treated adequately to avoid post-operative complications and the development of chronic pain. Pre-operative assessment and preparation of the patient allow in more effective pain management. Adequate post-operative pain assessment can lead to more effective pain control and fewer post-operative complications. GR B
A B
Specific pain treatment during ESWL Table 5: Analgesic drug options during extra-corporeal shock wave lithotripsy (ESWL)
Drug Alfentanil Fentanyl (or sufentanil or remifentanil) Dosage 0.5-1.0 mg/70 kg 1 g/kg Method of administration Intravenously Intravenously Frequency (maximum) On demand On demand (risk of respiratory depression)
GR Analgesics should be given on demand during and B after ESWL because not all patients need pain relief. Premedication with NSAIDs or midazolam often B decreases the need for opioids during the procedure. Intravenous opioids and sedation can be used in com- C bination during ESWL; dosage is limited by respiratory depression. Post-ESWL, analgesics with a spasmolytic effect are C preferable. ESWL = extracorporeal shock wave lithotripsy; NSAID = nonsteroidal anti-inflammatory drug.
Recommendations
Pain Management in Urology 285
Specific pain treatment after different urological operations Table 6: Analgesic drug options after transurethral procedures
Drug Diclofenac Dosage (mg) 50 100 Metamizole Paracetamol Tramadol Piritramid Pethidine 500-1000 500-1000 50-100 15 25-100 Method of administration Orally Rectally Orally or iv Orally or iv Orally, im, sc or iv iv or sc Orally, im, sc Frequency (maximum) Three times daily Every 16 hours Four times daily Four times daily Four times daily Four times daily Four to six times daily
iv = intravenously; im = intramuscularly; sc = subcutaneously.
Recommendations
Post-operative analgesics with a spasmolytic effect or mild opioids are preferable. Antimuscarinic drugs could be helpful in reducing discomfort resulting from the indwelling catheter. Antimuscarinic drugs may reduce the need for opioids.
GR C B B
Table 7: Analgesic drug options after laparoscopic surgery, minor surgery of the scrotum, penis, and inguinal region or transvaginal urological surgery
Drug Metamizole Paracetamol Tramadol Morphine Dosage (mg) 500-1000 500-1000 50-100 10 1 mg bolus 50 100 Method of Frequency administration (maximum) Orally or iv Four times daily Orally or iv Four times daily Orally, im, sc Four times or iv daily Intermittent im Eight times daily iv PCA, 5 minutes lockout Orally Three times daily Rectally Every 16 hours
Diclofenac
iv = intravenously; im = intramuscularly; sc = subcutaneously; PCA = patient-controlled analgesia.
Recommendations
Low intra-abdominal pressure and good desufflation at the end of the laparoscopic procedure reduces postoperative pain. NSAIDS are often sufficient for post-operative pain control. NSAIDs decrease the need for opioids. For post-operative pain control after minor surgery of the scrotum, penis and inguinal region, multi-modal analgesia with a combination of NSAIDs or paracetamol plus local anaesthetics should be used. If possible, avoid opioids for out-patients. NSAIDS are often sufficiently effective after minor or moderate surgery. NSAID = non-steroidal anti-inflammatory drug.
GR A
B B B
C B
Table 8: Analgesic drug options after major perineal open surgery, suprapubic extraperitoneal, retroperitoneal or transperitoneal laparotomy
Drug Bupivacaine 0.25% + fentanyl 2 g/ mL Morphine Metamizole Paracetamol Dosage 5-15 mL/ hour Method of Frequency administration (maximum) Continuous Not applicable epidural infusion iv Orally or iv Orally or iv PCA, 5-minute lockout Four times daily Four times daily
1 mg bolus 500-1000 mg 500-1000 mg
Tramadol Piritramid
50-100 mg 15 mg 50 mg 100 mg
Orally, im, sc or iv iv or sc Orally Rectally
Four times daily Four times daily Three times daily Every 16 hours
iv = intravenously; im = intramuscularly; sc = subcutaneously; PCA = patient-controlled analgesia.
Recommendations
GR The most effective method for systemic administration A of opioids is PCA, which improves patient satisfaction and decreases the risk of respiratory complications. Epidural analgesia, especially PCEA, provides superior A post-operative analgesia, reducing complications and improving patient satisfaction. It is therefore preferable to systemic techniques.
PCA = patient-controlled analgesia; PCEA = patient-controlled epidural analgesia.
Analgesics Recommendations
Paracetamol can be very useful for post-operative pain management as it reduces the consumption of opioids. Paracetamol can alleviate mild post-operative pain as a single therapy without major adverse effects. NSAIDs are not sufficient as a sole analgesic agent after major surgery. NSAIDs are often effective after minor or moderate surgery. NSAIDs often decrease the need for opioids. Avoid long-term use of COX inhibitors in patients with atherosclerotic cardiovascular disease. NSAID = non-steroidal anti-inflammatory drug. Metamizole (dipyrone) Metamizole is an effective antipyretic and analgesic drug used for mild-to-moderate post-operative pain and renal colic. Its use is prohibited in the USA and some European countries because of single reported cases of neutropenia and agranulo-cytosis. Dosage per day is 500-1000 mg four times daily (orally, intravenously or rectally). If given intravenously, metamizole should be administered as a drip (1 g in 100 mL normal saline). GR B B B B B B
Table 9: Drug, administration, dosage and delivery

Drug Method of administration Single dosage (mg) Frequency Maximal dosage (mg/24 hours)
Paracetamol
Orally
Antipyretics 500Four times 1000 daily 1000 Four times daily Four times daily
iv
Rectally
1000
Four times daily iv Four times 4000 daily Conventional NSAIDs (i.e. non-selective COX inhibitors) Ketorolac Orally 10-30 Four times 40 orally or iv daily 90 iv or im 60 iv or im (elderly) Ibuprofen Orally 200Three times 2400 800 daily Ketoprofen Orally 50 Four times 200 or iv daily Diclofenac Orally 75 Twice daily 150 or iv Orally 50 Three times 150 or iv daily
Metamizole
Orally
5001000 1000
4000 (50mg/ kg) 4000 (50mg/ kg) 4000 (50mg/ kg) 4000
Meloxicam Lornoxicam Celecoxib Parecoxib
Every 16 hours COX-2 selective inhibitors Orally 15 Once per day Orally 4 Three times or iv daily Orally 100Once per 200 day iv form 40 Once or only twice daily Opioids
Rectally
100
150
15 12 400 80
Strong opioids Morphine** Orally or Starting Six to eight rectally with 10 times daily mg Morphine** sc or im Starting Six to 12 with 5 times daily mg Morphine** iv Starting Six to 12 with 2 times daily mg Pethidine Orally, 25-150 Four times (meperidine) sc or im daily Pethidine Rectally 100 Four times (meperidine) daily Pethidine iv 25-100 Four times (meperidine) daily Oxycodone Orally, 5-10 Four to six iv or sc times daily Weak opioids
No maximal dose No maximal dose No maximal dose 500 500 500 400
Tramadol Codeine
Orally iv Orally or rectally
50 100 30-60 (plus paracetamol)
Four to six times daily Four times daily
400-600 300?
** A simple way of calculating the daily dosage of morphine for adults (20-75 years) is: 100 patients age = morphine per day in mg. NSAID = non-steroidal anti-inflammatory drug; sc = subcutaneous; im = intramuscularly; iv = intravenously.
Table 10: Common equi-analgesic dosages for parenteral and oral administration of opioids*
Drug Morphine Fentanyl Pethidine Oxycodone Dextropropoxyphene Tramadol Codeine Parenteral (mg) 10 0.1 75 15 37.5 130 Oral (mg) 30 300 20-30 50 150 200
*All listed opioid doses are equivalent to parenteral morphine 10 mg. The intrathecal opioid dose is 1/100th, and the epidural dose 1/10th, of the dose required systemically.
Table 11: Typical patient-controlled analgesia (PCA) dosing schedule

Drug (concentration) Morphine (1 mg/mL) Fentanyl (0.01 mg/mL) Pethidine (10 mg/mL Bolus size 0.5-2.5 mg 10-20 g 5-25 mg Lockout Continuous interval (min) infusion 5-10 0.01-0.03 mg/kg/hour 5-10 0.5-0.1 g/ kg/hour 5-10
Recommendations
Intravenous PCA provides superior post-operative analgesia, improving patient satisfaction and decreasing the risk of respiratory complications.
GR A
Table 12: Typical epidural dosing schemes*

Drug Morphine Fentanyl Sufentanil Pethidine Bupivacaine 0.125% or ropivacaine 0.2% + fentanyl 2 g/mL Single dose 1-5 mg 50-100 g 10-50 g 10-30 mg 10-15 mL Continuous infusion 0.1-1 mg/hour 25-100 g/hour 10-20 g/hour 10-60 mg/hour 2-6 mL/hour
* L-bupivacaine doses are equivalent to those of bupivacaine.
Table 13: Typical patient-controlled epidural analgesia (PCEA) dosing schemes

Drug Morphine Fentanyl Demand dose 100-200 g 10-15 g Lockout Continuous interval rate 10-15 300-600 g/ hour 6 80-120 g/ hour 30 10 4 mL/hour 20 5 mL/hour
Pethidine 30 mg Bupivacaine 0.125% 2 mL + fentanyl 4 g/mL Ropivacaine 0.2% + 2 mL fentanyl 5 g/mL
Recommendations
GR Epidural analgesia, especially PCEA, provides superior A post-operative analgesia, reducing complications and improving patient satisfaction. It is therefore preferable to systemic techniques.
Table 14: Examples of neural blocks

Procedure Iliohypogastric or ilioinguinal nerve infiltration after hernia repair Intercostal nerve infiltration Dosage Drug 10-20 mL Bupivacaine or ropivacaine 0.25-0.5% 5-10 mL Bupivacaine or ropivacaine 0.25-0.5% 10 mL/h Bupivacaine or ropivacaine 0.1-0.2% GR B
Continuous intrapleural infusion
Recommendations
Multi-modal pain management should be employed whenever possible since it helps to increase efficacy while minimising adverse effects. For post-operative pain control in out-patients, multimodal analgesia with a combination of NSAIDs or paracetamol plus local anaesthetics should be used. Multi-modal and epidural analgesia are preferable for post-operative pain management in elderly patients because these techniques are associated with fewer complications. Post-operative use of opioids should be avoided in obese patients unless absolutely necessary.
An epidural of local anaesthetic in combination with B NSAIDs or paracetamol is preferable in obese patients. There are insufficient data to support a specifc postC operative pain management plan for critically ill or cognitively impaired patients. NSAID = non-steroidal anti-inflammatory drug.
Peri-operative pain management in children Table 15: Pre-operative analgesia and sedation in children
Drug Morphine sulfate Dosage and route Action of administration 0.1mg/kg Can prevent crying, which therefore reduces oxygen consumption and pulmonary vasoconstriction 0.01-0.02 mg/kg Prevents bradycardia iv, im, orally, or during induction of anaesthesia rectally
Atropine
Pentobarbital Ketamine
Local application decreases venepuncture pain iv = intravenously; im = intramuscularly.
4-6 mg/kg im 6 mg/kg orally or intranasally Midazolam 0.5 mg/kg orally, intranasally, or rectally Dexmedetomidine 4 g/kg orally or intranasally Clonidine 4g/kg orally Chloral hydrate 50-100mg/kg orally Methoexital 25-30mg/kg rectally EMLA Lidocaine 2.5%; prilocaine 2.5%
Pre-operative sedation and separation anxiety in children
Table 16: Post-operative analgesia in children

Drug Dosage Administration Severity of surgical procedure minor minor minor, medium
Paracetamol
Ibuprofen
10-15 mg/kg Orally, rectally every 4 hours 20-30 mg/kg every 6 hours 10-15 mg/kg Orally, iv, recevery 6 hours tally
6-8 mg/kg Orally, iv, recevery 8-12 tally hours Codeine 0.5-1 mg/ Orally kg every 3-4 hours Morphine 0.1 mg/kg 0.3 mg/kg every 3-4 hours every 2-4 iv, sc hours Infusion: 0.03 Orally mg/kg/hour Oxycodone 0.1-0.2 mg/kg Orally every 3-4h Hydromorphone 0.04-0.08 mg/ Orally kg every 3-4 hours Tramadol 1 mg/kg every iv 4-6 hours Pethidine 2-3 mg/kg iv every 3-4 hours iv = intravenously; sc = subcutaneously.
Naproxen
minor, medium minor, medium medium, major
medium medium
medium, major medium, major
Patient-controlled analgesia can be used safely in children more than 6 years old. In infants and children unable to use PCA, nurse-controlled analgesia is effective. Locoregional techniques such as wound infiltration, nerve blocks, caudal and epidural analgesia are also used successfully.
Non-traumatic acute flank pain

Urological causes: Renal or ureteral stones Urinary tract infection (pyelonephritis, pyonephrosis, or renal abscess) Uretero-pelvic junction obstruction Renal vascular disorders (renal infarction, renal vein thrombosis) Papillary necrosis Intra- or peri-renal bleeding Testicular cord torsion Laboratory evaluation All patients with acute flank pain require a urine test (red and white cells, bacteria or urine nitrite), blood cell count, and serum creatinine measurement. In addition, febrile patients require C-reactive protein (CRP) and urine culture. Pyelonephritis obstructive uropathy should be suspected when the white blood count exceeds 15,000/mm3. GR Febrile patients (> 38C) with acute flank pain and/or B with a solitary kidney need urgent imaging. Unenhanced helical CT (UHCT) is the imaging A diagnostic modality with the highest sensitivity and specificity for evaluation of non-traumatic acute flank pain. Ultrasound can be an alternative to UHCT in the ini- A tial approach to non-traumatic acute flank pain.
Recommendations on Diagnostic imaging
Figure 2: Diagnostic approach to non-traumatic acute flank pain

