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European Association of Urology

EAU
PO Box 30016
6803 AA Arnhem
The Netherlands

Pocket Guidelines
2014
edition

European
Association
of Urology

Pocket Guidelines
2014 edition

European
Association
of Urology

Pocket Guidelines
2014 edition

Introduction
This 10th edition of the pocket guidelines includes many
changes and each text will list the year of update, which
should help the readers identify the2014 changes. These short
texts are an easy reference tool, but clinicians should also
consult the full text guidelines documents upon which they
are based, because the abbreviated information shows only a
fraction of the work done by the many experts involved in the
EAU guidelines panels.

Guidelines aim to help improve clinical practice and the EAU


Guidelines Office recognize that currency of the information provided is a key element and this is only relevant when
underpinned by a transparent production methodology. In
this respect, the Guidelines Office has progressed, under the
guidance of the Board and with the assistance of a growing
group of experts from related disciplines. The future will certainly hold further challenges and one will be to seek assistance from a forum of more diverse stakeholders. We also aim
to continue to upgrade production methodology; to assess
the impact of these documents on every-day practice; and to
enhance the use of IT to disseminate material withan iPhone
and Android version of the Pocket Guidelines now available.

Ultimately, the success and longevityof the EAU Guidelines


will be determined by the trust our readers have in themand
the Guidelines Office will do their utmost to meet their expectations. We listen to feedback and suggestions from our readers and always welcome any comments.

Introduction

This publication would not have been possible without the


valuable contributions of so many dedicated panel members,
and we wish to give a special Thank You to them all.

On behalf of the Guidelines Office Board,

Mr. K.F. Parsons


Chairman EAU Guidelines Office

EAU Guidelines Office Board members


Prof.Dr. J. Irani (vice-chair)
Prof.Dr. M. Fall
Prof Dr. C. Llorente Abarca
Prof.Dr. T. Loch
Prof.Dr. J. NDow
Prof.Dr. R. Sylvester
Prof.Dr. H. Van Poppel (ex-officio)

Introduction

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 (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
studies cannot be performed, perhaps for ethical or other
reasons and in this case unequivocal recommendations are
Introduction

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 (1).

References

1. 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 February 2013]

http://www.cebm.net/index.aspx?o=1025
2. 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
3. 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
4. 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

Introduction

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Non-muscle Invasive Bladder Cancer


Urothelial Carcinomas Of The Upper Urinary Tract
Muscle-invasive and Metastatic Bladder Cancer
Prostate Cancer
Renal CellCarcinoma
Penile Cancer
Testicular Cancer
Non-neurogenic Male LUTS,

incl. benign prostatic obstruction (BPO)

Male Sexual Dysfunction:

Erectile Dysfunction and Premature Ejaculation

Priapism
Penile Curvature
Male Infertility
Male Hypogonadism
Urinary Incontinence
Urological Infections
Neuro-Urology
Urological Trauma
Pain Management & Palliative Care
Chronic Pelvic Pain
Urolithiasis
Renal Transplantation
Paediatric Urology
5

GUIDELINES ON NON-MUSCLE
INVASIVE (Ta, T1, CIS) BLADDER
CANCER
(Text update April 2014)

M. Babjuk (chair), A. Bhle, M. Burger, E. Comprat, E. Kaasinen,


J. Palou, B.W.G. van Rhijn, M. Rouprt, S. Shariat, R. Sylvester,
R. Zigeuner

Eur Urol 2011 Apr;59(4):584-94


Eur Urol 2013 Oct;64(4):639-53

Introduction

The EAU Working Group has published guidelines on nonmuscle invasive bladder cancer (NMIBC). It comprises Ta and
T1 tumours as well as carcinoma in situ (CIS) according to the
TNM Classification of Malignant Tumours, 7th Edition, 2009
(Table 1).

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

Table 1: TNM Classification 2009


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
T2
Tumour invades muscle
T2a
Tumour invades superficial muscle
(inner half)
T2b
Tumour invades deep muscle (outer half)
T3
Tumour invades perivesical tissue:
T3a
Microscopically
T3b
Macroscopically (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
N0
No regional lymph node metastasis
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)
N3
Metastasis in a common iliac lymph node(s)
M - Distant Metastasis
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

CIS is classified into following clinical types:


Primary: isolated CIS with no previous or concurrent papillary tumours and no previous CIS;
Secondary: CIS detected during follow-up of patients with
a previous tumour that was not CIS;
Concurrent: CIS in the presence of any other urothelial
tumour in the bladder;
Recurrent: Repeat occurrence of isolated CIS after initial
successful response to intravesical treatment.
Currently two grading systems for NMIBC, WHO 1973 and
WHO 2004, are available (Table 2). The majority of clinical trials
published so far on NMIBC have been performed using the
1973 WHO classification, and therefore the guidelines recommendations are based on the 1973 WHO grade classification.

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

Table 2: WHO grading in 1973 and in 2004


1973 WHO grading
Urothelial papilloma
Grade 1: well differentiated
Grade 2: moderately differentiated
Grade 3: poorly differentiated
2004 WHO grading
Flat lesions
Hyperplasia (flat lesion without atypia or papillary aspects)
Reactive atypia (flat lesion with atypia)
Atypia of unknown significance
Urothelial dysplasia
Urothelial CIS (always high-grade [HG])
Papillary lesions
Urothelial papilloma (completely benign lesion)
Papillary urothelial neoplasm of low malignant potential
(PUNLMP)
Low-grade (LG) papillary urothelial carcinoma
High-grade (HG) papillary urothelial carcinoma

Diagnosis and Initial Treatment Steps

The patient history should be taken, including all information


possibly associated with bladder cancer (BC).
Papillary (Ta, T1) tumours
The diagnosis of papillary BC ultimately depends on cystoscopic examination of the bladder and histological evaluation
of the resected tissue.
The standard initial therapy for Ta and T1 papillary bladder tumours is complete macroscopic transurethral resection (TURB), including a part of the underlying muscle. TURB
should be performed systematically in individual steps, which
10

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

are described in the full version of the guidelines. Small


tumours (< 1 cm) can be resected en bloc including a part of
the underlying muscle. Larger tumours should be resected
separately in fractions, which include the exophytic part of the
tumour, the underlying bladder wall with the detrusor muscle
and the edges of the resection area. The specimens from different fractions must be referred to the pathologist in separate
containers.
A second TURB 2-6 weeks after initial resection is recommended in the following situations:
After incomplete initial TURB, if there was no muscle in the
specimen after initial resection (with exception of Ta low
grade (G1) tumours);
In all T1 tumours and in all high grade (G3) tumours (except
primary CIS).
CIS
CIS is diagnosed by a combination of cystoscopy, urine cytology, and histological evaluation of multiple bladder biopsies.
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. If equipment is available,
photodynamic diagnosis (PDD) is a useful tool to target the
biopsy in these patients. Urine cytology is useful in the diagnosis and follow-up of CIS.
CIS cannot be eradicated by TURB and further treatment is
mandatory.

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

11

Guidelines for primary assessment of NMIBC


Patient history should be taken and recorded regarding all important information with a possible association with bladder cancer, including risk factors and
suspicious symptoms.
Renal and bladder US may be used during the initial
work-up in patients with haematuria.
At the time of the initial diagnosis of bladder cancer,
CT urography (or IVU) should be performed only in
selected cases (e.g., tumours located in the trigone).
Cystoscopy is recommended in all patients with
symptoms suggestive of bladder cancer. It cannot be
replaced by cytology or by any other non-invasive test.
Cystoscopy should describe all macroscopic features
of the tumour (site, size, number and appearance) and
mucosal abnormalities. A bladder diagram is recommended.
Voided urine cytology is advocated to predict highgrade tumour before TURB.
Cytology should be performed on fresh urine with adequate fixation. Morning urine is not suitable because
of the frequent presence of cytolysis.

12

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

GR
A

C
B

C
C

TURB
TURB should be performed systematically in individual
steps:
bimanual palpation under anaesthesia;
insertion of the resectoscope, under visual control
with inspection of the whole urethra;
inspection of the whole urothelial lining of the bladder;
biopsy from prostatic urethra (if indicated);
cold-cup bladder biopsies (if indicated);
resection of the tumour;
bimanual palpation after resection;
protocol formulation;
formulation of order form for pathological evaluation.
Perform resection in one piece for small papillary
tumours (< 1 cm), including part from the underlying
bladder wall.
Perform resection in fractions (including muscle tissue) for tumours > 1 cm in diameter.
Biopsies should be taken from abnormal-looking
urothelium. Biopsies from normal-looking mucosa
(trigone, bladder dome, and right, left, anterior and
posterior bladder walls) are recommended only when
cytology is positive or when exophytic tumour has a
non-papillary appearance.
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.

B
C

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

13

Biopsy of the prostatic urethra should be taken


from abnormal areas and from the precollicular area
(between 5 and 7 oclock position) using a resection
loop. In primary non-muscle-invasive tumours when
stromal invasion is not suspected, the cold-cup biopsy
with forceps can be used.
If equipment is available, fluorescence-guided (PDD)
biopsy should be performed instead of random biopsies when bladder CIS or high-grade tumour is suspected (e.g., positive cytology, recurrent tumour with
previous history of a high-grade lesion).
The specimens from different biopsies and resection
fractions must be referred to the pathologist in separate containers and labelled separately.
TURB protocol must describe all steps of the procedure, as well as the extent and completeness of resection.
A second TURB is recommended in the following
situations:
after incomplete initial TURB;
if there is no muscle in the specimen after initial
resection, with exception of Ta G1 tumours and
primary CIS;
in all T1 tumours;
in all G3 tumours, except primary CIS.
When done, a second TURB should be performed
within 2-6 weeks after initial resection.
Classification and pathological report
Depth of tumour invasion is classified according to the
TNM system.

14

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

For histological classification, 1973 and 2004 WHO


A
grading systems are used. Until the WHO 2004 is
validated by more prospective trials and incorporated
into prognostic models, both classifications should be
used.
Whenever the terminology NMIBC is used in individual A
cases, the tumour stage and grade should be mentioned.
The pathological report should specify tumour locaA
tion, tumour grade, depth of tumour invasion, presence of CIS, and whether the detrusor muscle is
present in the specimen.
The pathological report should specify the presence of C
LVI or unusual histology.
CIS = carcinoma in situ; CT = computed tomography; IVU =
intravenous urography; LVI = lymphovascular invasion;
PDD = photodynamic diagnosis; US = ultrasound; TURB =
transurethral resection of the bladder.

Prognostic Factors and Adjuvant Treatment

It is recommended to stratify patients according to prognostic


factors into three risk groups that will facilitate treatment
recommendations. Their definition, which takes into account
the EORTC risk tables probabilities of recurrence and especially progression, can be found in Table 3. For individual
prediction of the risk of tumour recurrence and progression at
different intervals after TURB, application of EORTC risk tables
and calculator (http://www.eortc.be/tools/bladdercalculator/)
is strongly recommended.