Acute Flank Pain History, Physical examination, Temperature, Urinalysis Pain treatment If not conclusive Ultrasonography and/or unenhanced CT scan
Normal + normal urinalysis
Non-urologic flank pain
Normal + abnormal urinalysis (Leukocyturia, haematuria or bacteriuria)
Abnormal
Genitourinary abnormality
Non-Genitourinary abnormality
Refer patient
Further investigation and appropriate treatment
Refer patient
No hydronephrosis
Hydronephrosis
No stone
Stone
No stone Ureteral obstruction
Stone
Check for : Renal infarct Renal abscess Renal vein thrombosis Tumour Cyst Haematoma Urinoma Extrarenal mass
No UTI
UTI
Check for: Ureteral tumour Papillary necrosis UPJ obstruction Retroperitoneal fibrosis
No UTI
UTI
Stone management
Treat infection
Management to relieve pain or obstruction
Urinary drainage and infection treatment Stone management
CT = computed tomography; UTI = urinary tract infection. Pain Management in Urology 301
For a quick Differential Diagnosis and Management Options the Decision tree (figure 2) is suggested:
Initial emergency treatment

Systemic analgesia Pain relief is usually the first, most urgent, therapeutic step: A a slow intravenous infusion of dipyrone, 1 g or 2 g, is just as effective as diclofenac (75mg bolus) (LE: 1a). Intravenous papaverine (120 mg)can effectively and safely relieve patients not responding to conventional agents (diclofenac) and can be an alternative to diclofenac in patients with contraindications to NSAIDS (LE: 1b). The combination of intravenous morphine + ketorolac seems superior to either drug alone and appears to be associated with a decrease in rescue analgesia.
Recommendation
NSAIDs such as diclofenac (75 mg, bolus), and dipyrone (1-2 g, slow intravenous injection) are both very effective for acute flank pain.
GR A
Upper urinary tract decompression If pain relief cannot be achieved using medical therapy and there are signs of infection and of impaired renal function, upper urinary tract drainage should be carried out (Ureteral stenting or percutaneous nephrostomy).
Indications for stenting for urgent relief of obstruction

Urine infection with urinary tract obstruction Urosepsis Intractable pain and/or vomiting Obstruction of a solitary or transplanted kidney Bilateral obstructing stones Ureteral calculus obstruction in pregnancy
Aetiological treatment
Urolithiasis should be treated as defined in the EAU Guidelines on Urolithiasis. Infectious uncomplicated conditions (i.e. acute pyelonephritis in otherwise healthy individuals) should be treated with appropriate antibiotics and analgesics. When a diagnosis of UPJ obstruction, papillary necrosis, renal infarction renal vein thrombosis, spontaneous renal hemorrhage or testicular cord torsion has been made the patient should be treated accordingly (see long version).
GUIDELINES ON CHRONIC PELVIC PAIN

(Complete text update February 2012)
D. Engeler (chairman), A.P. Baranowski, S. Elneil, J. Hughes, E.J. Messelink, A. van Ophoven, P. Oliveira, A.C. de C. Williams Eur Urol 2004;46(6):681-9 Eur Urol 2010;57(1):35-48
This pocket version aims to synthesise the important clinical messages described in the full text and is presented as a series of graded action based recommendations, which follow the standard for levels of evidence used by the EAU (see Introduction chapter full text guidelines).
304 Chronic Pelvic Pain
Figure 1: an algorithm for diagnosing and managing CPP

Chronic Pelvic Pain
History
Physical examination
yes Symptom of a well known disease no
Specific disease associated pelvic pain
Treat according to specific disease guidelines
Pelvic pain syndrome
Organ specific symptoms present
no
Go to: Pain management
yes
urology
gynaecology
gastro-enterology
neurology
sexology
pelvic floor
see chapter 3
see chapter 4
see chapter 5
see chapter 6
see chapter 7
see chapter 9
Figure 2: an algorithm for pain management

Multidisciplinary team
Holistic approach
Psychology
Physiotherapy
Pain medicine
see chapter 8
see chapter 9
see chapter 10
Chronic Pelvic Pain 305
Table 1: Classification of chronic pelvic pain syndromes

Axis I Region Chronic pelvic pain Specific disease associated pelvic pain OR Pelvic pain syndrome Axis II System Urological Axis III End organ as pain sundrome as identified from Hx, Ex and Ix Prostate Bladder Scrotal Testicular Epididymal Penile Urethral Post-vasectomy Vulvar Vestibular Clitoral Endometriosis associated CPPS with cyclical exacerbations Dysmenorrhoea Irritable blowel Chronic anal Intermittent chronic anal Pudendal pain syndrome Dyspareunia Pelvic pain with sexual dysfunction Any pelvic organ Pelvic floor muscle Abdominal muscle Spinal Coccyx
Gynaecological
Gastrointestinal
Peripheral nervers Sexological Psychological Musculo-skeletal
Axis IV Axis V Referral Temporal characteristics characteristics Suprapubic ONSET Inguinal Acute Urethral Chronic Penile/clitoral Perineal ONGOING Rectal Sporadic Back Cyclical Buttocks Continuous Thighs TIME Filling Emptying Immediate post Late post TRIGGER Provoked Spontaneous
Axis VI Character Aching Burning Stabbing Electric
Axis VII Associated symptoms UROLOGICAL Frequency Nocturia Hesitance Dysfunctional flow Urge Incontinence GYNAECOLOGICAL Menstrual Menopause GASTROINTESTINAL Constipation Diarrhoea Bloatedness Urge Incontinence NEUROLOGICAL Dysaesthesia Hyperaesthesia Allodynia Hyperalegesie SEXUOLOGICAL Satisfaction Female dyspareunia Sexual avoidance Erectile dysfunction Medication MUSCLE Function impairment Fasciculation CUTANEOUS Trophic changes Sensory changes
Axis VIII Psychological symptoms ANXIETY About pain or putative cause of pain Catastrophic thinking about pain DEPRESSION Attributed to pain or impact of pain Attributed to other causes Unattributed PTSD SYMPTOMS Re-experiencing Avoidance
Figure 3: phenotyping and assessment algorithm for CPP

Phenotyping Urology Assessment Urinary flow, micturition diary, cystoscopy, ultrasound, uroflowmetry
Psychology
History of negative experiences, important loss, coping mechanism, depression
Organ specific
Ask for gynaecological, gastro-intestinal, ano-rectal, sexological complaints Gynaecological examination, rectal examination
Infection
Semen culture and urine culture, vaginal swab, stool culture
Neurological
Ask for neurological complaints (sensory loss, dysaesthesia). Neurological testing during physical examination: sensory problems, sacral reflexes and muscular function
Tender muscle
Palpation of the pelvic floor muscles, the abdominal muscles and the gluteal muscles
UROLOGICAL ASPECTS OF CHRONIC PELVIC PAIN PROSTATE PAIN SYNDROME Recommendations: assessment and diagnosis prostate pain syndrome (PPS)
GR
Specific diseases with similar symptoms must be A excluded. It is therefore recommended to adapt diagnostic procedures to the patient and to aim at identifying them. After primary exclusion of specific diseases, patients A with symptoms according to the above definition should be diagnosed with PPS. B A validated symptom and quality of life scoring instrument, such as the NIH-CPSI, should be considered for initial assessment as well as for follow-up.
It is recommended to assess PPS associated negative cognitive, behavioural, sexual, or emotional consequences, as well as symptoms of lower urinary tract and sexual dysfunctions.
Recommendations: treatment of prostate pain syndrome (PPS)

Consider multimodal and phenotypically directed treatment options for PPS. Alpha-blockers are recommended for patients with a duration of PPS < 1 year. Single use of antimicrobial therapy (quinolones or tetracyclines) is recommended in treatment-nave patients over a minimum of 6 weeks with a duration of PPS < 1 year. NSAIDs are recommended for use in PPS, but longterm side effects have to be considered. Allopurinol is not recommended for use in PPS. Phytotherapy might be used in patients with PPS. Consider high-dose pentosan polysulphate to improve symptoms and quality of life in PPS. Pregabalin is not recommended for use in PPS. Perineal extracorporeal shock wave therapy might be considered for the treatment of PPS. Electroacupuncture might be considered for the treatment of PPS. Posterior tibial nerve stimulation might be considered for the treatment of PPS. TUNA of the prostate is not recommended for the treatment of PPS.
GR B A A
B B B A A B B B B
For PPS with significant psychological distress, psychological treatment focussed on PPS should be attempted. Figure 4: assessment and treatment algorithm for PPS
Assessment Urine culture Uroflowmetry Transrectal US prostate NIH-CPSI scoring list Phenotyping Pelvic floor muscle testing Grade B recommended NSAID s. Be aware of long-term side effects Phytotherapy Perineal extracorporeal shockwave therapy Electroacupuncture Percutaneous tibial nerve stimulation (PTNS) Psychological treatment focused on the pain Allopurinol Pregabalin TransUrethral Needle Ablation (TUNA) Treatment Alpha-blockers when duration is < 1 year Single use antibiotics (6 weeks) when duration is < 1 year High dose Pentosan polysulfate to improve QoL and symptoms
Grade A recommended
Not recommended
[B] [A] [B]
BLADDER PAIN SYNDROME

Table 2: ESSIC classification of types of BPS according to the results of cystoscopy with hydrodistension and biopsies Cystoscopy with hydrodistension Hunners Not Normal Glomerulationsa lesionb done Biopsy Not done Normal Inconclusive Positivec
aCystoscopy: bLesion
XX XA XB XC
1X 1A 1B 1C
2X 2A 2B 2C
3X 3A 3B 3C
glomerulations grade 23 per Falls definition with/without glomerulations cHistology showing inflammatory infiltrates and/or detrusor mastocytosis and/or granulation tissue and/or intrafascicular fibrosis
Recommendations: assessment and diagnosis bladder pain syndrome (BPS)
GR
Specific diseases with similar symptoms have to be A excluded. It is therefore recommended to adapt diagnostic procedures to each patient and aim at identifying them. After primary exclusion of specific diseases, patients A with symptoms according to the above definition should be diagnosed with BPS by subtype and phenotype.
A validated symptom and quality of life scoring instrument should be considered for initial assessment as well as for follow-up. BPS associated non bladder diseases should be assessed systematically. BPS associated negative cognitive, behavioural, sexual, or emotional consequences should be assessed.
A A
Recommendations
Subtype and phenotype-oriented therapy for BPS is recommended. Multimodal behavioural, physical and psychological techniques should always be considered alongside oral or invasive treatments for BPS. Opioids might be used in BPS in disease flare-ups. Long term application solely if all treatments failed. Corticosteroids are not recommended as long-term treatment. Hydroxyzine is recommended for use in BPS. Consider cimetidine as valid oral option before invasive treatments. Amitriptyline is recommended for use in BPS. Oral PPS is recommended for use in BPS. Treatment with oral PPS plus subcutaneous heparin is recommended especially in low responders to PPS alone. Antibiotics can be offered when infection is present or highly suspected. Prostaglandins are not recommended. Insufficient data on BPS, adverse effects considerable.
GR A A
C C A B A A A
C C
Cyclosporin A might be used in PPS but adverse effects are significant and should be carefully considered. Duloxetin is not recommended for BPS treatment. Oxybutynin might be considered for the treatment of BPS. Gabapentin might be considered in oral treatment of BPS. Consider intravesical lidocain plus sodium bicarbonate prior to more invasive methods. Consider intravesical PPS before more invasive treatment alone or combined with oral PPS. Consider intravesical heparin before more invasive measures alone or in combination treatment. Consider intravesical hyaluronic acid before more invasive measures. Consider intravesical chondroitin sulphate before more invasive measures. Consider intravesical DMSO before more invasive measures. Consider intravesical bladder wall and trigonal injection of BTX-A if intravesical instillation therapies failed. Consider submucosal injection of BTX-A plus hydrodistension if intravesical instillation therapies failed. Intravesical therapy with Bacillus Calmette Gurin is not recommended in BPS. Intravesical therapy with clorpactin is not recommended in BPS. Intravesical therapy with vanilloids is not recommended in BPS.
C C C A A C B B A C
A A A C
Bladder distension is not recommendedas atreatment of BPS. Electromotive drug administration might be considered before more invasive measures. Consider transurethral resection (or coagulation or laser) of bladder lesions, but in BPS type 3 C only. Neuromodulation might be considered before more invasive interventions. Consider bladder training in patients with little pain. Consider manual and physical therapy in first approach. Consider in diet avoidance of triggering substances. Accupuncture is not recommended. Consider psychological therapy in multimodal approach. All ablative organ surgery should be last resort for experienced and BPS knowledgeable surgeons only. PPS = pentosanpolysulphate sodium; DMSO = dimethyl sulphoxide.
C C B B B B C C B A
Figure 5: diagnosis and therapy of BPS

Assessment Urine culture Uroflowmetry Cystoscopy with hydrodistension Bladder biopsy Micturition diary Pelvic floor muscle testing Phenotyping ICSI score list Grade B recommended Oral: Cimetidine , cyclosporin A Intravesical: hyaluronic acid, chondroitin sulphate Electromotive drug administration for intravesical drugs Neuromodulation, bladder training, physical therapy Psychological therapy Treatment Standard: Hydroxyzine, Amitriptyline, Pentosanpolysulphate Intravesical: PPS, DMSO, onabotulinum toxin A plus hydrodistension
Grade A recommended
Not recommended
Bacillus Calmette Guerin Intravesical Chlorpactin
Other comments
Data on surgical treatment are largely variable Coagulation and laser only for Hunners lesions
Figure 6: algorithm for BPS Type 3 C

Bladder Pain Syndrome
Hunner lesion at cystoscopy
yes
no
TUR / laser
Adequate: * Retreat when necessary
Inadequate: * Start other treatment
* Oral agents * TENS * Complimentary medicine
Inadequate relief: * start Intravesical therapy
Still inadequate response: * Refer to specialist pain management unit
GENITAL PAIN SYNDROME Recommendations: treatment of genital pain syndrome

We recommend to start with general treatment options for chronic pelvic pain (see chapter 10). We recommend informing about the risk of postvasectomy pain when counselling patients planned for vasectomy. To reduce the risk of scrotal pain, we recommend open instead of laparoscopic inguinal hernia repair. 316 Chronic Pelvic Pain GR A A
We recommend that during inguinal hernia repair all the nerves in the spermatic cord are identified. For patients who are treated surgically, we recommend microsurgical denervation of the spermatic cord. For patients who do not benefit from denervation we recommend to perform epididymectomy. We recommend that orchiectomy is reserved as last resort when every other treatment has failed.
A A
B C
Figure 7: assessment and treatment algorithm for scrotal pain syndrome

Assessment Semen culture Uroflowmetry Inform patients undergoing vasectomy about the risk of pain Ultrasound scrotum (see text) Pelvic floor muscle testing Phenotyping Grade B recommended For surgeons: open hernia repair yields less scrotal pain For surgeons: identify all nerves during hernia repair Treatment General treatment options for chronic pelvic pain - chapter 10 Microsurgical denervation of the spermatic cord Grade A recommended
Epididymectomy, in case patient did not benefit from denervation
Other comments
Orchiectomy is a last resort option, when everything else has failed Ultrasound has no clinical implications on the further treatment although physicians tend to still use ultrasound to reassure the patient
URETHRAL PAIN SYNDROME Recommendations: treatment of urethral pain syndrome

We recommend to start with general treatment options for chronic pelvic pain (see chapter 10). We recommend that patients with urethral pain syndrome are treated in a multidisciplinary and multimodal programme. GR A B
When patients are distressed, we recommend referring them for pain-relevant psychological treatment to improve function and quality of life.
Figure 8: assessment and treatment algorithm for urethral pain syndrome

Assessment Uroflowmetry Micturition diary Pelvic floor muscle testing Phenotyping Other comments Data on urethral pain are very sparse and of limited quality Grade B recommended Treat in a multidisciplinary and multimodal programme Pain-relevant psychological treatment to improve QoL and function Treatment General treatment options for chronic pelvic pain - chapter 10
Grade A recommended
GYNAECOLOGICAL ASPECTS OF CHRONIC PELVIC PAIN Recommendations: gynaecological aspects of chronic pelvic pain
All women with pelvic pain should have a full gynaecological history and evaluation, and including laparoscopy is recommended to rule out a treatable cause (e.g. endometriosis). Provide therapeutic options such as hormonal therapy or surgery in well-defined disease states. Provide a multidisciplinary approach to pain management in persistent disease states. Recommend psychological treatment for refractory chronic vulvar pain. Use alternative therapies in the treatment of chronic gynaecological pelvic pain. GR A
B B B C
Figure 9: assessment and treatment algorithm gynaecological aspects in chronic pelvic pain
Assessment Gynaecological examination Ultrasound Laparoscopy (see text) Grade B recommended Hormonal therapy in well defined states Multidisciplinary approach in persistent disease states Psychological treatment for refractory chronic vulvar pain Treatment Laparoscopy to rule out treatable causes
Grade A recommended
GASTROINTESTINAL ASPECTS OF CHRONIC PELVIC PAIN Recommendations for functional anorectal pain
Functional testing is recommended in patients with anorectal pain. Biofeedback treatment is recommended in patients with pelvic pain and dyssynergic defecation. Botulinum toxin and electrogalvanic stimulation can be considered in the chronic anal pain syndrome. Sacral neuromodulation is recommended in the chronic anal pain syndrome. Diltiazem is recommended in the intermittent chronic anal pain syndrome. GR A A B C C
Figure 10: assessment and treatment algorithm for anorectal pain syndrome
Assessment Endoscopy Pelvic floor muscle testing Anorectal manometry Rectal balloon expulsion test MRI-defecography Other comments Grade B recommended Botulinum toxine A in women with pelvic pain Electro-galvanic stimulation Treatment Biofeedback treatment
Grade A recommended
Sacral neuromodulation should be considered Diltiazem should be considered in intermittent anal pain syndrome
Figure 11: diagnosis algorithm for chronic anorectal pain

Chronic anorectal pain
Endoscopy normal
yes
no
Tenderness of puborectalis muscle
yes
no
* Anorectal manometry * Balloon expulsion test * MRI-Defecography
Anorectal pain syndrome
Specific disease guidelines
Dysfunction present
yes
no
Refer to specialist pain management unit
* Biofeedback * Electro stimulation
PERIPHERAL NERVE PAIN SYNDROMES Recommendations: pudendal neuralgia

It is important to rule out confusable diseases. If a peripheral nerve pain syndrome is suspected, early referral should occur to an expert in the field, working within a multidisciplinary team environment. Imaging and neurophysiology may help with the diagnosis, but the gold standard investigation is an image and nerve locator guided local anaesthetic injection. Neuropathic pain guidelines are well established. Standard approaches to management of neuropathic pain should be utalised. GR A B
Figure 12: assessment and treatment algorithm for peripheral nerve pain syndrome
Assessment Extended neurological tests Extended history on nature of pain Standardised questionnaires Grade B recommended Treatment Refer to an expert when a peripheral nerve problem is suspected
Grade A recommended
Imaging may be of help Neurophysiology may be of help Treatment is as for any other nerve injury
SEXOLOGICAL ASPECTS OF CHRONIC PELVIC PAIN Recommendations: sexological aspects of chronic GR pelvic pain
Clinicians may screen for abuse in patients present- B ing with symptoms suggestive for prostate pain syndrome, but should not assume the pain is psychological. Chronic Pelvic Pain 321
The biopsychosocial model should be applied in the evaluation of the effect of prostate pain syndrome on the sexual function of the patient. The biopsychosocial model should be incorporated in research in the role of chronic pelvic pain in sexual dysfunction. Behavioral strategies should be offered to the patient and his/her partner to cope with sexual dysfunctions. We recommend training of the pelvic floor muscles to improve quality of life and sexual function.
B B
Figure 13: assessment and treatment algorithm for sexologial aspects in chronic pelvic pain
Assessment History of sexual functioning History of negative experiences Ask about abuse Psychiatric history History of relationship Grade B recommended Screen for sexual abuse Use a bio-psycho-social model in treating the pain Offer behavioral strategies to cope with sexual dysfunctions Offer partner treatment Refer for pelvic floor physiotherapy Treatment Refer to sexologist when sexual dysfunction or trauma is present
Grade A recommended
PSYCHOLOGICAL ASPECTS OF CHRONIC PELVIC PAIN Recommendations: psychological aspects of chronic pelvic pain
Psychological distress is common in pelvic pain in women but should be interpreted in the context of pain. We recommend asking the patient what she thinks may be wrong to cause pain, to allow the opportunity to inform and reassure as appropriate. 322 Chronic Pelvic Pain GR A
We recommend trying psychological interventions in combination with medical and surgical treatment, or alone.
Figure 14: assessment and treatment algorithm for psychological aspects of chronic pelvic pain
Assessment Psychological history Investigate painrelated beliefs and behavior Treatment Interpret psychological distress in the context of pain Psychological interventions as adjuvant to other modalities
Grade A recommended
Grade B recommended
Ask the patient what he or she believes may be the problem that causes the pain
PELVIC FLOOR FUNCTION AND CHRONIC PELVIC PAIN Recommendations: pelvic floor function
We recommend the use of the ICS classification on pelvic floor muscle function and dysfunction. In patients with chronic pelvic pain syndrome we suggest to actively look for the presence of myofascial trigger points. In patients with chronic pelvic pain syndrome we suggest to apply pelvic floor muscle treatment as first line treatment. In patients with an overactive pelvic floor we recommend biofeedback as therapy adjuvant to muscle exercises. When myofascial triggerpoints are found we recommend treatment by pressure or needling. GR A B
Figure 15: assessment and treatment pelvic floor function

Assessment Palpation of the muscles Testing of pelvic floor function Pelvic floor muscle EMG Test for myofascial Triggerpoints History of all the involved organs Standardised questionnaires Other comments The role and options of a physiotherapist may differ between countries Grade B recommended Look actively for the presence of myofascial trigger points Apply pelvic floor muscle therapy as first line treatment Treatment Use the International Continence Society classification of dysfunction Use biofeedback in combination with muscle exercises Treat myofascial triggerpoints using pressure or needling
Grade A recommended
GENERAL TREATMENT OF CHRONIC PELVIC PAIN Recommendations: general treatment of chronic pelvic pain
All other reasonable treatments must have been tried and failed. The decision to instigate long-term opioid therapy should be made by an appropriately trained specialist in consultation with another physician (including the patients and their family doctor). Where there is a history or suspicion of drug abuse, a psychiatrist or psychologist with an interest in pain management and drug addiction should be involved. The patient should undergo a trial of opioids. The dose required needs to be calculated by careful titration. GR
A A
The patient should be made aware (and possibly give written consent): That opioids are strong drugs and associated with addiction and dependency. Opioids will normally only be prescribed from one source (preferably the family doctor). The drugs will be prescribed for fixed periods of time and a new prescription will not be available until the end of that period. The patient may be subjected to spot urine and possibly blood checks to ensure that the drug is being taken as prescribed, and that non-prescribed drugs are not being taken. Inappropriate aggressive behaviour associated with demanding the drug will not be accepted. Hospital specialist review will normally occur at least once a year. The patient may be requested to attend a psychiatric/psychological review. Failure to comply with the above may result in the patient being referred to a drug dependency agency and the use of therapeutic, analgesic opioids being stopped. Morphine is the first-line drug, unless there are contraindications to morphine or special indications for another drug. The drug should be prescribed in a slow-release/ modified release form. Short-acting preparations are undesirable and should be avoided where possible. Parenteral dosing is undesirable and should be avoided where possible.
A A A
Recommendations: medical treatment of chronic pelvic pain

Agent Paracetamol Pain Type LE Somatic pain 1a Gr A Comment Evidence based on arthritic pain with good benefit Good evidence for their use
NSAIDs
Pelvic pain 1a with inflammatory process (e.g. dysmenorrhoea) 1a Central mechanisms (e.g. endometriosis) Neuropathic 1a Antidepressants including tricyclic pain antidepressants, venlafaxine and duloxetine Anticonvulsants Neuropathic 1a gabapentin, prepain, fibrogabalin myalgia Gabapentin Women with 2b chronic pelvic pain
No good evidence for their use
Effective. No specific evidence for chronic pelvic pain Effective
Effective
Topical capsaicin
Neuropathic 1a pain Chronic non-malignant pain 1a
Opioids
Nerve blocks
TENS
1a
Neuromodulation Pelvic pain
Some evidence of benefit Beneficial in a small number of patients Have a role as part of a broad management plan No good evidence of benefit Role developing with increasing research.
Figure 16: algorithm for the use of neuropathic analgesics

Assessment General history Medications used Allergic reactions Use of alcohol Daily activities that will be effected Grade B recommended Treatment Paracetamol in somatic pain NSAID s when inflammation is present Antidepressants (including TCA) in neuropathic pain Anticonvulsants in neuropathic pain Topical Capsaicin in neuropathic pain Opiods in chronic non-malignant pain
Grade A recommended
Other comments
Nerve blocks as part of a broad management plan Neuromodulation may become an option, increasing research
[C] [C]
This short booklet text is based on the more comprehensive EAU guidelines (ISBN 978-90-79754-70-0), available to all members of the European Association of Urology at their website - http://www.uroweb.org.
GUIDELINES ON UROLITHIASIS
(Update February 2012)
C. Trk (chairman), T. Knoll (vice-chairman), A. Petrik, K. Sarica, C. Seitz, M. Straub
Epidemiology
Between 1,200 and 1,400 per 100,000 will develop urinary stones each year with a male/female ratio of 3:1. A number of known factors of influence to the development of stones are discussed in more detail in the extended version of the Urolithiasis guidelines.
Classification of stones
Correct classification of stones is important since it will impact treatment decisions and outcome. Urinary stones can be classified according to the following aspects: stone size, stone location, X-ray characteristics of stone, aetiology of stone formation, stone composition (mineralogy), and risk group for recurrent stone formation (Tables 1-3).
Urolithiasis 329
Table 1: X-ray characteristics

Radiopaque Calcium oxalate dihydrate Calcium oxalate monohydrate Calcium phosphates Poor radiopaque Magnesium ammonium phosphate Apatite Cystine Radiolucent Uric acid
Ammonium urate Xanthine 2,8-dihydroxyadenine Drug-stones
Table 2: Stones classified according to their aetiology