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

15

Table 3: Treatment recommendations in Ta, T1 tumours and


CIS according to risk stratification
Risk
Definition
Treatment
category
recommendation
Low-risk
Primary, solitary, Ta, LG/
One immediate
tumours
G1, < 3 cm, no CIS
instillation of
chemotherapy
Intermediate- All cases between catego- One immediate
risk tumours ries of low and high risk
instillation of
chemotherapy
followed by
further instillations, either
chemotherapy for
a maximum of 1
year or 1-year fulldose BCG
High-risk
Any of the following:
Intravesical fulltumours
T1 tumours;
dose BCG instilla HG/G3 tumours;
tions for 1-3 years
CIS;
or cystectomy
Multiple and recurrent
(in highest-risk
and large (> 3 cm) Ta
tumours)
G1G2 tumours (all these
conditions must be presented)

16

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

Subgroup of
highest-risk
tumours

T1G3 associated with


concurrent bladder CIS,
multiple and/or large
T1G3 and/or recurrent
T1G3, T1G3 with CIS
in prostatic urethra,
micropapillary variant of
urothelial carcinoma, LVI
BCG failures

Radical cystectomy should be


considered

Radical cystectomy is recommended


CIS = carcinoma in situ; HG = high-grade; LG = low-grade;
LVI = lymphovascular invasion.
Since there is considerable risk for recurrence and/or progression of tumours after TURB, adjuvant intravesical therapy is
recommended for all stages (Ta, T1, and CIS). Immediate postoperative instillation of chemotherapy within 6 hours after
TURB is recommended in tumours presumed to be at low or
intermediate risk, except in cases of bladder perforation or
severe bleeding. The choice of drug (mitomycin C, epirubicin,
or doxorubicine) is optional.
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. The individual choice
of further intravesical adjuvant therapy depends on the
patients risk (Table 3).
In patients at highest risk of progression (Table 3), radical
cystectomy should be considered in patients with BCG failure
Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

17

since they are unlikely to respond to further BCG therapy;


radical cystectomy is therefore the preferred option.
Recommendations for adjuvant therapy in Ta, T1
tumours and for therapy of CIS
Smokers with confirmed NMIBC should be counselled
to stop smoking.
The type of intravesical therapy should be based on
risk groups.
One immediate chemotherapy instillation is recommended in tumours presumed to be at low or intermediate risk.
In patients with low-risk tumours, one immediate
instillation of chemotherapy is recommended as the
complete adjuvant treatment.
In patients with intermediate-risk Ta tumours, one
immediate instillation of chemotherapy should be followed by 1-year full-dose BCG treatment, or by further
instillation of chemotherapy for a maximum of 1 year.
In patients with high-risk tumours, full-dose intravesical BCG for 1-3 years is indicated.
In patients with CIS in the epithelial lining of the prostatic urethra, TUR of the prostate followed by intravesical instillation of BCG can be offered.
In patients at highest risk of tumour progression (Table
3), immediate radical cystectomy should be considered.
In patients with BCG failure, radical cystectomy is
indicated.
In patients with BCG failure ineligible for radical cystectomy, gemcitabine or MMC in combination with
hyperthermia are options.

18

Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

GR
B
A
A

A
C

B
C

Intravesical chemotherapy
One immediate instillation should be administered
C
within 24 hours after TURB.
One immediate instillation of chemotherapy should
C
be omitted in any case of overt or suspected intra- or
extra-peritoneal perforation (after extensive TURB, or
bleeding requiring bladder irrigation).
The optimal schedule of further intravesical chemoC
therapy instillation and its duration is not defined and
should not exceed 1 year.
If intravesical chemotherapy is given, it is advised to
B
use the drug at its optimal pH and to maintain the
concentration of the drug during instillation by reducing fluid intake.
The length of individual instillation should be 1-2 hours. C
BCG intravesical immunotherapy
Absolute contraindications of BCG intravesical instil- C
lation are:
during the first 2 weeks after TURB;
in patients with macroscopic haematuria;
after traumatic catheterization;
in patients with symptomatic urinary tract infection.
The management of side effects after BCG intravesical C
instillation should reflect their type and grade.
BCG = bacillus Calmette-Gurin; CIS = carcinoma in situ;
MMC = mitomycin C; TUR = transurethral resection; TURB =
transurethral resection of the bladder.

Follow-up for Non-Muscle Invasive Bladder Tumours

As a result of the risk of recurrence and progression, patients


with Ta, T1 bladder tumours and with CIS need to be followed
up. However, the frequency and duration of cystoscopy and
imaging should reflect the individual patients degree of risk.
Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

19

When planning the follow-up schedule and methods, the following aspects should be considered:
The prompt detection of muscle-invasive and HG/G3 nonmuscle-invasive recurrence is crucial because a delay in
diagnosis and therapy can be life-threatening.
Tumour recurrence in the low-risk group is nearly always
low stage and LG/G1.
Small, non-invasive (Ta), LG/G1 papillary recurrence does
not present an immediate danger to the patient, and early
detection is not essential for successful therapy (LE: 2b).
Fulguration of small papillary recurrences on an outpatient
basis could be a safe option that reduces the therapeutic
burden.
The first cystoscopy after TURB at 3 months is a very
important prognostic indicator for recurrence and progression. The first cystoscopy should thus always be performed
3 months after TURB in all patients with Ta, T1 tumours and
CIS.
In tumours at low risk, the risk of recurrence after 5 recurrence-free years is low.
Discontinuation of cystoscopy or its replacement with lessinvasive methods can be considered.
In tumours originally intermediate- or high-risk, recurrences after 10 years tumour-free are not unusual. Therefore,
lifelong follow-up is recommended.
The risk of upper urinary tract recurrence increases in
patients with multiple and high-risk tumours.
Positive urine test results have a positive impact on the
quality of performed follow-up cystoscopy). It supports the
adjunctive role of urine tests during follow-up.
The following recommendations are only based on retrospective experience.

20 Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

Recommendations for follow-up


GR
The follow-up of Ta, T1 tumours and CIS is based on
A
regular cystoscopy.
Patients with low-risk tumours should undergo cystos- C
copy at 3 months. If negative, subsequent cystoscopy
is advised 9 months later, and then yearly for 5 years.
Patients with high-risk tumours should undergo
C
cystoscopy and urinary cytology at 3 months. If negative, subsequent cystoscopy and cytology should be
repeated every 3 months for a period of 2 years, and
every 6 months thereafter until 5 years, and then
yearly.
Patients with intermediate-risk Ta tumours should
C
have an in-between follow-up scheme using cystoscopy and cytology, which is adapted according to personal and subjective factors.
Regular (yearly) upper tract imaging (CT-IVU or IVU) is C
recommended for high-risk tumours.
Endoscopy under anaesthesia and bladder biopsies
B
should be performed when office cystoscopy shows
suspicious findings or if urinary cytology is positive.
During follow-up in patients with positive cytology and B
no visible tumour in the bladder, R-biopsies or biopsies
with PDD (if equipment is available) and investigation
of extravesical locations (CT urography, prostatic urethra biopsy) are recommended.
CIS = carcinoma in situ; CT-IVU = computed tomography intravenous urography; IVU = intravenous urography; PDD = photodynamic diagnosis; R-biopsies = random biopsies.
This short booklet text is based on the more comprehensive EAU
guidelines (ISBN 978-90-79754-65-5), available to all members of the
European Association of Urology at their website:,
http://www.uroweb.org.
Non-muscle invasive (Ta, T1, CIS) Bladder Cancer

21

GUIDELINES ON UROTHELIAL
CARCINOMAS OF THE UPPER
URINARY TRACT (UTUCs)
(Text update April 2014)

M. Rouprt, M. Babjuk, E. Comprat, R. Zigeuner, R. Sylvester,


M. Burger, A. Bhle, B.W.G. Van Rhijn, E. Kaasinen, J. Palou,
S.F. Shariat

Eur Urol 2011 Apr;59(4):584-94


Eur Urol 2013 Jun;63(6):1059-71

Introduction

UTUCs are uncommon and account for only 5-10% of urothelial cell carcinomas. They have a similar morphology to bladder
carcinomas and nearly all UTUCs are urothelial in origin.

22 Urothelial Carcinomas Of The Upper Urinary Tract

Classification
Table 1: TNM classification 2009 for renal pelvis and ureter
T - Primary Tumour
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Ta
Non-invasive papillary carcinoma
Tis
Carcinoma in situ
T1
Tumour invades subepithelial connective tissue
T2
Tumour invades muscularis
T3
(Renal pelvis) Tumour invades beyond muscularis
into peripelvic fat or renal parenchyma
(Ureter) Tumour invades beyond muscularis into
periureteric fat
T4
Tumour invades adjacent organs or through the
kidney into perinephric fat
N - Regional lymph Nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single lymph node 2 cm or less in the
greatest dimension
N2
Metastasis in a single lymph node more than 2 cm
but not more than 5 cm in the greatest dimension,
or multiple lymph nodes, none more than 5 cm in
greatest dimension
N3
Metastasis in a lymph node more than 5 cm in
greatest dimension
M - Distant Metastasis
M0
No distant metastasis
M1
Distant metastasis

Tumour grade

There are currently two main classifications used for UTUCs.


Urothelial Carcinomas Of The Upper Urinary Tract

23

They are the 1973 WHO classification, which classifies


tumours into three grades, G1, G2 and G3, and the 2004 WHO
classification, which classifies tumours into three groups:
papillary urothelial neoplasia of low malignant potential, lowgrade carcinomas, and high-grade carcinomas. Upper urinary
tract tumours with low malignant potential are very rare.

Diagnosis

UTUCs are diagnosed using imaging, cystoscopy, urinary


cytology and diagnostic ureteroscopy. The benefits of ureteroscopy in pre-operative assessment should also be discussed
with the patient.
Recommendations for the diagnosis of UTUCs
Urinary cytology
Cystoscopy to rule out a concomitant bladder tumour
CT urography
Diagnostic ureteroscopy and biopsy
Retrograde ureteropyelography

GR
A
A
A
C
C

Prognostic factors

UTUCs that invade the muscle wall usually have a very poor
prognosis. 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; and gender.

Risk stratification

It is necessary to risk stratify UTUC cases (i.e., with a functional contralateral kidney) before treatment to identify those
patients (and tumours) who are more suitable for conservative
treatment rather than radical extirpative surgery. Patients with
a normal contralateral kidney can be classified at the time of
24 Urothelial Carcinomas Of The Upper Urinary Tract

diagnosis as having low-risk UTUC


or high-risk UTUC, based on patient and/or clinical factors.

Management

Localised disease in UTUCs


Radical management (radical nephroureterectomy, [RNU])
The radical management of UTUCs consists of open surgery
RNU with excision of the bladder cuff. This is the gold standard treatment for UTUCs, regardless of tumour location. It
includes resection of the distal ureter and its orifice because
of the high risk of recurrence in this area. Lymph node dissection is also carried out as part of treatment and to provide
optimal staging.
Recommendations for RNU for UTUC
Indications
Suspicion of infiltrating UTUC on imaging
High-grade tumour (urinary cytology)
Multifocality (with two functional kidneys)
Non-invasive but large (i.e. > 1 cm) UTUC
Choice of technique
Open- and laparoscopic access are equivalent in terms
of efficacy in T1-T2/N0 tumours
Bladder cuff removal is imperative
Several techniques for bladder cuff excision are
acceptable, except stripping
Lymphadenectomy is recommended in cases of
invasive UTUC
Postoperative instillation (chemotherapy) is
recommended after RNU to avoid bladder recurrence

GR
B
B
B
B
B
A
C
C
B

Conservative management (low-risk UTUCs)


Conservative management of low-risk UTUCs consists of
surgery preserving the upper urinary renal unit. It is used in
Urothelial Carcinomas Of The Upper Urinary Tract

25

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.
Recommendations for the conservative management of
low-risk UTUCs
Indications
GR
Unifocal tumour
B
Small tumour (size < 1 cm)
B
Low-grade tumour (cytology or biopsies)
B
No evidence of an infiltrative lesion on CT urography
B
Understanding of close follow-up
B
Techniques
Laser should be used in the case of endoscopic
C
treatment
Flexible ureteroscopy is preferable over rigid
C
ureteroscopy
A percutaneous approach is an option for small, lowC
grade, caliceal tumours unsuitable for ureteroscopic
treatment
Ureteroureterostomy is indicated for non-invasive, low- C
grade tumours of the proximal ureter or mid-ureter that
cannot be removed completely by endoscopic means
Complete distal ureterectomy and neocystostomy is
C
indicated for non-invasive, low-grade tumours in
the distal ureter that cannot be removed completely by
endoscopic means and for high-grade, locally-invasive
tumours

26 Urothelial Carcinomas Of The Upper Urinary Tract

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 UTUCs. However, the benefits have not been
confirmed.
Advanced disease in UTUCs
RNU has no benefit in metastatic (M+) disease, but may be
used in palliative care. As UTUCs are urothelial tumours, platinum-based chemotherapy should give similar results to those
in bladder cancer. Currently, insufficient data are available to
provide any recommendations.
Radiotherapy is scarcely relevant nowadays both as a unique
therapy and associated with chemotherapy as a tumour adjuvant.