Non infection stones Calcium oxalates Calcium phosphates Uric acid Infection stones Magnesium ammonium phosphate Apatite Ammonium urate Genetic stones Cystine Drug stones e.g. Indinavir (see extended document)
Xanthine 2,8-dihydroxyadenine
Table 3: Stones classified by their composition

Chemical composition Calcium oxalate monohydrate Calcium-oxalate-dihydrate Uric acid dihydrate Ammonium urate 330 Urolithiasis Mineral whewellite wheddelite uricite
Magnesium ammonium phosphate Carbonate apatite (phosphate) Calcium hydrogenphosphate Cystine Xanthine 2,8-dihydroxyadenine Drug stones
struvite dahllite brushite
Risk groups for stone formation

The risk status of a stone former is of particular interest as it defines both probability of recurrence or (re)growth of stones and is imperative for pharmacological treatment.
Table 4: High risk stone formers

General factors Early onset of urolithiasis in life (especially children and teenagers) Familial stone formation Brushite containing stones (calcium hydrogen phosphate; CaHPO4.2H2O) Uric acid and urate containing stones Infection stones Solitary kidney (The solitary kidney itself does not present an increased risk of stone formation, but prevention of stone recurrence is more important) Diseases associated with stone formation Hyperparathyroidism Nephrocalcinosis Gastrointestinal diseases or disorders (e.g. jejuno-ileal bypass, intestinal resection, Crohns disease, malabsorptive conditions, enteric hyperoxaluaria after urinary diversion) Urolithiasis 331
Sarcoidosis Genetically determined stone formation Cystinuria (type A, B, AB) Primary hyperoxaluria (PH) Renal tubular acidosis (RTA) type I 2,8-dihydroxyadenine Xanthinuria Lesh-Nyhan-Syndrome Cystic fibrosis Drugs associated with stone formation (see Chapter 11 extended text) Anatomical abnormalities associated with stone formation Medullary sponge kidney (tubular ectasia) UPJ obstruction Calyceal diverticulum, calyceal cyst Ureteral stricture Vesico-uretero-renal reflux Horseshoe kidney Ureterocele
DIAGNOSIS Diagnostic imaging

Standard evaluation of a patient includes taking a detailed medical history and physical examination. The clinical diagnosis should be supported by an appropriate imaging procedure.
332 Urolithiasis
Recommendation
With fever or solitary kidney, and when diagnosis is doubtful, immediate imaging is indicated. *Upgraded following panel consensus.
LE 4
GR A*
If available, ultrasonography, should be used as the primary diagnostic imaging tool although pain relief, or any other emergency measures should not be delayed by imaging assessments. KUB should not be performed if NCCT is considered; however, it is helpful in differentiating between radiolucent and radiopaque stones and for comparison during follow-up.
Evaluation of patients with acute flank pain

Non-contrast enhanced computed tomography (NCCT) has become the standard for diagnosis of acute flank pain since it has higher sensitivity and specificity than IVU.
Recommendation
LE
GR A
NCCT should be used to confirm stone diag1a nosis in patients with acute flank pain, because it is superior to IVU
Indinavir stones are the only stones not detectable on NCCT.
Recommendation
A renal contrast study (enhanced CT or IVU) is indicated when planning treatment for renal stones. *Upgraded following panel consensus.
LE 3
GR A*
Urolithiasis 333
Biochemical work-up
Each emergency patient with urolithiasis needs a succinct biochemical work-up of urine and blood besides the imaging studies. At that point no difference is made between highand low-risk patients.
Recommendations: Basic analysis emergency stone patient

Urine Urinary sediment/dipstick test out of spot urine sample for: red cells / white cells / nitrite / urine pH level by approximation Urine culture or microscopy Blood Serum blood sample creatinine / uric acid / ionized calcium / sodium / potassium / CRP Blood cell count If intervention is likely or planned: Coagulation test (PTT and INR) *Upgraded following panel consensus. GR A*
A A* A* A*
Examination of sodium, potassium, CRP, and blood coagulation time can be omitted in the non-emergency stone patient. Patients at high risk for stone recurrences should undergo a more specific analytical programme (see section MET below). Analysis of stone composition should be performed in all first-time stone formers (GR: A). It should be repeated in case of: Recurrence under pharmacological prevention 334 Urolithiasis
Early recurrence after interventional therapy with complete stone clearance Late recurrence after a prolonged stone-free period (GR: B) The preferred analytical procedures are: X-ray diffraction (XRD) Infrared spectroscopy (IRS) Wet chemistry is generally deemed to be obsolete.
Acute treatment of a patient with renal colic

Pain relief is the first therapeutic step in patients with an acute stone episode.
Recommendations for pain relief during and LE prevention of recurrent renal colic
GR
First choice: start with an NSAID, e.g. 1b A diclofenac*, indomethacin or ibuprofen. Second choice: hydromorphine, pentazocine 4 C and tramadol. Diclofenac sodium* / alpha-blocker** is 1b A recommended to counteract recurrent pain after ureteral colic. Third-line treatment: Spasmolytics (metamizole sodium etc.) are alternatives which may be given in circumstances in which parenteral administration of a non-narcotic agent is mandatory. GFR = glomerular filtration rate; NSAID = non-steroidal antiinflammatory drug. *Caution: Diclofenac sodium affects GFR in patients with reduced renal function, but not in patients with normal renal function (LE: 2a). ** (see extended document section 5.3) Urolithiasis 335
If pain relief cannot be achieved by medical means, drainage, using stenting or percutaneous nephrostomy, or stone removal, should be carried out.
Management of sepsis in the obstructed kidney

The obstructed, infected kidney is a urological emergency.
Recommendations
For sepsis with obstructing stones, the collecting system should be urgently decompressed, using either percutaneous drainage or ureteral stenting. Definitive treatment of the stone should be delayed until sepsis is resolved.
LE 1b
GR A
1b
In exceptional cases, with severe sepsis and/or the formation of abscesses, an emergency nephrectomy may become necessary.
Further Measures - Recommendations

Collect urine for antibiogram following decompression. Start antibiotics immediately thereafter (+ intensive care if necessary). Revisit antibiotic treatment regimen following antibiogram findings. * Upgraded based on panel consensus.
GR A*
336 Urolithiasis
Stone relief
When deciding between active stone removal and conservative treatment using MET, it is important to consider all the individual circumstances of a patient that may affect treatment decisions.
Observation of ureteral stones Recommendations
LE
GR A
In patients with newly diagnosed ureteral 1a stones < 10 mm, and if active stone removal is not indicated, observation with periodic evaluation is optional initial treatment. Such patients may be offered appropriate medical therapy to facilitate stone passage during the observation period*. *see also Section MET.
Observation of kidney stones

It is still debatable whether kidney stones should be treated, or whether annual follow-up is sufficient for asymptomatic caliceal stones that have remained stable for 6 months.
Recommendations
GR
Kidney stones should be treated in case of growth, A formation of de novo obstruction, associated infection, and acute and/or chronic pain. Comorbidity and patient preference need to be taken C into consideration when making treatment decisions. A If kidney stones are not treated, periodic evaluation is needed. * Upgraded following panel consensus. Urolithiasis 337
Medical expulsive therapy (MET)

For patients with ureteral stones that are expected to pass spontaneously, NSAID tablets or suppositories (i.e. diclofenac sodium, 100-150 mg/day, over 3-10 days) may help to reduce inflammation and the risk of recurrent pain. Alpha-blocking agents, given on a daily basis, reduce recurrent colic (LE: 1a). Tamsulosin, has been the most commonly used alpha blocker in studies.
Recommendations for MET
LE
GR A A*
For MET, alpha-blockers or nifedipine are recommended. Patients should be counselled about the attendant risks of MET, including associated drug side effects, and should be informed that it is administered as off-label use. Patients, who elect for an attempt at spontaneous passage or MET, should have well-controlled pain, no clinical evidence of sepsis, and adequate renal functional reserve. Patients should be followed to monitor stone 4 position and to assess for hydronephrosis. MET in children cannot be recommended due 4 to the limited data in this specific population. *Upgraded following panel consensus.
A* C
Statements
LE MET has an expulsive effect also on proximal ureteral 1b stones.
338 Urolithiasis
After SWL for ureteral or renal stones, MET seems to 1a expedite and increase stone-free rates, reducing additional analgesic requirements. Based on studies with a limited number of patients, 1b no recommendation for the use of corticosteroids in combination with alpha-blockers in MET can be made.
Chemolytic dissolution of stones

Oral or percutaneous irrigation chemolysis of stones can be a useful first-line therapy or an adjunct to SWL, PNL, URS, or open surgery to support elimination of residual fragments. However, its use as first-line therapy may take weeks to be effective.
Percutaneous irrigation chemolysis Recommendations

GR In percutaneous chemolysis, at least two nephrosto- A my catheters should be used to allow irrigation of the renal collecting system, while preventing chemolytic fluid draining into the bladder and reducing the risk of increased intrarenal pressure*. Pressure- and flow-controlled systems should be used if available. * Alternatively, one nephrostomy catheter with a JJ stent and bladder catheter can serve as a through-flow system preventing high pressure.
Urolithiasis 339
Methods of percutaneous irrigation chemolysis

Stone composition Struvite Carbon apatite Irrigation solution 10% Hemiacidrin, pH 3.5-4 Subys G Comments Combination with SWL for staghorn stones Risk of cardiac arrest due to hypermagnesaemia Can be considered for residual fragments Takes significantly longer time than for uric acid stones Used for elimination of residual fragments Oral chemolysis is the preferred option
Brushite
Hemiacidrin Subys G Trihydroxymethylaminomethan (THAM; 0.3 or 0.6 mol/L), pH 8.5-9.0 N-acetylcysteine (200 mg/L) Trihydroxymethylaminomethan (THAM; 0.3 or 0.6 mol/L), pH 8.5-9.0
Cystine
Uric acid
Oral Chemolysis
Oral chemolitholysis is efficient for uric acid calculi only. The urine pH should be adjusted to between 7.0 and 7.2.
340 Urolithiasis
Recommendations
GR
The dosage of alkalising medication must be modified A by the patient according to the urine pH, which is a direct consequence of the alkalising medication. Dipstick monitoring of urine pH by the patient is A required at regular intervals during the day. Morning urine must be included. The physician should clearly inform the patient of A the significance of compliance.
SWL
The success rate for SWL will depend on the efficacy of the lithotripter and on: size, location (ureteral, pelvic or calyceal), and composition (hardness) of the stones; patients habitus; performance of SWL. Contraindications of SWL Contraindications to the use of SWL are few, but include: pregnancy; bleeding diatheses; uncontrolled urinary tract infections; severe skeletal malformations and severe obesity, which prevent targeting of the stone; arterial aneurism in the vicinity of the stone; anatomical obstruction distal of the stone.
Urolithiasis 341
Stenting prior to SWL Kidney stones A JJ stent reduces the risk of renal colic and obstruction, but does not reduce formation of steinstrasse or infective complications.
Recommendation - stenting & SWL
LE
GR A
Routine stenting is not recommended as part of 1b SWL treatment of ureteral stones.
Best clinical practice (best performance) Pacemaker Patients with a pacemaker can be treated with SWL, provided that appropriate technical precautions are taken; patients with implanted cardioverter defibrillators must be managed with special care (firing mode temporarily reprogrammed during SWL treatment). However, this might not be necessary with new-generation lithotripters.
Recommendation - Shock wave rate

The optimal shock wave frequency is 1.0 (to 1.5) Hz.
LE 1a
GR A
Number of shock waves, energy setting and repeat treatment sessions The number of shock waves that can be delivered at each session depends on the type of lithotripter and shockwave power. Starting SWL on a lower enegy setting with step-wise power (and SWL sequence) ramping prevents renal injury. 342 Urolithiasis
Clinical experience has shown that repeat sessions are feasible (within 1 day for ureteral stones). Procedural control Results of treatment are operator dependent. Careful imaging control of localisation will contribute to outcome quality. Pain control Careful control of pain during treatment is necessary to limit pain-induced movements and excessive respiratory excursions. Antibiotic prophylaxis No standard prophylaxis prior to SWL is recommended.
Recommendation
LE
GR C
In case of infected stones or bacteriuria, antibi- 4 otics should be given prior to SWL.
Medical expulsive therapy (MET) after SWL MET after SWL for ureteral or renal stones can expedite expulsion and increase stone-free rates, as well as reduce additional analgesic requirements.
Urolithiasis 343
Percutaneous nephrolitholapaxy (PNL) Recommendation

GR Ultrasonic, ballistic and Ho:YAG devices are recomA* mended for intracorporeal lithotripsy using rigid nephroscopes. When using flexible instruments, the Ho:YAG laser is currently the most effective device available. * Upgraded following panel consensus. Best clinical practice Contraindications: all contraindications for general anaesthesia apply; untreated UTI; atypical bowel interposition; tumour in the presumptive access tract area; potential malignant kidney tumour; pregnancy.
Pre-operative recommendation - imaging