Follow-up after initial treatment

In all cases, there should be strict follow-up after radical management to detect metachronous bladder tumours, as well as
invasive tumours, local recurrence and distant metastases. In
conservative management, the ipsilateral upper urinary tract
requires careful follow-up due to the high risk of recurrence.
Recommendation for follow-up of UTUC after initial
treatment
After radical management, over at least 5 years
Non-invasive tumour
Cystoscopy/urinary cytology at 3 months and then
yearly
CT every year
Invasive tumour
Cystoscopy/urinary cytology at 3 months and then
yearly

GR
C
C
C

Urothelial Carcinomas Of The Upper Urinary Tract

27

CT urography every 6 months for 2 years and then


yearly
After conservative management, over at least 5 years
Urinary cytology and CT urography at 3 months,
6 months and then yearly
Cystoscopy, ureteroscopy and cytology in situ at
3 months, 6 months, every 6 months for 2 years and
then yearly

C
C

Figure 1: Proposed flowchart for the management of UTUC


UTUC

Diagnostic evaluation: CT-urography, urinary


cytology, cystoscopy, retrograde pyelography
+/- flexible ureteroscopy with biopsies

High-risk UTUC

Low-risk UTUC
Unifocal tumour
Size less than 1 cm
Low-grade
Non-invasive aspect on MDCT-urography

Gold standard treatment:


Radical nephroureterectomy

Conservative management:
ureteroscopy, segmental resection

Open

Laparoscopic

Recurrence
Close and stringent follow-up

Single postoperative dose of intravesical


chemotherapy

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN: 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
28 Urothelial Carcinomas Of The Upper Urinary Tract

MUSCLE-INVASIVE AND METASTATIC


BLADDER CANCER
(Text update April 2014)

J.A. Witjes (chair), E. Comprat, N.C. Cowan, M. De Santis,


G. Gakis, T. Lebrt, M.J. Ribal, A. Sherif, A.G. van der Heijden

Eur Urol 2011 Jun;59(6):1009-18


Eur Urol 2014 Mar;65(3):778-92

Introduction

Optimal treatment strategies for Muscle-invasive Bladder


Cancer (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.

Muscle-invasive and Metastatic Bladder Cancer

29

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
T2
Tumour invades muscle
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 stroma,
seminal vesicles, ureterus, vagina, pelvic wall,
abdominal wall
T4a Tumour invades prostate stroma, seminal
vesicles, uterus or vagina
T4b Tumour invades pelvic wall or
abdominal wall
N - Lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph-node metastasis
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)
N3
Metastasis in a common iliac lymph node(s)
M - Distant metastasis
M0
No distant metastasis
M1
Distant metastasis
30 Muscle-invasive and Metastatic Bladder Cancer

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
Flat lesions
Hyperplasia (flat lesion without atypia or papillary aspects)
Reactive atypia (flat lesion with atypia)
Atypia of unknown significance
Urothelial dysplasia
Urothelial CIS is always high-grade
Papillary lesions
Urothelial papilloma (completely benign lesion)
Papillary urothelial neoplasm of low malignant potential
(PUNLMP)
Low-grade papillary urothelial carcinoma
High-grade papillary urothelial carcinoma
Morphological subtypes can be helpful in assessing the
prognosis and treatment options. The following differentiation
is currently 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. Nested carcinoma
5. Large cell nested
6. Urothelial carcinoma with small tubules
Muscle-invasive and Metastatic Bladder Cancer

31

7. Microcystic urothelial carcinoma


8. Lymphoepithelioma-like urothelial carcinoma
9. Lipoid-rich urothelial carcinoma
10. Clear cell (glycogen rich) urothelial carcinoma
11. Rhabdoid urothelial carcinoma
12. Plasmocytoid urothelial carcinoma
13. Sarcomatoid urothelial carcinoma.
14. Undifferentiated urothelial carcinoma (including with giant
cells/trophoblastic-like giant cells/osteoclast-like giant
cells differentiation)
15. Squamous cell carcinoma
16. Adenocarcinoma
17. Neuroendocrine carcinoma (small-cell carcinomas, largecell neuroendocrine carcinoma, carcinoid)
Recommendations for assessing tumour specimens
Mandatory evaluations
Histological subtype
Depth of invasion
Resection margins, including CIS
Extensive lymph-node representation
Optional evaluation
Lymphovascular invasion
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).

32 Muscle-invasive and Metastatic 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

Recommendations for staging of MIBC


In patients with confirmed MIBC, CT of the chest,
abdomen and pelvis is the optimal form of staging,
including excretory-phase CT urography for complete
examination of the upper urinary tracts.
Excretory-phase CT urography is preferred to MR
urography for diagnosis of UTUC in terms of greater
diagnostic accuracy, less cost, and greater patient
acceptability. MR urography is used when CT
urography is contraindicated for reasons related to
contrast administration or radiation dose.

GR
B

Muscle-invasive and Metastatic Bladder Cancer

33

Ureteroscopic-guided biopsy is recommended for


C
histopathological confirmation of preoperative diagnosis of UTUC.
CT or MRI is recommended for staging locally
B
advanced or metastatic disease in patients in whom
radical treatment is being considered.
CT and MRI are generally equivalent in diagnosing
C
local and distant abdominal metastases but CT is
preferred to diagnose pulmonary metastases.

Treatment failure of non-MIBC


Recommendations for treatment failure of non-MIBC GR
In all T1 tumours at high-risk of progression (i.e. high
C
grade, multifocality, carcinoma in situ, and tumour
size, as outlined in the EAU guidelines for Non-muscleinvasive bladder cancer), immediate radical treatment
is an option.
In all T1 patients failing intravesical therapy, radical
B
treatment should be offered.

MIBC - Radical surgery and urinary diversion


Conclusions
For MIBC 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.
There is data to support that an extended LND (vs.
standard or limited LND) improves survival after
radical cystectomy.

34 Muscle-invasive and Metastatic Bladder Cancer

LE
3
3
3
3

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.
The type of urinary diversion does not affect
oncological outcome.
Laparoscopic- and robotic-assisted laparoscopic cystectomy are feasible but still investigational. Current
best practice is open radical cystectomy.
In patients aged > 80 years with MIBC, cystectomy is
an option.
Surgical outcome is influenced by comorbidity, age,
previous treatment for bladder cancer or other pelvic
diseases, surgeon and hospital volumes of cystectomy,
and type of urinary diversion.
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 and urinary GR
diversion
Radical cystectomy is recommended in T2-T4a, N0M0, A*
and high-risk non-MIBC.

Muscle-invasive and Metastatic Bladder Cancer

35

Do not delay cystectomy for > 3 months because it


increases the risk of progression and cancer-specific
mortality.
Preoperative radiotherapy is not recommended in
case of subsequent cystectomy with urinary diversion.
Lymph node dissection should be an integral part of
cystectomy. Extended LND is recommended.
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 management options. However,
current data have not sufficiently proven the
advantages or disadvantages for oncological and
functional outcomes.
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.
The decision regarding bladder sparing or radical
cystectomy in the elderly/geriatric patient with invasive bladder cancer should be based on tumour stage
and comorbidity best quantified by a validated score,
such as the Charlson Comobidity Index. The ASA
score does not address comorbidity and should not be
used in this setting.
Pre-operative bowel preparation is not mandatory.
Fast track measurements may reduce the time of
bowel recovery.

36 Muscle-invasive and Metastatic Bladder Cancer

A
B
B

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 definitive
treatment (LE: 1a). Currently, no tools are available to select
patients who have a higher probability to benefit from neoadjuvant chemotherapy. In the future, genetic markers, in a
personalised medicine setting, might facilitate the selection of
patients for neoadjuvant chemotherapy and to
differentiate responders from non-responders. In case of
progression under neoadjuvant chemotherapy, this treatment
should be discontinued.
Recommendations
Neoadjuvant chemotherapy is recommended for
T2-T4a, cN0M0 bladder cancer and should always be
cisplatin-based combination therapy.
Neoadjuvant chemotherapy is not recommended in
patients who are ineligible for cisplatin-based
combination therapy.

GR
A

Muscle-invasive and Metastatic Bladder Cancer

37

Fig. 1: Flowchart for the management of


T2-T4a N0M0 urothelial bladder cancer
Diagnosis
Cystoscopy and tumour resection
Evaluation of urethra
CT imaging of abdomen, chest, UUT
MRI 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
pT2-4a, 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

CT = computed tomography; MRI = magnetic resonance


imaging; UUT = upper urinary tract.

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 restaging biopsies are negative for residual tumour.
38 Muscle-invasive and Metastatic Bladder Cancer

Recommendation
LE
TURB alone is not a curative treatment option in 2a
most patients.

GR
B

External beam radiotherapy (EBRT)


EBRT 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).
Chemotherapy and best supportive care
With cisplatin-based chemotherapy as primary therapy for
locally advanced tumours in highly selected patients, complete and partial local responses have been reported (LE: 2b).
Recommendation
Chemotherapy alone is not recommended as primary
therapy for localised bladder cancer.

GR
A

Multimodality treatment
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.
Recommendations
GR
Transurethral resection of bladder tumour alone can- B
not be offered as a standard curative treatment option
in most patients.
Radiotherapy alone is less effective than surgery and
B
is only recommended as a therapeutic option when
the patient is unfit for cystectomy or a multimodality
bladder-preserving approach.
Muscle-invasive and Metastatic Bladder Cancer

39

Chemotherapy alone is not recommended as primary A


therapy for MIBC.
Surgical intervention or multimodality treatments are B
the preferred curative therapeutic approaches as they
are more effective than radiotherapy alone.
Multimodality treatment could be offered as an
B
alternative in selected, well-informed, well selected
and compliant patients, especially for whom cystectomy is not an option.

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.
Prior to any further interventions, surgery3
related morbidity and quality-of-life should be
fully discussed with the patient.
Adjuvant Chemotherapy
There is insufficient data to support the routine use of
adjuvant chemotherapy.

40 Muscle-invasive and Metastatic Bladder Cancer

GR
B

Recommendation
Adjuvant chemotherapy should only be given within
clinical trials, whenever possible.
Adjuvant cisplatin-based combination chemotherapy
may be offered to patients with pN+ disease if no neoadjuvant chemotherapy has been given.

GR
A
C

Metastatic disease
Conclusions for metastatic disease
In a first-line setting, PS and the presence or absence
of visceral metastases are independent prognostic
factors for survival.
In a second-line setting, prognostic factors are: liver
metastasis, PS 1 and low haemoglobin (< 10 g/dL)
Cisplatin-containing combination chemotherapy can
achieve median survival of up to 14 months, with longterm disease-free survival reported in ~15% of patients
with nodal disease and good PS.
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 produces
substantial responses in first- and second-line
settings, but has not been tested against standard
chemotherapy in patients who are fit or unfit for
cisplatin combination chemotherapy.
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.

LE
1b

1b
1b

2a
2a

2a

2b

1b

Muscle-invasive and Metastatic Bladder Cancer

41

Post-chemotherapy surgery after partial or complete


response may contribute to long-term disease-free
survival.
Zoledronic acid and denosumab have been approved
for all cancer types including urothelial cancer,
because they reduce and delay SREs in metastatic
bone disease.

Recommendations for metastatic disease


GR
First-line treatment for fit patients:
Use cisplatin-containing combination chemotherapy
A
with GC, PCG, MVAC, preferably with G-CSF, or
HD-MVAC with G-CSF.
Carboplatin and non-platinum combination
B
chemotherapy is not recommended.
First-line treatment in patients ineligible (unfit) for cisplatin:
Use carboplatin combination chemotherapy or single C
agents.
For cisplatin-ineligible (unfit) patients, with PS2 or
A
impaired renal function, as well as those with 0 or 1
poor Bajorin prognostic factors and impaired renal
function, treatment with carboplatin-containing
combination chemotherapy, preferably with
gemcitabine/carboplatin is indicated.
Second-line treatment:
In patients progressing after platinum-based
A*
combination chemotherapy for metastatic disease,
vinflunine should be offered. Alternatively, treatment
within a clinical trial setting may be offered.
Zoledronic acid or denosumab is recommended for
B
treatment of bone metastases.
*Grade A recommendation is weakened by a problem of
statistical significance.
GC = gemcitabine plus cisplatin; HD MVAC = high-dose
42 Muscle-invasive and Metastatic Bladder Cancer

methotrexate, vinblastine, adriamycin plus cisplatin; G-CSF =


granulocyte colony stimulating factor; MVAC = methotrexate,
vinblastine, adriamycin plus cisplatin; PCG = paclitaxel,
cisplatin, gemcitabine; PS = performance status.
Recommendation on the use of biomarkers
GR
Currently, no biomarkers can be recommended in daily A*
clinical practice because they have no impact on
predicting outcome, treatment decisions or monitoring therapy in MIBC.
*Upgraded following panel consensus.
Health-related quality-of-life (HRQoL)
Important determinants of (subjective) QoL 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 MIBC.
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 followup 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
C

Muscle-invasive and Metastatic Bladder Cancer

43

Fig. 2: Flowchart for the management of metastatic urothelial


cancer
Patient characteristics:
PS 0-1/ 2/ > 2
GFR /< 60mL/min
Comorbidities
PS 0 -1 and
GFR 60mL/min
STANDARD GC
MVAC
HD MVAC
PCG

PS 2 or
GFR < 60mL/min
Comb. chemo:
Carbo-based

PS 2 and
GFR < 60mL/min
NO comb chemo
studies,
monotherapy, BSC

CISPLATIN?
yes

no

no

Second-line treatment

PS > 2

PS 0-1

1. Progression > 6 -12 mo


after first-line
chemotherapy, adequate
renal function
a. re-exposition to firstline treatment
(cisplatin-based)
b. clinical study

2. Progression
> 6 -12 mo
after first-line
chemotherapy,
PS 0-1, impaired
renal function
a. vinflunine
b. clinical study

3. Progression
< 6 -12 mo
after first-line
chemotherapy,
PS 0-1
a. vinflunine
b. clinical study

a. Best supportive care


b. Clinical study

GC = gemcitabine plus cisplatin; GFR = glomular filtration rate;


HD MVAC = high-dose methotrexate, vinblastine, adriamycin
plus cisplatin; MVAC =methotrexate, vinblastine, adriamycin
plus cisplatin; PCG = paclitaxel, cisplatin, gemcitabine; PS =
performance status.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org/guidelines/.
44 Muscle-invasive and Metastatic Bladder Cancer

GUIDELINES ON PROSTATE CANCER


(Text update April 2014)

N. Mottet (chair), P.J. Bastian, J. Bellmunt, R.C.N. van den Bergh,


M. Bolla, N.J. van Casteren, P. Cornford, S. Joniau, M.D. Mason,
V. Matveev, T.H. van der Kwast, H. van der Poel, O. Rouvire,
T. Wiegel

Eur Urol 2014 Jan;65(1)124-37


Eur Urol 2014 Feb;65(2):467-79

Introduction

Prostate cancer (PCa) is the most common cancer in elderly


males in Europe. It is a big health concern, especially in developed countries with their greater proportion of older men in
the general population.
There are three well-established risk factors for PCa: increasing age, ethnic origin, and genetic predisposition.
There is currently no evidence to suggest that dietary interventions would reduce the risk of PCa.

Screening

Early prostate specific antigen (PSA) testing could be used to


detect the cohorts of men at risk and in need of further followup. An individualized risk-adapted strategy for early detection
might be offered to a well-informed man with a least 10-15
years of individual life expectancy.
Systemic population-based screening is not advised since
it is associated with harms such as overdiagnosis and overtreatment.

Prostate Cancer

45

Staging system

The 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

T2

T3

T4

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
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)
including bladder neck involvement
T3b Tumour invades seminal vesicle(s)
Tumour is fixed or invades adjacent structures other
than seminal vesicles: external sphinter, rectum,
levator muscles and/or pelvic wall

N - Regional Lymph Nodes3


NX
N0
N1

Regional lymph nodes cannot be assessed


No regional lymph node metastasis
Regional lymph node metastasis

46 Prostate Cancer

M - Distant Metastasis4
MX
M0
M1

Distant metastasis cannot be assessed


No distant metastasis
Distant metastasis
M1a Non-regional lymph node(s)
M1b Bone(s)
M1c Other site(s)

 umour found in one or both lobes by needle biopsy, but


T
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.

Gleason grading system

Prostate Cancer grading is based on the 2005 International


Society of Urological Pathology (ISUP) modified Gleason
grading system.

Diagnosis and staging

Prostate cancer is usually suspected on the basis of digital


rectal examination (DRE) and PSA levels. Definitive diagnosis
depends on the histopathological verification of adenocarcinoma in prostate biopsy cores or operative specimens.
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
Prostate Cancer

47

transparent and more complete pathology reporting. The use


of a checklist is encouraged (see example).
Checklist for processing and pathology reporting of radical
prostatectomy (RP) specimens
Histological type
Type of carcinoma, e.g. conventional acinar, ductal, etc.
Histological grade
Primary (predominant) grade
Secondary grade
Tertiary grade (if applicable)
Total/global Gleason score
Approximate percentage of Gleason grade 4 or 5 (optional)
Tumour quantitation (optional)
Percentage of prostatic gland involved
Tumour size of dominant nodule (if identified), greatest
dimension in millimetres
Pathological staging (pTNM)
If extraprostatic extension is present:
indicate whether it is focal or extensive
specify site(s)
Indicate whether there is seminal vesicle invasion
If applicable, regional lymph nodes:
location
number of lymph nodes retrieved
number of lymph nodes involved
Surgical margins
If carcinoma is present at the margin:
specify sites and extra- or intraprostatic involvement

48 Prostate Cancer

Other
If identified, presence of angio-invasion and/or intraductal
carcinoma
Location (site, zone) of dominant tumour (optional)
Perineural invasion (optional):
if present, specify extra- or intraprostatic location

Guidelines for the Diagnosis and Staging of PCa


Recommendations for the Diagnosis of PCa
Prostate cancer should be graded according
to the ISUP 2005 modified Gleason grading
system.
The decision to biopsy should be based on PSA
testing and DRE.
For initial diagnosis, a core biopsy of 10-12
systematic transrectal or transperineal
peripheral zone biopsies should be performed
under ultrasound imaging guidance.
Transrectal prostate needle biopsies should be
taken under antibiotic protection.
Local anaesthetic by periprostatic infiltration is
recommended for prostate needle biopsies.
Prostate core biopsies from different prostatic sites should be submitted separately for
processing and pathology reporting.
Processing and reporting of prostatectomy
specimens by pathology should follow the
guidelines provided by the ISUP.
When available, mMRI of the prostate can be
used to trigger a (targeted) repeat prostate
biopsy.

LE
2a

GR
A

2b

2a

1b

1a

2b

Prostate Cancer

49

One set of repeat biopsies is warranted in cases 2a


B
with persistent indication for PCa (abnormal
DRE, elevated PSA or histopathological findings
suggestive of malignancy at the initial biopsy).
Overall recommendations for further (three
3
C
or more) sets of biopsies cannot be made; the
decision must be made based on an individual
patient.
DRE = digital rectal examination; ISUP = International Society
of Urological Pathology; mMRI = multiparametric magnetic
resonance imaging; PSA = prostate-specific antigen.
Recommendations for the Staging of PCa
Imaging is not indicated for staging in low-risk
tumours.
For local staging (T-staging) of PCa most relevant information will be provided by the number
and sites of positive prostate biopsies, the
tumour grade, and the level of serum PSA.
For local staging, CT and TRUS should not be
used.
Prostate mMRI should be used in local staging
only if its results change patient management.
Prostate mMRI is not recommended for
staging purposes in patients with low-risk
prostate cancer.
Lymph node status (clinical N-staging) need
only be assessed when potentially curative
treatment is planned.

50 Prostate Cancer

LE
3

GR
A

2b

2b

Lymph node imaging (using CT or MRI) is recom- 2b


A
mended in asymptomatic patients only in case
of PSA level > 10 ng/mL or Gleason score 8 or
clinical stage T3 (i.e. intermediate-/high-risk
situations).
Bone scan is recommended in asymptomatic
2b
A
patients only in case of PSA level > 10 ng/mL
or Gleason score 8 or clinical stage T3 (i.e.
intermediate-/high-risk situations).
Bone scan is indicated in patients with symp3
A
toms evocative of bone metastases.
CT = computed tomography; mMRI = multiparametric magnetic resonance imaging; TRUS = transrectal ultrasound.

Treatment of Prostate Cancer

An overview of the treatment options for patients with PCa,


subdivided by stage at diagnosis, is presented below.
Active surveillance and watchful waiting
Active surveillance is also known as active monitoring. As
opposed to watchful waiting, active surveillance aims at the
proper timing of curative treatment rather than the delayed
application of palliative treatment options.

Prostate Cancer

51

Recommendations for Active Surveillance and


Watchful Waiting
Active surveillance
Active surveillance is an option in patients with
the lowest risk of cancer progression: over 10
years of life-expectancy, cT1-2, PSA 10 ng/mL,
biopsy Gleason score 6 (at least 10 cores), 2
positive biopsies, minimal biopsy core involvement ( 50% cancer per biopsy)
Follow-up should be based on DRE, PSA and
repeated biopsies
The optimal timing for follow-up is still unclear
(yearly or every two years)
Patients with biopsy progressions should be recommended to undergo active treatment
Watchful waiting
Watchful waiting may be offered to all patients
not willing to accept the side-effects of active
treatment, particularly patients with a short lifeexpectancy
When on watchful waiting, the decision to start
any non-curative treatment should be based on
symptoms and disease progression.
DRE = digital rectal examination.

52 Prostate Cancer

LE

GR

2a

2a

2a

2a

1b

1a

Experimental therapeutic options for clinically localized PCa


Recommendations
In patients who are unfit for surgery or radiotherapy,
cryotherapy can be an alternative treatment for PCa.
If HIFU is offered, the lack of long-term comparative
outcome data (> 10 y) should be discussed with the
patient.
Focal therapy of PCa is still in its infancy and cannot
be recommended as a therapeutic alternative outside
clinical trials.
HIFU = high-intensity focused ultrasound.
Guidelines for the Primary Treatment of PCa
Stage Treatment
Comment
T1a
Watchful
In patients with < 10-year life
waiting
expectancy standard treatment for Gleason score 6
and 7 adenocarcinomas.
Active
In patients with > 10-year life
surveillance
expectancy, re-staging with
TRUS and biopsy is recommended.
Radical
Optional in younger patients
prostatectomy with a long life-expectancy,
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.

GR
C
C

GR
B

Prostate Cancer

53

T1bT2b

T1aT2c

Hormonal
Combination
Active
surveillance

Not an option.
Not an option.
Treatment option in patients
with cT1c-cT2a, PSA
< 10 ng/mL, biopsy Gleason
score 6, 2 biopsies positive,
50% cancer involvement in
each biopsy.
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.
Watchful
Patients with life expectancy <
waiting
10 years and Gleason score < 7.
Patients with life expectancy <
10 years and Gleason score = 7.
Radical
Optional in patients with pT1a
prostatectomy PCa.
Standard treatment for
patients with a life expectancy
> 10 years who accept treatment-related complications.

54 Prostate Cancer

A
C
B

A
B
A

Radiotherapy

Patients with a life expectancy


> 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).
Brachytherapy Low-dose rate brachytherapy
can be considered for low-risk
PCa patients with a prostate
volume 50 mL and an IPSS
12.
Hormonal
Symptomatic patients, who
need palliation of symptoms,
unfit for curative treatment.
Anti-androgens are associated
with a poorer outcome compared to watchful waiting and
are not recommended.
Combination For high-risk patients, neoadjuvant hormonal treatment and
concomitant hormonal therapy plus radiotherapy results in
increased overall survival.

Prostate Cancer

55

T3- T4 Watchful
waiting

Option in asymptomatic
C
patients with T3, Gleason
score 7, and a life expectancy
< 10 years who are unfit for
local treatment.
Radical
Optional for selected patients C
prostatectomy 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.
Radiotherapy T3 with > 5-10 years of life
A
expectancy. Dose escalation of
> 74 Gy seems to be of benefit.
A combination with hormonal
therapy can be recommended.

56 Prostate Cancer

Hormonal

N+,
M0

Symptomatic patients, extensive T3-T4, high PSA level


(> 25-50 ng/mL), PSADT < 1
year.
Patient-driven, unfit patients.
Hormone monotherapy is not
an option for patients who are
fit enough for radiotherapy.
Combination Overall survival is improved
by concomitant and adjuvant
hormonal therapy (3 years)
combined with external beam
radiation.
NHT plus radical prostatectomy: no indication.
Watchful
Asymptomatic patients.
waiting
Patient-driven (PSA <20-50ng/
mL), PSADT > 12 months.
Requires very close follow-up.
Radical
Optional for selected patients
prostatectomy with a life expectancy of > 10
years as part of a multimodal
treatment approach.
Radiotherapy Optional in selected patients
with a life expectancy of > 10
years, combination therapy
with adjuvant androgen deprivation for 3 years is mandatory.