Preprocedural imaging, including contrast medium where possible or retrograde study when starting the procedure, is mandatory to assess stone comprehensiveness, view the anatomy of the collecting system, and ensure safe access to the kidney stone. * Upgraded based on panel consensus.
GR A*
Positioning of the patient: prone or supine? Traditionally, the patient is positioned prone for PNL, supine position is also possible, showing advantages in shorter operating time, the possibility of simultaneous ret344 Urolithiasis
rograde transurethral manipulation, and easier anaesthesia. Disadvantages are limited manoeuvrability of instruments and the need of appropriate equipment. Nephrostomy and stents after PNL
Recommendation
LE
GR A
In uncomplicated cases, tubeless (without 1b nephrostomy tube) or totally tubeless (without nephrostomy tube and without ureteral stent) PNL procedures provide a safe alternative.
Ureterorenoscopy (URS)
(including retrograde access to renal collecting system) Best clinical practice in URS Before the procedure, the following information should be sought and actions taken (LE: 4): Patient history; physical examination (i.e. to detect anatomical and congenital abnormalities); thrombocyte aggregation inhibitors/anticoagulation (anti-platelet drugs) treatment should be discontinued. However, URS can be performed in patients with bleeding disorders, with only a moderate increase in complications; imaging.
Recommendation
Short-term antibiotic prophylaxis should be administered.
GR A*
Urolithiasis 345
Contraindications Apart from general considerations, e.g. with general anaesthesia, URS can be performed in all patients without any specific contraindications. Access to the upper urinary tract Most interventions are performed under general anaesthesia, although local or spinal anaesthesia are possible. Intravenous sedation is possible for distal stones, especially in women. Antegrade URS is an option for large, impacted proximal ureteral calculi. Safety aspects Fluoroscopic equipment must be available in the operating room. If ureteral access is not possible, the insertion of a JJ stent followed by URS after a delay of 7-14 days offers an appropriate alternative to dilatation.
Recommendation
Placement of a safety wire is recommended. *Upgraded following panel consensus.
GR A*
Ureteral access sheaths

Hydrophilic-coated ureteral access sheaths (UAS), can be inserted via a guide wire, with the tip placed in the proximal ureter. Ureteral access sheaths allow easy multiple access to the upper urinary tract and therefore significantly facilitate URS. The use of UAS improves vision by establishing a continuous outflow, decrease intrarenal pressure and potentially reduce operating time. 346 Urolithiasis
Stone extraction The aim of endourological intervention is complete stone removal (especially in ureteric stones). Smash and go strategies might have a higher risk of stone regrowth and postoperative complications.
Recommendation
LE
GR A*
Stone extraction using a basket without endo- 4 scopic visualisation of the stone (blind basketing) should not be performed. Nitinol baskets preserve the tip deflection of 3 flexible ureterorenoscopes, and the tipless design reduces the risk of mucosa injury. Nitinol baskets are most suitable for use in flexible URS. Ho:YAG laser lithotripsy is the preferred method when carrying out (flexible) URS. *Upgraded following panel consensus.
Stenting before and after URS Pre-stenting facilitates ureteroscopic management of stones, improves the stone-free rate, and reduces complications. Following URS, stents should be inserted in patients who are at increased risk of complications.
Recommendation
LE
GR A
Stenting is optional before and after uncompli- 1a cated URS.
Urolithiasis 347
Open surgery
Most stones should be approached primarily with PNL, URS, SWL, or a combination of these techniques. Open surgery may be a valid primary treatment option in selected cases. Indications for open surgery: Complex stone burden Treatment failure of SWL and/or PNL, or URS Intrarenal anatomical abnormalities: infundibular stenosis, stone in the calyceal diverticulum (particularly in an anterior calyx), obstruction of the ureteropelvic junction, stricture if endourologic procedures have failed or are not promising Morbid obesity Skeletal deformity, contractures and fixed deformities of hips and legs Comorbidity Concomitant open surgery Non-functioning lower pole (partial nephrectomy), nonfunctioning kidney (nephrectomy) Patient choice following failed minimally invasive procedures; the patient may prefer a single procedure and avoid the risk of needing more than one PNL procedure Stone in an ectopic kidney where percutaneous access and SWL may be difficult or impossible For the paediatric population, the same considerations apply as for adults.
Laparoscopic surgery
Laparoscopic urological surgery is increasingly replacing open surgery. 348 Urolithiasis
Indications for laparoscopic kidney-stone surgery include: complex stone burden; failed previous SWL and/or endourological procedures; anatomical abnormalities; morbid obesity; nephrectomy in case of non-functioning kidney. Indications for laparoscopic ureteral stone surgery include: large, impacted stones; multiple ureteral stones; in cases of concurrent conditions requiring surgery; when other non-invasive or low-invasive procedures have failed. If indicated, for upper ureteral calculi, laparoscopic urolithomy has the highest stone-free rate compared to URS and SWL (LE: 1a). Laparoscopic ureterolithotomy should be considered when other non-invasive or low-invasive procedures have failed.
Urolithiasis 349
Recommendations
LE
GR C
Laparoscopic or open surgical stone removal 3 may be considered in rare cases where SWL, URS, and percutaneous URS fail or are unlikely to be successful. When expertise is available, laparoscopic sur- 3 gery should be the preferred option before proceeding to open surgery. An exception is complex renal stone burden and/or stone location. For Ureterolithotomy, laparoscopy is recom2 mended for large impact stones or when endoscopic lithotripsy or SWL have failed.
Indication for active stone removal and selection of procedure

Ureter: stones with a low likelihood of spontaneous passage; persistent pain despite adequate pain medication; persistent obstruction; renal insufficiency (renal failure, bilateral obstruction, single kidney). Kidney: stone growth; stones in high-risk patients for stone formation; obstruction caused by stones; infection; symptomatic stones (e.g. pain, haematuria); stones > 15 mm; stones < 15 mm if observation is not the option of choice; patient preference (medical and social situation); > 2-3 years persistent stones. 350 Urolithiasis
The suspected stone composition might influence the choice of treatment modality.
Recommendations
GR
For asymptomatic caliceal stones in general, active C surveillance with an annual follow-up of symptoms and stone status (KUB, ultrasonography [US], NCCT) is an option for 23 years, whereas intervention should be considered after this period provided patients are adequately informed. Observation might be associated with a greater risk of necessitating more invasive procedures.
STONE REMOVAL Recommendations

GR
Urine culture or urinary microscopy is mandatory A* before any treatment is planned. Urinary infection should be treated when stone A removal is planned. Anticoagulation therapy including salicylates should B be stopped before stone removal, in particular if SWL is planned. If intervention for stone removal is essential and salicylate therapy should not be interrupted, retrograde URS is the preferred treatment of choice. *Upgraded based on panel consensus. Radiolucent uric acid stones, but not sodium urate or ammonium urate stones, can be dissolved by oral chemolysis. Determination is done by urinary pH. Urolithiasis 351
Recommendation
GR
Careful monitoring of radiolucent stones during/after A therapy is imperative. * Upgraded based on panel consensus.
Selection of procedure for active removal of renal stones

Figure 1: Treatment algorithm for renal calculi within the renal pelvis or upper and middle calices
Kidney stone in renal pelvis or upper/middle calyx
> 2 cm
1. Endourology (PNL, flex. URS*) 2. SWL 3. Laparoscopy
1-2 cm
SWL or Endourology*,**
< 1 cm
1. SWL 2. Flex. URS 3. PNL
* Flexible URS is used less as first-line therapy for renal stones > 1.5 cm. ** The ranking of the recommendations reflects a panel majority vote. *** see Table 19 extended document 352 Urolithiasis
Figure 2: Treatment algorithm for renal calculi in the inferior calyx

Kidney stone in lower pole
> 2 cm
1. Endourology (PNL, flex. URS*) 2. SWL
Yes
SWL or Endourology*,**
1-2 cm
Favourable factors for SWL***

No
1. Endourology 2. SWL
< 1 cm
1. SWL 2. Flex. URS 3. PNL
Selection of procedure for active stone removal of ureteral stones (GR: A*)
First choice Second choice Proximal ureter < 10 mm SWL URS Proximal ureter > 10 mm URS (retrograde or antegrade) or SWL Distal ureter < 10 mm URS or SWL Distal ureter > 10 mm URS SWL *Upgraded following panel consensus. Urolithiasis 353
Recommendation
Percutaneous antegrade removal of ureteral stones is an alternative when SWL is not indicated or has failed, and when the upper urinary tract is not amenable to retrograde URS. Patients should be informed that URS is associated with a better chance of achieving stone-free status with a single procedure, but has higher complication rates.
GR A
Steinstrasse
Steinstrasse occurs in 4% to 7% of cases after SWL, the major factor in steinstrasse formation is stone size.
Recommendations
Medical expulsion therapy increases the stone expulsion rate of steinstrasse. PCN is indicated for steinstrasse associated with UTI/fever. SWL is indicated for steinstrasse when large stone fragments are present. Ureteroscopy is indicated for symptomatic steinstrasse and treatment failure.
LE 1b 4 4 4
GR A C C C
354 Urolithiasis
Residual stones Recommendations

Identification of biochemical risk factors and appropriate stone prevention is particularly indicated in patients with residual fragments or stones. Patients with residual fragments or stones should be followed up regularly to monitor disease course. After SWL and URS, MET is recommended using an alpha-blocker to improve fragment clearance and reduce the probability of residual stones. For well-disintegrated stone material residing in the lower calix, inversion therapy during high diuresis and mechanical percussion facilitate stone clearance. LE 1b GR A
1a
1a
The indication for active stone removal and selection of the procedure is based on the same criteria as for primary stone treatment and also includes repeat SWL.
Management of urinary stones and related problems during pregnancy Recommendations (GR: A*)
US is the method of choice for practical and safe evaluation of pregnant women. In symptomatic patients with suspicion of ureteral stones during pregnancy, limited IVU, MRU, or isotope renography is a possible diagnostic method. Urolithiasis 355
Following correct diagnosis, conservative management should be the first-line treatment for all non-complicated cases of urolithiasis in pregnancy (except those that have clinical indications for intervention). If intervention becomes necessary, placement of an internal stent, percutaneous nephrostomy, or ureteroscopy are treatment options. Regular follow-up until final stone removal is necessary due to higher encrustation of stents during pregnancy. * Upgraded following panel consensus.
Management of stone problems in children

Spontaneous passage of a stone and of fragments after SWL is more likely to occur in children than in adults (LE: 4). For paediatric patients, the indications for SWL and PNL are similar to those in adults, however they pass fragments more easily. Children with renal stones with a diameter up to 20 mm (~300 mm2) are ideal candidates for SWL.
Recommendation
Ultrasound evaluation is the first choice for imaging in children and should include the kidney, the filled bladder and adjoining portions of the ureter. *Upgraded from B following panel consensus.
GR A*
356 Urolithiasis
Stones in exceptional situations

Caliceal diverticulum stones SWL, PNL (if possible) or RIRS (retrograde intrarenal surgery via flexible ureteroscopy). Can also be removed using laparoscopic retroperitoneal surgery. Patients may become asymptomatic due to stone disintegration (SWL) whilst welldisintegrated stone material remains in the original position due to narrow caliceal neck. Horseshoe kidneys Can be treated in line with the stone treatment options described above. Passage of fragments after SWL might be poor. Stones in pelvic kidneys SWL, RIRS or laparoscopic surgery For obese patients, the options are SWL, PNL, RIRS or open surgery
Urolithiasis 357
Patients with obstruction of the ureteropelvic junction
When the outflow abnormality has to be corrected, stones can be removed with either percutaneous endopyelotomy or open reconstructive surgery. URS together endopyelothomy with Ho:YAG. Incision with an Acucise balloon catheter might be considered, provided the stones can be prevented from falling into the pelvo-ureteral incision. Stones in transplanted kidUse of PNL is recommended, neys however SWL or (flexible) ureteroscopy are valuable alternatives. Stones formed in urinary Individual management necdivision essary. For smaller stones SWL is effective. PNL and antegrade flexible URS are frequently used endourological procedures. Stones formed in a continent Present a varied and often reservoir difficult problem. Each stone problem must be considered and treated individually.
358 Urolithiasis
Stones in patients with neurogenic bladder disorder
For stone removal all methods apply based on individual situation. Careful patient follow-up and effective precentive strategies are important.
General considerations for recurrence prevention (all stone patients)

Drinking advice (2.5 3L/day, neutral pH); Balanced diet; Lifestyle advice.
High-risk patients: stone-specific metabolic work-up and pharmacological recurrence prevention

Pharmacological stone prevention is based on a reliable stone analysis and the laboratory analysis of blood and urine including two consecutive 24-hour urine samples.
Pharmacological treatment of calcium oxalate stones

(Hyperparathyreoidism excluded by blood examination) Risk factor Hypercalciuria Hyperoxaluria Hypocitraturia Enteric hyperoxaluria Suggested treatment Thiazide + potassium citrate Oxalate restriction Potassium citrate Potassium citrate Calcium supplement Oxalate absorption LE 1a 2b 1b 3-4 2 3 GR A A A C B B
Urolithiasis 359
Small urine volume Increased fluid intake Distal renal tubular Potassium citrate acidosis Primary hyperoxaluria Pyridoxine
1b 2b 3
A B B
Pharmacological treatment of calcium phosphate stones

Risk factor Rationale Hypercalciuria Calcium excretion > 8 mmol/day pH constantly Inadequate > 6.2 urine pH Medication Hydrochlorothiazide, initially 25 mg/day, increasing up to 50 mg/day L-Methionine, 200-500 mg 3 times daily, with the aim of reducing urine pH to 5.8-6.2 Antibiotics
Urinary tract infection
Eradication of urea-splitting bacteria
Hyperparathyroidism
Elevated levels of ionized calcium in serum (or total calcium and albumin) require assessment of intact parathyroid hormone (PTH) to confirm or exclude suspected hyperparathyroidism (HPT). Primary HTP can only be cured by surgery.
360 Urolithiasis
Pharmacological treatment of uric acid and ammonium urate stones