B
B

Prostate Cancer

57

Hormonal

Combination
M+

Watchful
waiting

Standard treatment after


extended node dissection if >
2 positive nodes (irrespective
of the local treatment: surgery
or radiotherapy). 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

Radical
C
prostatectomy
Radiotherapy Not an option for curative
C
intent; therapeutic option in
combination with androgen
deprivation for treatment of
local cancer-derived symptoms.
Hormonal
Standard option. Mandatory in A
symptomatic patients.
DT = doubling time; NHT = neoadjuvant hormonal treatment;
IPSS = International Prostatic Symptom Score;
PSA = prostate specific antigen; TRUS = transrectal ultrasound; TURP = transurethral resection of the prostate.
For more detailed information and discussion on second-line
therapy, please see the full text version of the guidelines.
58 Prostate Cancer

Follow-up of Prostate Cancer Patients

Reasons for follow-up may vary depending on the treatment


given, patient age, co-morbidity and the patients own wishes.
In general, patients who receive curative therapy are followed
up to assess:
The possibility of second-line treatment with curative
intent;
The possibility of early hormonal therapy after failure.
Guidelines for follow-up after treatment with curative GR
intent
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
B
associated 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 recurrent disease.
Both a palpable nodule and a rising serum PSA level
B
can be signs of local disease recurrence.
Detection of local recurrence by TRUS and biopsy is
B
only recommended if it will affect the treatment plan.
In most cases TRUS and biopsy are not necessary
before second-line therapy.
Routine bone scans and other imaging studies are not B
recommended in asymptomatic patients. If a patient
has bone pain, a bone scan should be considered
irrespective of the serum PSA level.
DRE = digital rectal examination; RP = radical prostatectomy.

Prostate Cancer

59

Guidelines for follow-up after hormonal treatment


Patients should first be evaluated at 3 and 6 months
after treatment initiation.
As a minimum, tests should include serum PSA
measurement, DRE, serum testosterone, and careful
evaluation of symptoms in order to assess the treatment response and side effects.
In patients undergoing intermittent androgen deprivation, PSA and testosterone should be monitored at
set intervals during the treatment pause (one or three
months).
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.
In patients with stage M1 disease with a good treatment response, follow-up is scheduled for every 3 to 6
months. As a minimum, this should include a diseasespecific history, DRE and serum PSA determination,
and is frequently supplemented with haemoglobin,
serum creatinine and alkaline phosphatase measurements. The testosterone level should be checked,
especially during the first year.
Patients (especially with M1b status) should be
advised about the clinical signs that could suggest
spinal cord compression.
When disease progression occurs, or if the patient
does not respond to the treatment given, follow-up
needs to be individualised.

60 Prostate Cancer

GR
A
A

In patients with suspected progression, the testoB


sterone level must be checked. By definition, CRPC is
based on the assumption that the patient has a
testosterone level of at least < 50 ng/dL.
Routine imaging of stable patients is not
B
recommended.
CRPC = castration-resistant prostate cancer; DRE = digital
rectal examination.

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 PSA-relapse
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 PSA-doubling 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.
Guidelines for imaging and second-line therapy LE
after treatment with curative intent
Biochemical failure (BCF) after RP
In case of BCF, bone scan and abdominopelvic
3
CT should be performed only in patients with a
PSA level > 10 ng/mL, or with high PSA kinetics
(PSA doubling time < 6 months or a PSA velocity
> 0.5 ng/mL/month) or in patients with symptoms of bone disease.
A choline PET/CT is not recommended in
3
patients with BCF and a PSA-level < 1 ng/mL.

GR

Prostate Cancer

61

For patients with a PSA rising out of the


3
B
undetectable range and favourable prognostic
factors (PSADT > 1 year and Gleason 7) surveillance and possibly delayed salvage RT (SRT) can
be offered.
Patients with a PSA rising out of the
2
A
undetectable range should be treated with SRT
to the prostatic bed at least. The total dose of
SRT should be at least 66 Gy and should be
given early (PSA < 0.5 ng/mL).
Patients with persistent PSA should be treated 3
C
with SRT to the prostatic bed at least. The total
dose of SRT should be at least 66 Gy and has to
be given early (PSA < 0.5 ng/mL).
Biochemical failure after RT
In patients with BCF who are candidates for
3
C
local salvage therapy, prostate multiparametric
MRI can guide biopsy.
Selected patients with localized PCa at primary 3
B
treatment and histologically proven recurrence
without evidence of metastatic disease should
be treated with SRP.
Due to the increased rate of side effects, SRP
3
A
and salvage brachytherapy should be performed
in experienced centres.
HIFU and cryosurgical ablation are treat3
B
ment options for patients without evidence
of metastasis and with histologically proven
local recurrence. However, patients must be
informed about the experimental nature of
these approaches.
BCF = biochemical failure; CT = computed tomography; HIFU =
high-intensity focused ultrasound; MRI = magnetic resonance
imaging; PET = positron emission tomography; PSADT = pros62 Prostate Cancer

tate-specific antigen doubling-time; RP = radical prostatectomy; RT = radiotherapy; SRP = salvage radical prostatectomy.

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 the treatment after hormonal
LE
therapy (first second-line modality) in
metastatic CRPC
In patients with a PSA rise only, two consecutive 2b
increases of PSA serum levels above a previous
reference level should be documented.
Patients should not be started on second-line
therapy unless their testosterone serum levels
are < 50 ng/dL.
Patients should not be started on second-line
therapy unless their PSA serum levels are > 2
ng/mL to ensure correct interpretation of therapeutic efficacy.
Men treated with maximal androgen blockade
1
should stop the anti-androgen therapy once
PSA progression is documented. Comment:
Four to six weeks after discontinuation of flutamide or bicalutamide, an eventual anti- androgen withdrawal effect will be apparent.

GR

Prostate Cancer

63

No clear-cut recommendation can be made for 3


A
the most effective drug for secondary treatment
(i.e. hormone therapy or chemotherapy) as no
clear predictive factors exist.
Cabazitaxel, abiraterone and enzalutamide are
1b
A
effective in the management of progressive
CRPC following docetaxel therapy.
Second-line salvage hormonal treatment using 2b
A
abiraterone acetate is considered to be a valid
option. It must be remembered that one of the 2
coprimary end-points of the pivotal trial has not
yet been met.
Second-line salvage hormonal treatment using 2b
C
enzalutamide might become a valid option, but
a full paper is awaited.
In non-metastatic CRPC, secondary hormonal
3
A
treatment (AA, Enza) should only be used in a
clinical trial setting
Ra223 improves survival in men with bone pre1b
A
dominant disease without visceral metastasis
CRPC = castration-resistant prostate cancer; PSA = prostatespecific antigen; MAB = maximal androgen blockade.

64 Prostate Cancer

Prostate Cancer

65

Docetaxel
Alpharadin

No visceral mets

Symptomatic patients

Docetaxel

Asymptomatic
Monitoring
Anti-androgens

Symptomatic bone metastasis


Alpharadin

Visceral mets

PS 2+

Second line therapies (dependent on previous treatments)


Docetaxel
Abiraterone
Enzalutamide
Cabazitaxel

Mildly symptomatic or asymtomatic men


with no evidence of visceral metastasis
Abiraterone
Sipuleucel T
Enzalutamide
? Docetaxel

Good performance status 0 or 1

mCRPC

Management of PCa in senior Adults*


Conclusions and recommendations
Evaluation of health status
Senior adults with localized PCa should systematically undergo health status screening.
Health status screening should be performed
using the G8 screening tool.
Patients with a G8 score 14 should undergo a
full geriatric evaluation, preferably by a medical
team specialized in geriatric medicine.
Based on this evaluation, senior adults can be
classified into one of four groups:
1. Fit or healthy older men, should receive
standard treatment;
2. Vulnerable patients (i.e. reversible impairment), may be given standard treatment after
resolution of any geriatric problems through
geriatric interventions;
3. Frail patients (i.e. irreversible impairment),
should receive an adapted treatment;
4. Patients who are too sick with have a terminal illness should receive only symptomatic
palliative treatment.
Treatment
Localized disease
Fit and vulnerable senior adults with a life
expectancy of > 10 years, diagnosed with highrisk disease, should be offered standard treatment.
In frail patients or patients who are too sick,
immediate ADT should only be used for symptom palliation.
66 Prostate Cancer

LE

GR

1b

2a

2a

2b

1b

Minimally invasive therapies should not be


3
B
applied routinely in senior adults. These therapies have a role only in highly selected fit and
vulnerable senior adults with intermediate-risk
disease.
Advanced disease
Evaluation of bone mineral status and preven2b
A
tion of osteoporotic fracture are recommended
in patients at high-risk of fractures.
New chemotherapeutic and hormonal agents
1b
B
can be used successfully in senior adults.
*Prof.Dr. J-P. Droz provided considerable expertise for this
section.

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.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Prostate Cancer

67

GUIDELINES ON RENAL CELL


CARCINOMA
(Text update April 2014)

B. Ljungberg, K. Bensalah, A. Bex, S. Canfield, S. Dabestani,


F. Hofmann, M. Hora, M.A. Kuczyk, T. Lam, L. Marconi,
A.S. Merseburger, P.F.A. Mulders, T. Powles, M. Staehler, A. Volpe

Introduction

The use of imaging techniques such as ultrasound (US) and


computed tomography (CT) has increased the detection of
asymptomatic renal cell cancer (RCC). In addition, during the
last 10 years, mortality rates have stabilised and even declined
in some European countries. The peak incidence of RCC
occurs between 60 and 70 years of age, with a 3:2 ratio of men
to women. Aetiological factors include lifestyle, such as
smoking, obesity and hypertension. The most effective
prophylaxis is to avoid cigarette smoking and obesity.

Diagnosis and classification

Many renal masses remain asymptomatic until the late stages


of the disease. Currently, more than 50% of RCCs are detected
incidentally when imaging is used to investigate a variety of
nonspecific symptoms and other abdominal diseases. The
classic triad of flank pain, gross haematuria and palpable
abdominal mass is rare. Clinical symptoms include visible
(gross) haematuria, palpable mass, arising varicocele or bilateral lower extremity oedema; these symptoms should initiate
radiological examination.
Paraneoplastic syndromes are found in approximately
30% of patients with symptomatic RCCs. A few symptomatic
patients present with symptoms caused by metastatic disease, such as bone pain or persistent cough.
68 Renal Cell Carcinoma

Radiological and other investigations of RCC

Radiological investigation includes 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
(LNs) and adrenals. Abdominal US and magnetic resonance
imaging (MRI) are supplements to CT. Contrast-enhanced US
can be helpful in specific cases (e.g. chronic renal failure with
a relative contraindication for iodinated or gadolinium contrast media, complex cystic masses, and differential diagnosis
of peripheral vascular disorders such as infarction and cortical
necrosis). In patients with possible venous involvement, or
allergy to intravenous contrast MRI can be used. Chest CT is
the most accurate chest staging and is recommended in the
primary work-up of patients with suspected RCC.
Percutaneous renal tumour biopsies are increasingly being
used:
1. For histological diagnosis of radiologically indeterminate
renal masses;
2. To select patients with small renal masses for surveillance
approaches;
3. To obtain histology before ablative treatments;
4. To select the most suitable form of targeted pharmacologic
therapy in the setting of metastatic disease.
In patients with any sign of impaired renal function, a renal
scan and total renal function evaluation using estimated
glomerular filtration rate (eGFR) should always 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 (Table 1).
Renal Cell Carcinoma

69

Table 1: The 2009 TNM staging classification system


T - Primary tumour
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 7 cm in greatest dimension, limited to the
kidney
T1a Tumour 4 cm in greatest dimension, limited to
the kidney
T1b Tumour > 4 cm but 7 cm in greatest dimension
T2 Tumour > 7 cm in greatest dimension, limited to the
kidney
T2a Tumour > 7 cm in greatest dimension but 10cm
T2b Tumours > 10 cm limited to the kidney
T3 Tumour extends into major veins or perinephric
tissues, 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)
N - Regional lymph nodes
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single regional lymph node
N2 Metastasis in more than one regional lymph node
70 Renal Cell Carcinoma

M - Distant metastasis
M0 No distant metastasis
M1 Distant metastasis
A help desk for specific questions about TNM classification is
available at http://www.uicc.org/tnm.

Histopathological classification

Fuhrman nuclear grade is the most commonly used grading


system. The most aggressive pattern observed defines the
Fuhrman grade. RCC comprises different subtypes with genetic and histological differences. The three most common RCC
types are: clear cell RCC (cRCC 80-90%), papillary RCC (pRCC
10-15%), and chromophobe RCC (chRCC 4-5%). Generally, the
RCC types have different clinical courses and responses to
therapy.

Renal Cell Carcinoma

71

Recommendations for the diagnosis and staging of


RCC
The Fuhrman grading system and classification of RCC
subtype should be used.
Contrast-enhanced abdominal CT and MRI are recommended for the work-up of patients with RCC. These
are the most appropriate imaging modalities for renal
tumour staging prior to surgery.
A chest CT is recommended for staging assessment of
the lungs and mediastinum.
Bone scan is not routinely recommended.
Evaluation of renal function is recommended before
treatment decision in any patient in whom renal
impairment is suspected.
Percutaneous biopsy is recommended in patients in
whom active surveillance is pursued.
Percutaneous biopsy is always required before
ablative therapy and systemic therapy without
previous pathology.
When biopsy is indicated, good-quality needle cores
should be obtained with a coaxial technique in order
to increase the safety of the procedure and maximize
its diagnostic yield.

Other renal tumours

GR
B
B

C
C
C

C
C

The RCC types account for 85-90% of all renal tumours. The
remaining 10-15% include a variety of uncommon carcinomas,
a group of unclassified carcinomas, and several benign renal
tumour masses.

72 Renal Cell Carcinoma

Recommendations for other renal tumours


Except for angiomyolipomas, most of these less
common renal tumours cannot be differentiated
from RCC on the basis of radiology and should
therefore be treated in the same way as RCC.
Bosniak cysts type III should be regarded as
RCC and be treated accordingly.
In oncocytomas verified on biopsy, follow-up is
an option.
In angiomyolipomas, treatment (surgery, thermal ablation, and selective arterial embolisation) can be considered in well selected cases.
A nephron-sparing procedure is preferred.
In advanced uncommon types of renal tumours,
a standardised oncological treatment approach
does not exist.

LE
3

GR
C

Primary treatment of RCC

Current evidence suggests that localised renal tumours are


best managed by nephron-sparing surgery (partial nephrectomy) rather than by radical nephrectomy, irrespective of the
surgical approach used. Radical nephrectomy with complete
removal of the tumour-bearing kidney with perirenal fat and
Gerotas fascia is currently recommended only 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 local growth. Complete resection
of the primary RCC either by open-, laparoscopic- or robotassisted surgery offers a reasonable chance for cure.
If pre-operative imaging and intra-operative findings
are normal, routine adrenalectomy is not indicated.
Lymphadenectomy should be restricted to staging because
Renal Cell Carcinoma

73

the survival benefit of extended lymph node dissection (eLND)


is unclear. 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 visible (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.
Low level data suggests that tumour thrombus in the
setting of non-metastatic disease should be excised.
Adjunctive procedures such as tumour embolization or IVC
filter do not appear to offer any benefits in the treatment of
tumor thrombus.
Recommendations for the primary treatment of RCC
Surgery is recommended to achieve cure in localised
RCC.
Ipsilateral adrenalectomy is not recommended when
there is no clinical evidence of invasion of the adrenal
gland.
Lymph node dissection is not recommended in
localised tumour without clinical evidence of lymph
node invasion.
In patients with clinically enlarged lymph nodes, lymph
node dissection can be performed for staging
purposes or local control.
Excision of the kidney tumour and caval thrombus is
recommended in patients with non-mRCC.

Nephron-sparing surgery

GR
B
B

Absolute indications for partial nephrectomy are anatomical


74 Renal Cell Carcinoma

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 forms of RCC
with a high-risk of developing a tumour in the contralateral
kidney. Also localised unilateral RCC with a healthy contralateral kidney is an indication for nephron-sparing surgery since
recurrence-free and long-term survival rates are similar to
those for radical nephrectomy. Even in patients with a tumour
diameter of up to 7 cm, nephron-sparing surgery can achieve
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 nephronsparing surgery, follow-up should be intensified, as there is an
increased risk of intrarenal recurrences.

Laparoscopic radical- and partial nephrectomy

Laparoscopic- and robot-assisted radical nephrectomy has a


lower morbidity compared with open surgery.
It has become an established surgical procedure for RCC.
Whether the nephrectomy was done retro- or transperitoneally, the laparoscopic approach must duplicate established,
open surgical and oncological principles. Equivalent cancerfree survival rates are achieved versus open radical nephrectomy and 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 partial resection has a risk for longer intraoperative ischaemia time than open partial nephrectomy and
therefore carries a higher risk for reduced long-term renal
function. The oncological outcome seems comparable in
available series. Robotic-assisted partial nephrectomy
Renal Cell Carcinoma

75

requires further evaluation but preliminary data suggest lower


estimated blood loss and a shorter warm ischaemia time
compared with pure laparoscopic surgery.
Table 2: 2014 recommendations for primary surgical
treatment of RCC according to T-stage
Stage
Surgery
T1

Nephron-sparing surgery

Open
Laparoscopic/
Robot-assisted

Radical nephrectomy

Laparoscopic

T2

Radical nephrectomy

Open
Laparoscopic
Open

T3,T4

Nephron-sparing surgery
Radical nephrectomy

Open
Laparoscopic

Therapeutic approaches as alternatives to surgery

Active surveillance (initial monitoring of tumour size by


serial abdominal imaging with delayed intervention reserved
for those tumours that show clinical progression during
follow-up) can be considered in the management of small
renal masses in elderly and comorbid patients with limited
life expectancy and high surgical risk. In active surveillance
cohorts, the growth of small renal masses is low in most cases
and progression to metastatic disease is rare (1-2%).
Other alternatives to surgery for these patients are minimallyinvasive techniques, such as ablation with percutaneous
radio-frequency, cryotherapy, microwave, and high-intensity
focused US. Potential advantages of these techniques include
76 Renal Cell Carcinoma

Recommendations
Recommended
Recommended
Recommended standard only 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
reduced morbidity, outpatient therapy, and the ability to treat
high-risk patients not fit for conventional surgery.
These experimental treatments might be used for selected
patients as in elderly and /or comorbid patients. The oncological efficacy remains to be determined for both cryotherapy
and radiofrequency ablation (RFA), which are the most frequently used minimally-invasive techniques. Data suggest
that for both treatments, tumour recurrence rates are higher
compared with nephron-sparing surgery.

Renal Cell Carcinoma

77

Recommendations for minimally-invasive alternative


treatment
Due to the low quality of the available data no
recommendation can be made on RFA and
cryoablation.
In the elderly and/or comorbid patients with small
renal masses and limited life expectancy, active
surveillance, RFA and cryoablation can be offered.
RFA = radiofrequency ablation.

GR
C

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.
Recommendations for adjuvant therapy
Outside controlled clinical trials, there is no indication
for adjuvant therapy following surgery.

GR
A

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 palliative. For targeting agents cytoreductive
nephrectomy is recommended before or after successful
medical therapy, when possible.
Complete removal of metastases contributes to improved
clinical prognosis. Metastasectomy should be carried out in
patients with resectable disease and a good performance
status (PS). It should also be considered in patients with
residual and respectable metastatic lesions, who have
previously responded to systemic therapy.
78 Renal Cell Carcinoma

Radiotherapy for metastases

For selected patients with non-resectable brain or osseous


lesions, radiotherapy can induce significant symptom relief.
Recommendations for surgical treatment of mRCC
Cytoreductive nephrectomy is recommended in
appropriately selected patients with mRCC.
No general recommendations can be made. The decision to resect metastases has to be taken for each
site, and on a case-by-case basis; performance status,
risk profiles, patient preference and alternative techniques to achieve local control, must be considered.
In individual cases, stereotactic radiotherapy for bone
metastases, and stereotactic radiosurgery for brain
metastases can be offered for symptom relief.

GR
C
C

Systemic therapy for mRCC (Table 2)

Chemotherapy
Chemotherapy as monotherapy is not considered effective in
patients with mRCC.
Immunotherapy
In general, interferon-alpha (IFN-) monotherapy is inferior to
targeted therapy in mRCC. IL-2 monotherapy may have a role
in selected cases (good PS, clear-cell type, lung metastases
only), since high-dose IL-2 is associated with durable complete
responses in a limited number of patients. However, IL-2 has
more side effects than IFN-. A combination of bevacizumab
and IFN- is more effective than IFN- in treatment-nave, lowrisk and intermediate-risk tumours.
No recommendations can be made at present for
vaccination therapy.

Renal Cell Carcinoma

79

Recommendation for immunotherapy


Monotherapy with IFN- or high-dose bolus IL-2 can
only be recommended as a first-line treatment for
mRCC in selected patients with clear cell histology
and good prognostic factors.
INF- = interferon-alpha.

GR
A

Table 2: European Association of Urology 2014 evidence-based


mRCC
RCC type
MSKCC risk group First-line
LE^
(3)
Clear cell* favourable,
sunitinib
1b
intermediate and
pazopanib
1b
poor
bevacizumab +
1b
IFN-a (favourableintermediate only)

Clear cell*

poor

temsirolimus

1b

Non-clear
cell

any

sunitinib
everolimus
temsirolimus

2a
2b
2b

IFN- = interferon alpha; LE = level of evidence; MSKCC = Memorial


Sloan-Kettering Cancer Center; mTOR = mammalian target of rapamycin inhibitor; RCC = renal cell carcinoma; TKI= tyrosine kinase inhibitor.
* Doses: IFN-, 9 MU three times per week subcutaneously, bevacizumab 10 mg/kg biweekly intravenously; sunitinib 50 mg daily orally for a
period of 4 weeks, followed by 2 weeks of rest (37.5 mg continuous dosing did not show significant differences); temsirolimus 25 mg weekly
intravenously; pazopanib 800 mg daily orally. Axitinib 5 mg twice daily,
to be increased to 7 mg twice daily, unless > grade 2 toxicity, blood
pressure higher than 150/90mmHg, or the patient is receiving antihy80 Renal Cell Carcinoma

Targeting agents
Novel agents for the treatment of mRCC include drugs
targeting VEGF, other receptor kinases and mammalian target
of rapamycin (mTOR). At present, several targeting drugs have
been approved both in the USA and in Europe for the
treatment of mRCC.
recommendations for systemic therapy in patients with
Second-line*
after VEGFR:
axitinib
sorafenib#
everolimus
after
cytokines:
sorafenib#
axitinib
pazopanib
any targeted
agent
any targeted
agent

LE^ Third-line*

2a
2a
2a

after VEGFR:
everolimus
after mTOR:
sorafenib

LE^ Later lines

2a
1b

any
targeted
agent

LE
4

1b
2a
2a

pertensive medication. Everolimus, 10 mg daily orally.


 o standard treatment available. Patients should be treated in the
N
framework of clinical trials. If a trial is not available, a decision can
be made in consultation with the patient to perform treatment in line
with clear-cell renal cell carcinoma.
Poor risk criteria in the NCT00065468 trial consisted of MSKCC (3) risk
plus metastases in multiple organs.
# Sorafenib was inferior to axitinib in an RCT in terms of PFS but not OS.
^ Level of evidence was downgraded in instances when data was
obtained from subgroup analysis within an RCT.

Renal Cell Carcinoma

81

Recommendations for systemic therapy in mRCC


Systemic therapy for mRCC should be based on
targeted agents
Sunitinib and pazopanib are recommended as first-line
therapy for advanced/metastatic clear-cell RCC.
Bevacizumab + IFN- is recommended as first-line
therapy for advanced/metastatic RCC in favourablerisk and intermediate-risk clear-cell RCC.
Temsirolimus is recommended as a first-line treatment
in poor-risk RCC patients.
Axitinib is recommended as a second-line treatment
for mRCC.
Everolimus is recommended for clear-cell RCC
patients who have failed VEGF-targeted therapy.
Pazopanib and sorafenib are alternatives to axitinib
and are recommended as second-line therapy after
failure of prior cytokines.
Sequencing of targeted agents is recommended.