Risk factor Rationale for pharmacological therapy Inadequate urine Urine pH constantly < 6.0; pH acidic arrest in uric acid stones Medication
Hyperuricosuria
Alkaline citrate OR Sodium bicarbonate Prevention: targeted urine pH 6.2-6.8 Chemolitholysis: targeted urine pH 7.0-7.2 Adequate antibiotUrine pH constantly > 6.5 in ics in case of UTI ammonium urate L-Methionine, 200-500 mg 3 times stones daily; targeted urine pH 5.8-6.2 Uric acid excretion Allopurinol, > 4.0 mmol/day 100 mg/day (LE: 3; GR: B) Hyperuricosuria Allopurinol, and hyperuricemia 100-300 mg/day, > 380 mol depending on kidney function
Urolithiasis 361
Struvite and infection stones

Therapeutic measure recommendations Surgical removal of the stone material as completely as possible Short-term antibiotic course Long-term antibiotic course Urinary acidification: ammonium chloride; 1 g, 2 - 3 x daily Urinary acidification: methionine; 200-500 mg, 1 - 3 x daily Urease inhibition LE GR
3 3 3 3 1b
B B B B A
Pharmacological treatment of cystine stones

Risk factor Rationale for pharmacological therapy Cystine excretion > 3.0-3.5 mmol/day Medication
Cystinuria
Inadequate urine pH
Improvement of cystine solubility Urine pH optimum 7.5-8.5
Tiopronin, 250 mg/ day initially, up to a maximum dose of 2 g/day NB: TACHYPHYLAXIS IS POSSIBLE (LE: 3; GR: B) Alkaline Citrate or Sodium Bicarbonate Dosage is according to urine pH (LE: 3, GR: B)
362 Urolithiasis
2,8-dihydroyadenine stones and xanthine stones

Both stone types are rare. In principle, diagnosis and specific prevention is similar to that of uric acid stones.
Investigating a patient with stones of unknown composition

Investigation Medical history Rationale for investigation - Stone history (former stone events, family history) - Dietary habits - Medication chart - Ultrasound in case of a suspected stone - NCCT (Determination of the Houndsfield unit provides information about the possible stone composition) - Creatinine - Calcium (ionized calcium or total calcium + albumin) - Uric acid - Urine pH profile (measurement after each voiding, minimum 4 times a day) - Dipstick test: leucocytes, erythrocytes, nitrite, protein, urine pH, specific weight - Urine culture - Microscopy of urinary sediment (morning urine)
Diagnostic imaging
Blood analysis
Urinalysis
Urolithiasis 363
This short booklet text is based on the more comprehensive EAU guidelines (ISBN 978-90-79754-83-0) available to all members of the European Association of Urology at their website, http://www.uroweb.org.
364 Urolithiasis
GUIDELINES ON RENAL TRANSPLANTATION

G. Karam (chairman), T. Klble, A. Alcaraz, F.T. Aki, K. Budde, U. Humke, F. Kleinclauss, G. Nicita, J.O. Olsburgh, C. Ssal
Introduction
As attitudes and practice to renal transplantation (RT) vary significantly, the Guidelines provide general guidance only.
Kidney donation
There is a widening gap between donation and demand for kidney transplants, with not enough deceased donors. There is, however, a clear trend towards an increase in living-donor transplants.
Recommendations for increasing donation
GR Deceased donors C In all countries without presumed consent law, increase efforts to recruit donors through an opting-in register or by carrying donor cards. B Greater use of non-heart-beating donors (NHBD) should be made. Create policies for recently dead admissions to casualty departments which may be used as NHBDs.
Renal Transplantation 365
Use of carefully selected donors > 60 years should be encouraged as a continuing source of deceased-donor kidneys. Organs from deceased donors > 70 years should be individually evaluated. Living donors Organ donation should be considered a charitable gift. Society can express gratitude to organ donors for their gift (e.g. Medal of Honour, donor insurance). Explore living donation when a patient first presents with end-stage renal disease. Decisions about multiple renal artery or grafts with anatomical anomalies should be made on an individual basis. Laparoscopic nephrectomy offers similar results (complications, graft function and graft survival) compared to open nephrectomy, with less post-operative morbidity, shorter convalescence and better cosmetic results. Laparoscopic nephrectomy increases the number of people wainting to donate. Paired kidney exchange, if permitted by national law, laparoscopy is a way of increasing the number of kidney transplants.
C C
C C
Kidney donor selection and refusal criteria The physical condition of the donor, especially of the organ to be donated, is more important than age. Important risk factors for organ failure are a prolonged history of diabetes mellitus or serious hypertension with retinal vascular damage. Factors for excluding potential donors or for considering 366 Renal Transplantation
single- rather than multi-organ donations include previous myocardial infarction, coronary bypass angina, severe systemic vascular disease and long-lasting hypotension, oliguria, and a long period in intensive care. The potential donor should be assessed for human immunodeficiency virus-1, -2 (HIV-1, HIV-2), hepatitis C virus (HCV) and hepatitis B surface antigen (HBsAg), anti-hepatitis B core (anti-HBc) antibody, acute hepatitis (liver enzymes), cytomegalovirus (CMV), Epstein-Barr virus if the recipient is paediatric, active syphilis, other viral infections, sepsis, tuberculosis, infections of unknown aetiology, and a family history (or possible clinical signs) of Creutzfeldt-Jacob disease. Different circumstances apply when a recipient is already infected with HIV or hepatitis and transplant from infectious donors is possible in certain situations. A previous history of malignancy need not be a contraindication for organ donation. However, absolute contraindications are active cancer or a history of metastatic cancer (with a few exceptions, e.g. testicular cancer) and cancers with high recurrence rates, e.g. lymphoma. Exclude metastasis as a cause of intracranial bleeding in a potential donor with a brain haemorrhage of unknown aetiology. For special exceptions in malignancy, consult the full Guidelines. Kidneys from marginal donors must have a calculated creatinine clearance rate (CrCl) of 50-60 mL/min. Kidneys with CrCl < 50 mL/min are only suitable for dual transplant. Renal Transplantation 367
Recommendations for brain dead donors
GR Consider every brain-dead comatose subject as a potential organ donor, without age limits. Obtain agreement for organ harvesting from relatives (significant others) according to local law and policies. Authorisation for explantation by the donors close relatives is always recommended, even if local legislation presumes consent. Always exclude individuals who objected to donation C during life. A donor organ affected by a potentially transmissible B pathology (infections, neoplasias) must be carefully evaluated considering the risk/benefits for the recipient. A good-quality organ must be guaranteed to the recip- C ient and every transplant centre must establish its own guidelines on organ acceptability. Marginal organs can only be used after thorough assessment. Counsel recipients and confirm their acceptance.
Surgical techniques
GR Living-donor transplantation is associated with higher B success rates than deceased-donor transplantation. The surgeon is responsible for making sure the donor B is medically and psychologically suitable, the donated organ is healthy, and success in the recipient is likely. B Always leave the donor with the better kidney. The transperitoneal approach carries a higher risk of splenic and intestinal complications.
368 Renal Transplantation
Open-donor nephrectomy should be performed by an extraperitoneal approach through a subcostal or dorsal lumbotomy incision. Laparoscopic donor nephrectomy (either trans- or retro-peritoneal) should only be performed by those trained in the procedure. Hand-assisted laparoscopic donor nephrectomy minimises warm ischaemia time compared to classic laparoscopic procedures.
Kidney recipient
Careful pre-operative work-up of all transplant candidates is mandatory to improve organ and patient survival in the posttransplant period. The work-up should be repeated regularly.
Recommendations for pre-transplant therapy

In the abnormal urogenital tract, meticulous pretransplant work up is necessary, with urodynamics being the key investigation. If pharmacological therapy or intermittent catheterisation fails or is impossible, urinary diversion is necessary using catheterisable pouches, conduits, or cystoplasties. Remove kidneys with autosomal-dominant polycystic kidney disease if there is insufficient space or complications (chronically infected kidneys, or kidneys with suspected tumour growth).
GR B/C
B/C
B/C
Other special considerations in a recipient
Recommendations
Active malignancy is a contraindication because immunosuppression may aggravate underlying malignancy jeopardising the patients life and graft outcome. The waiting period before transplantation in recipients with a history of malignancy depends on the type, TNM stage and grade of the tumour, age, and general health. Active infection may exacerbate after transplantation and may be life-threatening. Screen for viral and bacterial diseases in all transplant candidates including hepatitis B (HBV), hepatitis C (HCV), human immunodeficiency virus (HIV), cytomegalovirus (CMV), and tuberculosis (TB). Routine screening examination of all patients in all subspecialties is not necessary. However, a patient with history and symptoms suspicious for an underlying active infection should be seen by the appropriate specialist (e.g. ear, nose, and throat specialist; dentist; dermatologist; urologist and/or gynaecologist) to firmly rule out infectious foci. Re-evaluation of non-compliance (and serious morbidity) may be appropriate.
GR B
The pre-transplant work-up should focus on looking for cardiac disease. The work-up should be extensive in patients at high risk of cardiac disease to firmly rule out coronary artery disease. Perform any revascularisation before transplantation. Peripheral artery disease is common in uraemic patients. Special attention should be paid to iliacal, peripheral, and cerebrovascular disease using appropriate diagnostic and therapeutic measures. Patients with diabetes mellitus should be transplanted. They require an extensive pre-transplant work-up. Obesity itself is not a contraindication for transplantation. A thorough pre-transplant evaluation and attempt to reduce weight are recommended. Patients at risk of coagulopathies should be carefully evaluated to prevent early post-transplant thrombotic events. Diseases that might influence post-transplant course (e.g. diverticulosis, cholecystolithiasis, hyperparathyroidism) should be identified during pre-transplant work-up and if possible treated before transplantation. Age itself is not a contraindication, but the recipient must undergo a thorough pre-transplant evaluation and risk-benefit assessment and be counselled about the increased risks associated with age.
B C
C Recurrence of the original renal disease is common, though graft loss due to recurrence is not. Only a few rare diseases with a high recurrence rate leading to early graft loss are contraindications for transplantation. Patients at risk of recurrent disease should be counselled especially before living related-donor transplantation.
Matching of donors and recipients Recommendations
GR Determine ABO blood group and HLA-A, -B, and -DR B phenotypes of all candidates awaiting transplantation. To avoid hyper-acute rejection (HAR), cross-matching B must be performed before transplantation.
Kidneys from deceased donors should be allocated to recipients with the lowest number of HLA mismatches. Falsepositive results for cross-matching may occur especially in autoimmune diseases. Potential recipients with a high percentage of panel-reactive antibodies (%PRA) can be further analysed to ensure a negative cross-match. ABO blood group matching prevents HAR, but technical advances have resulted in successful ABO-incompatible transplantation.
Immunosuppression after kidney transplantation

The current standard initial immunosuppression provides excellent efficacy with good tolerability: calcineurin inhibitor (CNI; cyclosporine or tacrolimus) + mycophenolate (mycophenolate mofetil [MMF] or enteric-coated mycophenolate sodium [EC-MPS]) + corticosteroid (prednisolone or methylprednisolone). Induction therapy may also be given. 372 Renal Transplantation
Recommendations for immunosuppressive therapy GR

Rejection prophylaxis using CNIs remains current best practice. Choice of CNI (cyclosporine or tacrolimus) depends on immunological risk, recipient characteristics, concomitant immunosuppression, and socio-economic factors. Blood-level monitoring of both cyclosporine and tacrolimus is mandatory to prevent under-immunosuppression (increased risk of rejection) and excessively high blood levels (increased risk of chronic sideeffects, particularly nephrotoxicity). Mycophenolates are the current standard of care. The standard dose of MMF combined with cyclosporine is 1 g twice daily or EC-MPS 720 mg twice daily. Combination therapy of Mycophenolates with tacrolimus is not formally approved. Optimal mycophenolate (MPA) dosing is unclear, as tacrolimustreated patients have a higher MPA exposure than cyclosporine-treated patients. The standard starting dose of MMF combined with tacrolimus is MMF 1 g twice daily or EC-MPS 720 mg twice daily. This dosage is often dose-reduced with 30-50% lower doses at 1 year. MPA monitoring cannot be recommended for all patients due to limited evidence of benefit. Azathioprine may be used in a low-risk population for initial immunosuppression, especially in patients intolerant to MPA formulations. A A
A A
Initial steroid therapy remains the standard of care in perioperative and early postoperative period. In order to reduce steroid associated side effects, steroids may be stopped in most patients after 3-12 months on combination therapy with CNI and MPA.
A A
Recommendations for other immunosuppressive therapies

mTOR inhibitors (sirolimus, everolimus) Acute rejection can be effectively prevented by inhibitors of the mammalian target of rapamycin (mTOR) (sirolimus, everolimus) combined with CNIs. Reduce CNI dosage to avoid aggravated nephrotoxicity. Initial CNI-free combination therapy of mTOR inhibitors with MPA and steroids is not sufficient to prevent acute rejection compared to a standard regimen. Prophylactic surgical measures must be used when mTOR inhibitors are given in the perioperative period because of impaired wound healing. mTOR inhibitors are an alternative to CNIs if there are severe CNI-related side-effects. Blood levels of sirolimus and everolimus must be regularly monitored. T-cell depleting induction therapy Potential life-threatening side-effects include a higher incidence of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative disease. T-cell depleting therapy has not resulted in improved outcomes overall. 374 Renal Transplantation GR A
A A
T-cell depleting therapy should not be routinely used B in a low-risk first-transplant recipient. Patients must be informed of the increased risks of B infection and cancer. Interleukin-2 receptor antibodies (IL-2R) They reduce the rate of acute rejection, enabling CNI- A and steroid-sparing regimens.
Complications
Hyper-acute rejection (HAR) is rare and usually occurs within minutes or hours of vascularisation, although it may occur up to 1 week post transplant. It is cured by graft removal. Acute allograft rejection can be classified into acute cellular rejection (ACR, T-cell mediated) or acute humoral rejection (AHR, antibody-mediated). Test patients with ACR immediately for HLA IgG antibodies reactive with the graft. Steroid bolus therapy is recommended as initial treatment. In severe, or steroid-resistant, rejection, consider intensified immunosuppression, including high-dose steroid treatment, conversion to tacrolimus, and T-cell depleting agents. Treatment of AHR may include steroid bolus therapy, conversion to tacrolimus, antibody elimination and intravenous immunoglobulin treatment. Anti-CD20 (rituximab) or T-cell depleting agents may be efficacious. Chronic allograft dysfunction may take months or years to develop. Perform a renal biopsy and determine donor-specific alloantibodies if changes develop during follow-up monitoring of serum creatinine, creatinine clearance, blood pressure, blood lipids, and urinary protein excretion. If IF/TA is conRenal Transplantation 375
firmed, begin appropriate medical treatment, e.g. control of hypertension. Consider conversion to an mTOR inhibitor in patients under current CNI therapy and/or with histological signs suggesting CNI toxicity without significant proteinuria (< 800 mg/day). Alternatives are substantial CNI reduction under MPA protection or, in chronic maintenance patients, CNI withdrawal under MPA and steroids. Post-transplantation cancer is a common long-term cause of death. Most malignancy affects the skin (40%) or lymphatic system (11%). Closely monitor young recipients and patients who have received T-cell depleting agents. Annual screening for cancer and co-morbidity is mandatory.
Annual screening
Lifelong regular post-transplant follow-up by an experienced and trained transplant specialist is strongly recommended at least every 6-12 months. Monitoring of renal function and immunosuppression and side-effects by a physician, every 4-8 weeks is strongly advised.
GUIDELINES ON PAEDIATRIC UROLOGY

(Limited text update February 2012)
S. Tekgl (co-chairman), H. Riedmiller (co-chairman), H.S. Dogan, P. Hoebeke, R. Kocvara, J.M. Nijman (vice-chairman), Chr. Radmayr, R. Stein
Introduction
Due to the scope of the extended Guidelines on Paediatric Urology, no attempt has been made to include all topics, but rather to provide a selection based on practical considerations.
PHIMOSIS Background
At the end of the first year of life, retraction of the foreskin behind the glanular sulcus is possible in only about 50% of boys. The phimosis is either primary (physiological) with no sign of scarring, or secondary (pathological), resulting from scarring due to conditions such as balanitis xerotica obliterans. Phimosis must be distinguished from normal agglutination of the foreskin to the glans, which is a physiological phenomenon. If the tip remains narrow and glanular adhesions were separated, then the space is filled with urine during voiding, causing the foreskin to balloon outward. Paediatric Urology 377
Treatment
Treatment of phimosis in children is dependent on the parents preferences, and can be plastic or radical circumcision after completion of the second year of life. Plastic circumcision (dorsal incision, partial circumcision) carries the potential for recurrence of the phimosis. Associated frenulum breve is corrected by frenulotomy. Meatoplasty is added if necessary. Childhood circumcision should not be recommended without a medical reason. Circumcision: indication and contraindication An absolute indication for circumcision is secondary phimosis. The indications for early surgery in primary phimosis are recurrent balanoposthitis, and recurrent urinary tract infections in patients with urinary tract abnormalities. Routine neonatal circumcision to prevent penile carcinoma is not indicated. Contraindications for circumcision are coagulopathy, an acute local infection and congenital anomalies of the penis, particularly hypospadias or buried penis, because the foreskin may be required for a reconstructive procedure. Conservative treatment As a conservative treatment option of the primary phimosis, a corticoid ointment or cream (0.05-0.10%) can be administered twice a day over a period of 20-30 days. This treatment has no side-effects. Agglutination of the foreskin does not respond to steroid treatment.
378 Paediatric Urology
Paraphimosis Paraphimosis must be regarded as an emergency situation. It is characterised by retracted foreskin with the constrictive ring localised at the level of the sulcus. Treatment of paraphimosis consists of manual compression of the oedematous tissue with a subsequent attempt to retract the tightened foreskin over the glans penis. A dorsal incision of the constrictive ring may be required, or circumcision is carried out immediately or in a second session.
CRYPTORCHIDISM
Cryptorchidism is a very common congenital anomaly affecting nearly 1% of full-term male infants. Clinical management is determined by classification into palpable and non-palpable testes. Retractile testes have completed their descent, but may be retained in the groin by a strong cremasteric reflex, and require only observation. Bilateral, non-palpable testes with any suggestion of sexual differentiation problems require urgent endocrinological and genetic evaluation (LE: 3; GR: B). Physical examination is the only method of differentiating palpable and non-palpable testes. There is no benefit from ultrasound (US), computed tomography (CT), magnetic resonance imaging (MRI) or angiography. Diagnostic laparoscopy is the only reliable examination to confirm or exclude an intra-abdominal, inguinal and absent/vanishing testis (non-palpable testis) (LE: 1b; GR: A). Before trying laparoscopy, examination under general anaesthesia should be carried out because some, originally non-palpable, testes are palpable under anaesthesia. Paediatric Urology 379
Treatment
Medical therapy To prevent histological deterioration, medical or surgical treatment should be carried out and finished before 12-18 months of age. Medical therapy (human chorionic gonadotrophin or gonadotrophin-releasing hormone) is not recommended for descending the testis as it may produce testicular descent in only up to 20% of cases. There is some evidence that this may improve future fertility; yet there is no long term data. Surgery Surgery differs for palpable or non-palpable testes. Orchidopexy (inguinal approach) is used for palpable testis (up to 92% success). Inguinal surgical exploration should be attempted for non-palpable testes and the abdomen should be searched laparoscopically, if, rarely, there are no vessels or vas deferens in the groin. Laparoscopy can be used for testis removal or orchidolysis and orchiopexy. Remove an intra-abdominal testis in a boy > 10 years with a normal contralateral testis. A one-stage or two-stage Fowler-Stephens procedure can be performed in a bilateral intra-abdominal testes or in a boy < 10 years. Microvascular auto-transplantation has a 90% testicular survival rate, but requires very skilful and experienced surgical techniques.
Prognosis
Boys with one undescended testis have a lower fertility rate, but the same paternity rate as boys with bilateral descended testes. Boys with an undescended testis are 20 times more 380 Paediatric Urology
likely to develop testicular malignancy, independent of treatment choice. Early orchiopexy may reduce the risk of testicular cancer and surgical orchidolysis and orchidopexy should therefore be performed by 12-18 months of age.
HYDROCELE Background
Incomplete obliteration of the processus vaginalis peritonei results in formation of various types of communicating hydrocele, alone or connected with other intrascrotal pathology (hernia). Non-communicating hydroceles are found secondary to minor trauma, testicular torsion, epididymitis, or varicocele operation, or may appear as a recurrence after primary repair of a communicating hydrocele. A communicating hydrocele vacillates in size, usually relative to activity. It is diagnosed by medical history and physical investigation, the swelling is translucent, and transillumination of the scrotum makes the diagnosis. If there are any doubts about the intrascrotal mass, ultrasound should be performed. Contralateral disease should be excluded.
Treatment (Surgery)
Surgical treatment of hydrocele is not indicated within the first 12-24 months because of the tendency for spontaneous resolution. Early surgery is indicated if there is suspicion of a concomitant inguinal hernia or underlying testicular pathology. There is no evidence that this type of hydrocele risks Paediatric Urology 381
testicular damage. In the paediatric age group, the operation consists of ligation of the patent processus vaginalis via an inguinal incision, leaving the distal stump open, whereas in hydrocele of the cord, the cystic mass is excised or unroofed. Sclerosing agents should not be used because of the risk of chemical peritonitis in the communicating processus vaginalis peritonei. The scrotal approach (Lord or Jaboulay technique) is used in the treatment of a secondary non-communicating hydrocele.
HYPOSPADIAS Background
Hypospadias are usually classified according to the anatomical location of the proximally displaced urethral orifice: distal - anterior hypospadias (glanular, coronal or distal penile); intermediate - middle (penile); proximal - posterior (penoscrotal, scrotal, perineal). The pathology may be much more severe after skin release.
Assessment
Patients with hypospadias should be diagnosed at birth. The diagnostic evaluation also includes an assessment of associated anomalies, which are cryptorchidism and open processus vaginalis or inguinal hernia. Severe hypospadias with unilaterally or bilaterally impalpable testis, or with ambiguous genitalia, require a complete genetic and endocrine work-up immediately after birth to exclude intersexuality, especially congenital adrenal hyperplasia. 382 Paediatric Urology
Trickling urine and ballooning of the urethra require exclusion of meatal stenosis. The length of the hypospadiac penis may be distorted by penile curvature, by penoscrotal transposition, or may be smaller due to hypogonadism. Differentiation between functionally necessary and aesthetically feasible operative procedures is important for therapeutic decision-making. As all surgical procedures carry the risk of complications, thorough pre-operative counselling of the parents is crucial. The therapeutic objectives are to correct the penile curvature, to form a neo-urethra of an adequate size, to bring the neomeatus to the tip of the glans, if possible, and to achieve an overall acceptable cosmetic appearance. This goal is achieved by using different surgical techniques according to the individual findings.
Surgery
The age at surgery for primary hypospadias repair is usually 6-18 months. For repeat hypospadias repairs, no definitive guidelines can be given.
Outcome
Excellent long-term functional and cosmetic results can be achieved after repair of anterior penile hypospadias. The complication rate in proximal hypospadias repair is higher. Figure 1 gives an algorithm for the management of hypospadias. Paediatric Urology 383
Figure 1: Algorithm for the management of hypospadias

Hypospadias
Diagnosis at birth
Intersex
Paediatric urologist
No reconstruction
Reconstruction required
Preparation (foreskin, hormone therapy)
Distal
Proximal
Chordee
No chordee
Urethral plate cut
Urethral plate preserved
TIP, Mathieu, MAGPI, King, advancement, etc.
Tube-onlay, inlay-onlay, Koyanagi, two-stage procedure (local skin, bucal mucosa)
Onlay, TIP, two-stage procedure (local skin, buccal mucosa)
TIP = tubularised incised plate; MAGPI = meatal advancement and glanuloplasty technique. 384 Paediatric Urology
MICROPENIS
Micropenis is defined as a small but otherwise normally formed penis with a stretched length of less than 2.5 cm SD below the mean (Table 1).
Table 1: Length of the penis in boys

(according to Feldmann and Smith) Age Newborns 0-5 months 6-12 months 1-2 y 2-3 y 3-4 y 4-5 y 5-6 y 6-7 y 7-8 y 8-9 y 9-10 y 10-11 y Adults Mean SD (cm) 3.5 0.4 3.9 0.8 4.3 0.8 4.7 0.8 5.1 0.9 5.5 0.9 5.7 0.9 6.0 0.9 6.1 0.9 6.2 1.0 6.3 1.0 6.3 1.0 6.4 1.1 13.3 1.6
VARICOCELE IN CHILDREN AND ADOLESCENTS Background

Varicocele is unusual in boys under 10 years of age, but becomes more frequent at the beginning of puberty. Fertility problems will arise in about 20% of adolescents with varicocele. The adverse influence of varicocele increases with time. Paediatric Urology 385
Testicular catch-up growth and improvement in sperm parameters after varicocelectomy has been reported in adolescents. Varicocele is mostly asymptomatic, rarely causing pain at this age. It may be noticed by the patient or parents, or discovered by the paediatrician at a routine visit. Diagnosis and classification depends upon the clinical finding and ultrasound investigation.
Treatment (Surgery)
Surgical intervention is based on ligation or occlusion of the internal spermatic veins. Microsurgical lymphatic-sparing repair (microscopic or laparoscopic) are associated with the lowest recurrence and complication rates. There is no evidence that treatment of varicocele at paediatric age will offer a better andrological outcome than an operation performed later. Follow-up During adolescence, testicular size should be checked annually. After adolescence, repeated sperm analysis is to be recommended. Figure 2 shows an algorithm for the diagnosis of varicocele in children and adolescents, and Figure 3 shows an algorithm for its treatment.
Figure 2: Algorithm for the diagnosis of varicocele in children and adolescents

Varicocele in children and adolescents Physical examination in the upright position Grade I - Valsalva positive Grade II - palpable Grade III - visible
Ultrasound investigation Venous reflux detected on Doppler ultrasound Size of the testes
Figure 3: Algorithm for the treatment of varicocele in children and adolescents

Varicocele in children and adolescents
Surgery: indication type Small testis (growth arrest) Additional testicular pathology Bilateral palpable varicocele Pathological spermiogram Symptomatic varicocele Microsurgical lymphaticsparing repair (microscopic or laparoscopic)
Conservative treatment: indication follow-up
Symmetrical testes Normal spermiogram (in older adolescents)
Measurement of testicular size (during adolescence) Repeated sperm analysis (after adolescence)
Paediatric Urology 387
MONOSYMPTOMATIC NOCTURNAL ENURESIS Background