GR
A
A
A

A
A
A
B

Surveillance following surgery for RCC


Table 3: An example of an algorithm for surveillance following
treatment efficacy
Risk profile
Treatment
Surveillance
6 months
1 year
Low
RN/PN only
US
CT
Intermediate
RN/PN/cryo/RFA CT
US
High

RN/PN/cryo/RFA

CT

CT

RN = radical nephrectomy; PN = partial nephrectomy;


US = ultrasound of abdomen, kidneys and renal bed;
82 Renal Cell Carcinoma

The aim of surveillance is to detect either local recurrence or


metastatic disease while the patient is still surgically curable.
There is no evidence whether early versus later diagnosis of
recurrence improves survival. Surveillance also allows the
urologist to identify postoperative complications, renal function and other morbidities.
Depending on the availability of new effective treatments,
more intensive follow-up schedules may be required, particularly as there is a higher local recurrence rate after cryotherapy and RFA. At present there is no evidence-based standard
for the follow-up of patients with RCC; nor for the optimal
duration of follow-up. An example of a surveillance algorithm
monitoring patients after treatment for RCC that recognises
not only the patients risk profile but also treatment efficacy is
provided in Table 3. For patients with metastatic disease, individualised follow-up is indicated

treatment for RCC taking into account patient risk profile and

2 years
US
CT

3 years
CT
US

4 years
US
CT

5 years
CT
CT

CT

CT

CT

CT

After 5 years
Discharge
CT alternate
2 years
CT alternate
years

CT = computed tomography of chest and abdomen;


cyro = cryotherapy; RFA = radiofrequency ablation.
Renal Cell Carcinoma

83

Recommendations for follow-up in RCC


Follow-up after treatment for RCC should be based
on a patients risk factors and the type of treatment
delivered.
For low-risk disease, CT/MRI can be used infrequently.
In the intermediate-risk group, intensified follow-up
should be performed, including CT/MRI scans at
regular intervals in accordance with a risk-stratified
nomogram.
In high-risk patients, the follow-up examinations
should include routine CT/MRI scans.
There is an increased risk of intrarenal recurrences in
patients treated with minimal invasive therapy, in
larger-size (> 7 cm) tumours treated with nephronsparing surgery, or when there is a positive margin.
Follow-up should be intensified in these patients.

GR
C

C
C

C
C

This short booklet text is based on the more comprehensive


EAU guidelines (ISBN 978-90-79754-65-6), available to all members
of the European Association of Urology at their website http://www.uroweb.org/guidelines/online-guidelines/.
84 Renal Cell Carcinoma

GUIDELINES ON PENILE CANCER


(Text update April 2014)

O.W. Hakenberg (chair), E. Comprat, S. Minhas, A. Necchi,


C. Protzel, N. Watkin

Introduction

The incidence of penile cancer increases with age, with an


age peak during the sixth decade of life. However, the disease
does occur in younger men. There are significant geographical
variations within Europe as well as worldwide. Penile cancer
is common in regions with a high prevalence of human papilloma virus (HPV), which may account for the global incidence
variation as the worldwide HPV prevalence varies considerably. There is at present no recommendation for the use of
HPV vaccination in boys as this controversial.

Classification and pathology

The 2009, Tumour Node Metastasis (TNM) classification


should be used (Table 1). A subclassification of the T2 category
regarding invasion of the corpus spongiosum only or the
corpora cavernosa as well would be desirable as it has been
shown that the prognosis for corpus spongiosum invasion
only is much better than for corpora cavernosa invasion.

Penile Cancer

85

Table 1: 2009 TNM clinical and pathological classification of


penile cancer
Clinical Classification
T - Primary Tumour
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Tis
Carcinoma in situ
Ta
Noninvasive verrucous carcinoma
T1
Tumour invades subepithelial connective tissue
T2
Tumour invades corpus spongiosum or cavernosum
T3
Tumour invades urethra or prostate
T4
Tumour invades other adjacent structures
N - Regional Lymph Nodes
NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis in a single superficial inguinal lymph
node
N2
Metastasis in multiple or bilateral superficial inguinal
lymph nodes
N3
Metastasis in deep inguinal or pelvic lymph node(s),
unilateral or bilateral
M - Distant Metastasis
MX
Distant metastasis cannot be assessed
M0
No distant metastasis
M1
Distant metastasis
pTNM Pathological Classification
The pT, pN and pM categories correspond to the T, N, and M
categories.
pN - Regional Lymph Nodes
pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
86 Penile Cancer

pN1
pN2

Intranodal metastasis in a single inguinal lymph node


Metastasis in multiple or bilateral inguinal lymph
nodes
pN3
Metastasis in pelvic lymph node(s), unilateral or
bilateral or extranodal extension of any regional
lymph node metastasis
pM - Distant Metastasis
pM0 No distant metastasis
pM1
Distant metastasis
G - Histopathological Grading
GX
Grade of differentiation cannot be assessed
G1
Well differentiated
G2
Moderately differentiated
G3-4 Poorly differentiated/undifferentiated
Pathology
Squamous cell carcinoma (SCC)in different variants accounts
for >95% of cases of malignant penile disease. Table 2 lists
premalignant lesions and Table 3 lists the pathological subtypes of penile carcinomas.
Table 2: Premalignant penile lesions (precursor lesions)
Cutaneous horn of the penis
Bowenoid papulosis of the penis
Lichen sclerosus (balanitis xerotica obliterans)
Premalignant lesions (up to one-third transform to invasive
SCC)
Intraepithelial neoplasia grade III
Giant condylomata (Buschke-Lwenstein)
Erythroplasia of Queyrat
Bowens disease
Pagets disease (intradermal ADK)
Penile Cancer

87

Diagnosis and staging of penile cancer

Penile cancer can be cured in > 80% of cases but it is a lifethreatening disease with poor prognosis once metastatic
spread has occurred. Local treatment, although potentially
life-saving, can be mutilating and devastating for the
psychological well-being of the patient supporting the need
for careful diagnosis and adequate staging before any treatment decisions can be made.
Biopsy
In the management of penile cancer there is need for
histological confirmation if:
there is doubt about the exact nature of the lesion (e.g. CIS,
metastasis or melanoma) and/or;
treatment with topical agents, radiotherapy or laser surgery
is planned.

88 Penile Cancer

Table 3: Histological subtypes of penile carcinomas, their


frequency and prognosis
Subtype
Frequency Prognosis
(%)
common SCC 48-65
depends on location, stage and
grade
basaloid
4-10
poor prognosis, frequently early
carcinoma
inguinal nodal metastasis
warty
7-10
good prognosis, metastasis rare
carcinoma
verrucous
3-8
good prognosis, no metastasis
carcinoma
papillary
5-15
good prognosis, metastasis rare
carcinoma
sarcomatoid 1-3
very poor prognosis, early
carcinoma
vascular metastasis
mixed
9-10
heterogenous group
carcinoma
pseudohyper- <1
foreskin, related to lichen
plastic
sclerosus, good prognosis,
carcinoma
metastasis not reported
carcinoma
<1
variant of verrucous carcinoma,
cuniculatum
good prognosis, metastasis not
reported
pseudoglan- <1
high grade carcinoma, early
dular
metastasis, poor prognosis
carcinoma
warty9-14
poor prognosis, high metastatic
basaloid
potential, (higher than warty,
carcinoma
lower than basaloid SCC)

Penile Cancer

89

adenosquamous
carcinoma

<1

mucoepidermoid
carcinoma
clear cell
variant of
penile
carcinoma

<1

1-2

central and peri-meatal glans,


high grade carcinoma, high
metastatic potential but low
mortality
highly aggressive, poor
prognosis
exceedingly rare, associated
with HPV, aggressive, early
metastasis, poor prognosis,
outcome lesion dependent, frequent lymphatic metastasis

Physical Examination
Physical examination of a patient with penile cancer should
include palpation of the penis to examine the extent of local
invasion and careful examination of the groins for regional
lymph node enlargement.
Imaging
Ultrasound (US) can give information about infiltration of
the corpora.
Magnetic resonance imaging (MRI) in combination with
an artificial erection with prostaglandin E1 may be used
for excluding tumour invasion of the corpora cavernosa if
organ-preservation is planned and preoperative decisions
are needed.
In case of non-palpable inguinal nodes current imaging
techniques are not reliable in detecting micro-metastases.
A pelvic CT scan can be performed to assess pelvic lymph
nodes.
In case of positive inguinal nodes, CT of the abdomen and
pelvis and a chest X-ray are recommended; a thoracic CT
will be more sensitive than an X-ray.
90 Penile Cancer

Recommendations for the diagnosis and staging of


penile cancer
Primary tumour
Physical examination, recording morphology, extent
and invasion of penile structures.
MRI with artificial erection in selected cases with
intended organ preserving surgery.
Inguinal lymph nodes
Physical examination of both groins, recording
number, laterality and characteristics of inguinal
nodes
If nodes are not palpable, invasive lymph node
staging in high-risk patients.
If nodes are palpable, a pelvic CT may be indicated,
PET/CT is an option.
Distant metastases
In N+ patients, abdomino-pelvic CT scan and chest
X-ray are required for systemic staging. PET/CT scan
is an option. In patients with systemic disease or with
relevant symptoms, a bone scan may be indicated.
CT = computed tomography; MRI = magnetic resonance
imaging; PET = positron emission tomography.

GR

Treatment

The aims of the treatment of the primary penile cancer lesion


are complete tumour removal with as much organ preservation as possible while radicality of the treatment should not be
compromised.

Penile Cancer

91

Guidelines for stage-dependent local treatment of penile


carcinoma
Primary tumour Conservative treatment is to
LE GR
be considered whenever
possible
Tis
Topical treatment with 5-fluor- 3
C
ouracil or imiquimod for superficial lesions with or without
photodynamic control
Laser ablation with CO2 or
Nd:YAG laser
Glans resurfacing
Ta, T1a (G1, G2)
Wide local excision with
3
C
circumcision
CO2 or Nd:YAG laser surgery
with circumcision
Laser ablation with CO2 or
Nd:YAG laser
Glans resurfacing
Glansectomy with reconstructive surgery, with or without
skin grafting
Radiotherapy by external beam 3
C
or as brachytherapy for lesions
< 4 cm

92 Penile Cancer

T1b (G3) and T2


confined to the
glans

Wide local excision plus reconstructive surgery, with or without skin grafting
Laser ablation with circumcision
Glansectomy with circumcision, with reconstruction
Radiotherapy by external beam
or brachytherapy for lesions
<4 cm in diameter
T2 with invasion Partial amputation and
of the corpora
reconstruction
cavernosa
Radiotherapy by external beam
or brachytherapy for lesions
<4 cm in diameter
T3 with invasion Partial penectomy or total
of the urethra
penectomy with perineal
urethrostomy
T4 with invasion Neoadjuvant chemotherapy
of other adjacent followed by surgery in
structures
responders
Alternative: palliative external
beam radiation.
Local recurrence Salvage surgery with penisafter conservasparing treatment in small
tive treatment
recurrences or partial
amputation.

C
Large or high stage recurrence: 3
partial or total amputation.
CO2 = carbon dioxide; Nd:YAG = neodymium:yttrium-aluminium-garnet.

Penile Cancer

93

Management of inguinal lymph nodes

The treatment of regional lymph nodes is crucial for the survival of the patient. A surveillance strategy carries considerable
risk as regional lymph node recurrence dramatically reduces
the chance of long-term survival. Invasive staging by modified
inguinal lymphadenectomy or dynamic sentinel node biopsy is
recommended for penile cancers pT1G2 and higher.
Guidelines for treatment strategies for nodal metastases
Regional
lymph nodes

LE

GR

2a

> T1G2: invasive lymph node


2a
staging by bilateral modified
inguinal lymphadenectomy or
DSNB.
Palpable
Radical inguinal
inguinal nodes lymphadenectomy
(cN1/cN2)
Fixed inguinal Neoadjuvant chemotherapy follymph nodes
lowed by radical inguinal
(cN3)
lymphadenectomy in responders
Pelvic
Ipsilateral pelvic lymphadenec2a
lymphadenec- tomy is indicated if two or more
tomy
inguinal nodes are involved on
one side (pN2) and in extracapsular nodal metastasis (pN3)
Adjuvant
Indicated in pN2/pN3 patients
2b
chemoafter radical lymphadenectomy
therapy
Radiotherapy Radiotherapy is not indicated for
the treatment of nodal disease in
penile cancer
DSNB = dynamic sentinel node biopsy.