Enuresis is incontinence during the night. Any wetting during sleep above the age of five years is enuresis. It is important to note that there is a single symptom only. Due to an imbalance between night-time urine output and night-time bladder capacity, the bladder can easily become full at night, and the child will either wake up to empty the bladder or will void during sleep.
Assessment
A voiding diary, registering the daytime bladder function and the night-time urine output will help guide the treatment. Measuring the daytime bladder capacity gives an estimate of bladder capacity to compare with normal values for age. Figure 4 gives an algorithm for the diagnosis and treatment of monosymptomatic nocturnal enuresis.
Figure 4: Algorithm for the diagnosis and treatment of monosymptomatic nocturnal enuresis
Nocturnal enuresis Initial assessment
Monosymptomatic Nocturnal enuresis Education Supportive therapy Alarm or desmopressin
Voiding diary or direct questioning

Voiding habits Wetting episodes Bowel function
Urinalysis
Daytime wetting Urge syndrome Lower tract dysfunction Infection Other
still wet
Uroflowmetry, urine V, Osm * Check for night time polyuria investigate for sleep disorders Overactivity of the bladder Urotherapy, Ab, Ach, ** Biofeedback
Consider longer use of desmopression Combination therapies Imipramine
Vesicouretereric reflux (VUR) in children

VUR present within a wide range of severity, and a majority of reflux patients will not develop renal scars and probably will not need any intervention. The main goal in management is the preservation of kidney function. Diagnosis The diagnostic work-up should evaluate the overall health and development of the child. A basic diagnostic work-up includes a detailed medical history (including family history, Paediatric Urology 389
and screening for lower urinary tract dysfunction [LUTD]), physical examination including blood pressure measurement, urinalysis (assessing proteinuria), urine culture, and serum creatinine in patients with bilateral renal parenchymal abnormalities. Infants presenting because of prenatally diagnosed hydronephrosis Ultrasound of the kidney and bladder is the first standard evaluation tool for children with prenatally diagnosed hydronephrosis. It should be delayed to the end of first week after birth because of early oliguria in the neonate. It is essential to evaluate the bladder, as well as the kidneys.
Recommendations for the use of VCUG in prenatal hydronephrosis

US findings of bilateral high-grade hydronephrosis, duplex kidneys, ureterocele, ureteric dilatation, and abnormal bladders, because the likelihood of VUR is much higher. In all other conditions, the use of VCUG to detect reflux is optional. When cases identified by prenatal US become symptomatic with UTIs, further evaluation with VCUG should be considered.
Recommendations for paediatric screening of VUR

The parents of children with VUR should be informed that siblings and offspring have a high prevalence of VUR. If screening is performed, siblings should be screened by renal US. VCUG is recommended if there is evidence of renal scarring on US or a history of UTI. 390 Paediatric Urology
In older children who are toilet-trained, there is no added value in screening for VUR. UTI = urinary tract infecting; VCUG = voiding cystourethrography. Conservative therapy The objective of conservative therapy is prevention of febrile UTI. It is based on the understanding that: VUR resolves spontaneously, mostly in young patients with low-grade reflux. However, spontaneous resolution is low for bilateral high-grade reflux). VUR does not damage the kidney when patients are free of infection and have normal lower urinary tract function. There is no evidence that small scars can cause hypertension, renal insufficiency or problems during pregnancy. The conservative approach includes watchful waiting, intermittent or continuous antibiotic prophylaxis, and bladder rehabilitation in those with LUTD. Circumcision during early infancy may be considered as part of the conservative approach, because it is effective in reducing the risk of infection in normal children. Surgical treatment Surgical treatment comprises endoscopic injection of bulking agents or ureteral reimplantation. Subureteric infection of bulking agents: due to the availability of biodegradable substances, endoscopic subureteric injection of bulking agents has become an alternative to long-term antibiotic prophylaxis and surgical intervention. Paediatric Urology 391
Open surgical techniques: Overall, all surgical procedures offer very high and similar success rates for correcting VUR. Laparoscopy: a laparoscopic approach cannot be recommended as a routine procedure. It can be offered as an alternative to the parents in centres where there is enough experience.
Recommendations for the management of VUR in childhood

Regardless of the grade of reflux or presence of renal scars, all patients diagnosed within the first year of life should be treated initially with CAP. During early childhood, the kidneys are at higher risk of developing new scars. Immediate, parenteral antibiotic treatment should be initiated for febrile breakthrough infections. Definitive surgical or endoscopic correction is the preferred treatment in patients with frequent breakthrough infections. Surgical correction should be considered in patients with persistent high-grade reflux (grades IV/V). There is no consensus about the timing and type of surgical correction. The outcome of open surgical correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results can be achieved by endoscopic injection for lower grades. There is no evidence that correction of persistent low-grade reflux (grades IIII) without symptoms and normal kidneys offers a significant benefit. These patients may be candidates for endoscopic treatment.
In all children presenting at age 15 years, CAP is the preferred option for initial therapy. For those with high-grade reflux or abnormal renal parenchyma, surgical repair is a reasonable alternative. In patients with lower grades of reflux and without symptoms, close surveillance without antibiotic prophylaxis may be an option. A detailed investigation for the presence of LUTD should be performed in all children after toilet-training. If LUTD is found, the initial treatment should always be for LUTD. If parents prefer definitive therapy to conservative management, surgical correction may be considered. Endoscopic treatment is an option for all children with low grades of reflux. The traditional approach of initial medical treatment after diagnosis and shifting to interventional treatment in case of breakthrough infections and new scar formation needs to be challenged, because the treatment should be tailored to different risk groups. The choice of management depends on the presence of renal scars, clinical course, grade of reflux, ipsilateral renal function, bilaterality, bladder function, associated anomalies of the urinary tract, age, compliance, and parental preference (79). Febrile UTI, high-grade reflux, bilaterality, and cortical abnormalities are considered to be risk factors for possible renal damage. The presence of LUTD is an additional risk factor for new scars. In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed. CAP = continuous antibiotic prophylaxis.
This short text is based on the more comprehensive EAU/ESPU Paediatric Urology Guidelines (ISBN 978-90-79754-83-0), available at their website, http://www.uroweb.org.
Table 2: Management and follow-up according to different risk groups

Risk Groups High Presentation Symptomatic male or female patients after toilet-training with high-grade reflux (grades IV/V), abnormal kidneys and LUTD Initial treatment Initial treatment is always for LUTD; intervention may be considered in cases of recurrent febrile infections or persistent reflux Intervention should be considered
CAP is the initial treatment. Intervention may be considered in cases of breakthrough infections or persistent reflux Moderate Asymptomatic patients CAP is the initial treat(PNH or sibling) with ment. Intervention high-grade reflux and may be considered in cases of breakthrough abnormal kidneys infections or persistent reflux
Symptomatic male or female patients after toilet-training with high-grade reflux (grade IV/V), abnormal kidneys and no LUTD Moderate Symptomatic male or female patients before toilet-training, with high-grade reflux and abnormal kidneys
High
Follow-up Greater possibility of earlier intervention More aggressive follow-up for UTI and LUTD; full reevaluation after 6 months
Open surgery has better results Postoperative VCUG on than endoscopic surgery indication only; follow-up of kidney status until after puberty
Spontaneous resolution is higher in males
Follow-up for UTI/hydronephrosis; full re-evaluation after 1224 months
Follow-up for UTI/hydronephrosis; full re-evaluation after 1224 months
Initial treatment is always for LUTD. Intervention may be considered in cases of breakthrough infections or persistent reflux Choice of treatment Moderate Symptomatic male or is controversial. female patients after Endoscopic treatment toilet-training with may be an option. low-grade reflux, abnormal kidneys with LUTD treatment should be given if or without LUTD needed. Initial treatment is Moderate All symptomatic always for LUTD patients with normal kidneys, with lowgrade reflux, with LUTD No treatment or CAP Low All symptomatic patients with normal kidneys, with lowgrade reflux, with no LUTD No treatment or CAP Low All asymptomatic in infants patients with normal kidneys with low-grade reflux Moderate Symptomatic male or female patients after toilet-training, with high-grade reflux and normal kidneys with LUTD PNH = prenatal diagnosed hydronephrosis.
In case of persistent LUTD, despite urotherapy, intervention should be considered. The choice of intervention is controversial
Follow-up for UTI and LUTD, kidney status; full re-evaluation after successful urotherapy
Follow-up for UTI, LUTD, and kidney status until after puberty
Follow-up for UTI and LUTD
If no treatment is given, parents should be informed about risk of infection
Follow-up for UTI
If no treatment is given, parents should be informed about risk of infection
Follow-up for UTI
Disclaimer The European Association of Urology (EAU) Clinical Guidelines published by the EAU Guidelines Office are systematically developed evidence statements incorporating data from a comprehensive literature review of the most recent studies available (up to their publication date). The aim of clinical guidelines is to help clinicians to make informed decisions about their patients. However, adherence to a guideline does not guarantee a successful outcome. Ultimately, healthcare professionals must make their own treatment decisions about care on a case-bycase basis, after consultation with their patients, using their clinical judgement, knowledge and expertise. A guideline is not intended to take the place of physician judgment in diagnosing and treatment of particular patients. Guidelines may not be complete or accurate. The EAU and their Guidelines Office, and members of their boards, officers and employees disclaim all liability for the accuracy or completeness of a guideline, and disclaim all warranties, express or implied to their incorrect use. Guidelines users always are urged to seek out newer information that might impact the diagnostic and treatment recommendations contained within a guideline. Due to their unique nature as international guidelines, the EAU Guidelines are not embedded within one distinct healthcare setting - variations in clinical settings, resources, or common patient characteristics, are not accounted for.
399
400
These Guidelines are edited for the EAU Guidelines Office ISBN-13: 978-90-79754-99-1 Cover image: courtesy of Gunnar Aus - Sweden. Printed by: Drukkerij Gelderland bv, Arnhem - the Netherlands. Copyright European Association of Urology 2012 No part of this publication may be reproduced, stored in a retrieval system, or transmitted by any means, electronic, mechanical or photocopying without written permission from the copyright holder.

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Table 1: Level of evidence*

Table 2: Grade of recommendation*

GUIDELINES ON NON-MUSCLEINVASIVE BLADDER CANCER

Table 1: TNM classification 2009 for urinary bladder

Non-muscle-invasive Bladder Cancer

M - Distant Metastasis MX Metastasis not assessed M0 No distant metastasis M1 Distant metastasis

Characteristics of stages Ta, T1, and CIS

Table 2: 2004 WHO classification of non-invasive urothelial neoplasia

Diagnosis and initial treatment steps

Prognostic factors and adjuvant treatment

Recommendations for low risk tumours

Recommendations for high risk tumours

Non-muscle-invasive Bladder Cancer

Recommendations for intermediate risk tumours

Table 3: Calculation of recurrence and progression scores

Non-muscle-invasive Bladder Cancer

Table 4: Probability of recurrence and progression according to total score

16 Non-muscle-invasive Bladder Cancer

Recommendations for the treatment of CIS

Non-muscle-invasive Bladder Cancer

Follow-up for non-muscle-invasive bladder tumours

Recommendations for follow-up cystoscopy

Non-muscle-invasive Bladder Cancer

20 Non-muscle-invasive Bladder Cancer

GUIDELINES ON UPPER URINARY TRACT UROTHELIAL CELL CARCINOMAS

Upper Urinary Tract Urothelial Cell Carcinomas

Table 1: TNM classification 2009 for renal pelvis and ureter*

22 Upper Urinary Tract Urothelial Cell Carcinomas

Recommendations for diagnosis of UUT-UCC

Recommendations for radical management of UUT-UCC: RNU

Recommendations for conservative management of UUT-UCC

26 Upper Urinary Tract Urothelial Cell Carcinomas

Recommendations for follow-up of UUT-UCC patients after initial treatment

Upper Urinary Tract Urothelial Cell Carcinomas 27

28 Upper Urinary Tract Urothelial Cell Carcinomas

Figure 1: Proposed flowchart for the management of UUTUCC

Diagnostics evaluation: CT-urography, urinary cytology, cystoscopy ( ureteroscopy with biopsies)

- Unifocal tumour - Size < 1 cm - Low-grade tumour - Superficial aspect on MDCTU

Gold standard treatment: Radical nephroureterectomy

MDCT = multidetector computed tomography.

Upper Urinary Tract Urothelial Cell Carcinomas 29

MUSCLE-INVASIVE AND METASTATIC BLADDER CANCER

30 Muscle-invasive and Metastatic Bladder Cancer

Table 1: 2009 TNM classification of urinary bladder cancer

Table 2: WHO grading 1973 and 2004

32 Muscle-invasive and Metastatic Bladder Cancer

Muscle-invasive and Metastatic Bladder Cancer 33

Recommendations for staging of verified bladder GR tumour

34 Muscle-invasive and Metastatic Bladder Cancer

Muscle-invasive bladder cancer - standard treatment

Muscle-invasive and Metastatic Bladder Cancer 35

Recommendations for radical cystectomy

36 Muscle-invasive and Metastatic Bladder Cancer

Neoadjuvant/adjuvant radiotherapy in muscle-invasive bladder cancer Conclusions

38 Muscle-invasive and Metastatic Bladder Cancer

Findings: pT2-3, clinical N0M0 urothelial carcinoma of the bladder

2 - neoadjuvant radiotherapy is not recommended

Direct adjuvant chemotherapy Not indicated after cystectomy

Bladder-sparing treatments for localised disease

Muscle-invasive and Metastatic Bladder Cancer 39

Surgically non-curable tumours