No palpable
inguinal
nodes (cN0)

94 Penile Cancer

Management of regional lymph


nodes is fundamental in the
treatment of penile cancer
Tis, Ta G1, T1G1: surveillance

Guidelines for chemotherapy in penile cancer


patients
Adjuvant chemotherapy (3-4 cycles of TPF) is an
option for patients with pN2-3 tumours.
Neoadjuvant chemotherapy (4 cycles of a cisplatin and taxane-based regimen) followed by
radical surgery is recommended in patients with
non-resectable or recurrent lymph node metastases.
Chemotherapy for systemic disease is an option
in patients with limited metastatic load.
TPF = cisplatin, 5FU plus paclitaxel or docetaxel.

LE

GR

2b

2a

Follow-up

Follow-up after curative treatment in penile carcinoma as in


any malignant disease is important for two reasons:
early detection of recurrence allows for potentially curative
treatment;
the detection and management of treatment-related
complications.
Local recurrence does not significantly reduce long-term
survival if successfully treated while inguinal nodal recurrence
leads to a drastic reduction in the probability of long-term
disease-specific survival.

Penile Cancer

95

Guidelines for follow-up in penile cancer


Interval of follow-up
Years 1-2
Follow-up of the primary tumour
Penile preserving
3 months
treatment

Years 3-5

Amputation

1 year

3 months

6 months

Follow-up of the inguinal lymph nodes


Surveillance
3 months

6 months

pN0 at initial treatment

3 months

1 year

pN+ at initial treatment

3 months

6 months

CT = computed tomography; FNAC = fine-needle aspiration cytology;

Quality of life

Overall, nearly 80% of penile cancer patients of all stages


can be cured. Partial penectomy has negative consequences
for the patients self-esteem and sexual function. Organpreserving treatment allows for better quality of life and sexual function and should be offered to all patients whenever
feasible. Referral to centres with experience is recommended
and psychological support is very important for penile cancer
patients.

96 Penile Cancer

Examinations and
investigations

Maximum duration
of follow-up

GR

Regular physician or
self-examination.
Repeat biopsy after topical or
laser treatment for CIS.
Regular physician or
self-examination.

5 years

5 years

5 years

5 years

5 years

Regular physician or
self-examination.
Regular physician or
self-examination.
US with FNAC optional
Regular physician or
self-examination.
US with FNAC optional
CT/MRI optional.
US = ultrasound.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Penile Cancer

97

GUIDELINES ON TESTICULAR CANCER


(Limited text update March 2011)

P. Albers (chair), W. Albrecht, F. Algaba, C. Bokemeyer,


G. Cohn-Cedermark, K. Fizazi, A. Horwich, M.P. Laguna

Eur Urol 2008 Mar;53(3):478-96,497-513


Eur Urol 2011 Aug;60(2):304-19

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. 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
Familial history of testis cancer in first-grade relatives
Presence of contralateral tumour
Tin or infertility

98 Testicular Cancer

Pathological prognostic risk factors for occult metastatic


disease (for stage I)
For seminoma (not prospectively evaluated)
- 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.
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

Testicular Cancer

99

 eratoma (mature, immature, with malignant component)


T
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
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 (US) of both testes should be performed whenever
a testicular tumour is suspected. An additional US of the
retroperitoneum is recommended to screen for extensive
retroperitoneal metastasis. Ultrasound of both testes should
also be performed in patients with a retroperitoneal mass and/
or elevated tumour serum markers without a palpable scrotal
mass.
100 Testicular Cancer

Serum tumour markers, both before, and 5-7 days after


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

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 is indicated
following 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 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
Testicular Cancer 101

viscera by abdominal CT and thoracic CT/plain radiography


chest. Supraclavicular nodes are to be assessed by 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 US
should be performed if metastases are suspected.
In patients diagnosed with testicular seminoma and a positive
abdominopelvic CT, a chest CT is recommended.
A chest CT scan should be routinely performed in patients
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
102 Testicular Cancer

N - Regional lymph nodes clinical


NX
Regional lymph nodes cannot be assessed
N0
No regional lymph node metastasis
N1
Metastasis with a lymph node mass 2 cm in
greatest dimension, or multiple lymph nodes, none
>2 cm in greatest dimension
N2
Metastasis with a lymph node mass > 2 cm but 5
cm in greatest dimension, or multiple lymph nodes,
any one mass > 2 cm but 5 cm in greatest
dimension
N3
Metastasis with a lymph node mass > 5 cm in
greatest 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

Testicular Cancer 103

S - Serum tumour markers


Sx
Serum markers studies not available or not
performed
S0
Serum marker study levels within normal limits
LDH (U/L)
hCG (mlU/mL)
AFP (ng/mL)
S1
< 1.5 x N and
< 5,000 and
< 1,000
S2
1.5-10 x N or
5,000-50,000 or
1,000-10,000
S3
> 10 x N or
> 50,000 or
> 10,000
1 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.

104 Testicular Cancer

Table 4: Prognostic-based staging system for metastatic


germ cell cancer (IGCCCG)
Good-prognosis group
Non-seminoma (56% of All of the following criteria:
cases)
5-year PFS 89%
Testis/retroperitoneal primary
5-year survival 92%
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
All of the following criteria:
(90% of cases)
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
All of the following criteria:
(28% of 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
All of the following criteria:
(10% of cases)

Testicular Cancer 105

5-year PFS 67%


5-year survival 72%

Poor-prognosis group
Non-seminoma
(16% of cases)
5-year PFS 41%
5-year survival 48%

Any primary site


Non-pulmonary visceral
metastases
Normal AFP
Any hCG
Any LDH
Any of the following criteria:

Mediastinal primary
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.
 uidelines for the diagnosis and staging of testicular
G
GR
cancer
Testicular US is mandatory.
A
Orchidectomy and pathological examination of the
A
testis is necessary to confirm the diagnosis and to
define the local extension (pT category). In a life-threatening situation due to extensive metastasis, chemotherapy has to be started before orchidectomy.

106 Testicular Cancer

Serum determination of tumour markers (AFP, hCG,


A
and LDH) must be performed before and after
orchidectomy for staging and prognostic reasons.
The state of the retroperitoneal, mediastinal, and
A
supraclavicular nodes and visceral state must be
assessed in testicular cancer.
AFP = alpha-fetoprotein; hCG = human chorionic gonadotrophin; LDH = lactate dehydrogenase; US = ultrasound.

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 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.

Testicular Cancer 107

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.
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).

108 Testicular Cancer

GR
A
B
A
A

GR
A

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.

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

Testicular Cancer 109

7. In seminoma stage CS IIB, chemotherapy (4 x EP or


B
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.
8. Seminoma stage IIC and higher should be treated
A
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
recurrence 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
110 Testicular Cancer

epidemiological evidence of increased risk, should also


guide the selection of 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
Year 1
Year 2 Year 3-5 Year 6-10
Physical
4 times
4 times Once/yr. Once/yr.
examination
Tumour markers 4 times
4 times Once/yr. Once/yr.
Plain radioTwice
Twice
graphy chest
Abdominopelvic Twice
CT
(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
Year 2 Year 3-5 Year 6-10
Physical
4 times
4 times Once/yr. Once/yr.
examination
Tumour markers 4 times
4 times Once/yr. Once/yr.
Plain radioTwice
Twice
graphy chest
Abdominopelvic Once
Once
CT
CT = computed tomography; RPLND = retroperitoneal lymph
node dissection.

Testicular Cancer

111

Table 7: Recommended minimum follow-up schedule for


post-orchidectomy surveillance, radiotherapy or
chemotherapy: stage I seminoma
Procedure
Year 1
Year 2 Year 3
Year 4-5
Physical
3 times
3 times Once/yr. Once/yr.
examination
Tumour markers 3 times
3 times Once/yr. Once/yr.
Plain radioTwice
Twice
graphy chest
Abdominopelvic Twice
Twice
CT
CT = computed tomography.
Table 8: Recommended minimum follow-up in advanced
NSGCT and seminoma
Procedure
Year 1
Year 2
Year 3-5
thereafter
Physical
4 times 4 times Twice/yr. Once/yr.
examination
Tumour markers 4 times 4 times Twice/yr. Once/yr.
Plain radio4 times 4 times Twice/yr. Once/yr.
graphy chest
Abdominopelvic Twice
Twice
As indiAs indiCT*
cated
cated
Chest CT
As indi- As indi- As indiAs indicated
cated
cated
cated
Brain CT
As indi- As indi- As indiAs indicated
cated
cated
cated

112 Testicular Cancer

* Abdominal CT 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 should be
repeated 2 and 4 months later to ensure that the mass is
continuing to regress. If available, FDG-PET/CT can be
performed.
A chest CT is indicated if abnormality is detected on plain
radiography chest and after pulmonary resection.
In patients with headaches, focal neurological findings, or
any central nervous system symptoms.
CT = computed tomography; FDG-PET/CT = fluorodeoxyglucose-positron emission tomography computed tomography.

Testicular stromal tumours

Testicular stromal tumours are rare, however, Leydig cell and


Sertoli cell tumours are of clinical relevance.

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
Testicular Cancer 113

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 are
malignant in 10-22% of cases. Morphological signs of
malignancy are:
Large size (> 5 cm);
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
114 Testicular Cancer

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
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.

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.
Testicular Cancer 115

GUIDELINES ON NON-NEUROGENIC
MALE LUTS INCLUDING BENIGN
PROSTATIC OBSTRUCTION (BPO)
(Text update April 2014)

S. Gravas (chair), A. Bachmann, A. Descazeaud, M. Drake,


C. Gratzke, S. Madersbacher, C. Mamoulakis, M. Oelke,
K.A.O. Tikkinen

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 40 years. The multifactorial
aetiology of LUTS is illustrated in Figure 1.

116 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

Figure 1: Causes of male lower urinary tract symptoms (LUTS)

OAB detrusor
overactivity

Benign
Prostatic
Obstruction
(BPO)

And others
...

Distal
ureteral
stone

Nocturnal
polyuria

LUTS

Detrusor
underactivity

Bladder
tumour

Neurogenic
bladder
dysfunction

Urethral
stricture

Urinary
tract
infection

Prostatitis
Foreign
body

Assessment

The high prevalence and the underlying multifactorial pathophysiology mean an accurate assessment of LUTS is critical
to provide best evidence-based care. Clinical assessment of
LUTS aims to differentially diagnose and to define the clinical
profile. A practical algorithm has been developed (Figure 2).

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 117

Recommendations for the assessment of male


LUTS
A medical history must always be taken from
men with LUTS.
A validated symptom score questionnaire with
QoL question(s) should be used for the routine
assessment of male LUTS in all patients and
should be applied for re-evaluation of LUTS
during treatment.
Micturition frequency/volume charts (FVC) or
bladder diaries should be used to assess male
LUTS with a prominent storage component or
nocturia.
FVCs should be performed for the duration of at
least 3 days.
Physical examination including DRE should be a
routine part of the assessment of male LUTS.
Urinalysis (by dipstick or urinary sediment) must
be used in the assessment of male LUTS.
PSA measurement should be performed only
if a diagnosis of PCa will change the management or if PSA can assist in decision-making in
patients at risk of progression of BPE.
Renal function assessment must be performed
if renal impairment is suspected, based on
history and clinical examination or in the presence of hydronephrosis or when considering
surgical treatment for male LUTS.
Measurement of post-void residual (PVR) in
male LUTS should be a routine part of the
assessment.

LE

GR

A*

2b

A*

1b

A*

118 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

Uroflowmetry in the initial assessment of male


LUTS may be performed and should be
performed prior to any treatment.
Imaging of the upper urinary tract (with ultrasound [US]) in men with LUTS should be
performed in patients with a large PVR, haematuria or a history of urolithiasis.
When considering medical treatment for male
LUTS, imaging of the prostate (either by TRUS
or transabdominal US) should be performed if it
assists the choice of the appropriate drug.
When considering surgical treatment, imaging
of the prostate (either by TRUS or transabdominal US) should be performed.
Urethrocystoscopy should be performed in
men with LUTS to exclude suspected bladder
or urethral pathology and/or prior to minimally
invasive/surgical therapies if the findings may
change treatment.
PFS should be performed only in individual
patients for specific indications prior to surgery
or when evaluation of the underlying pathophysiology of LUTS is warranted.
PFS should be performed in men who have had
previous unsuccessful (invasive) treatment for
LUTS.
When considering surgery, PFS may be used for
patients who cannot void > 150 mL.
When considering surgery in men with bothersome, predominantly voiding LUTS, PFS may be
performed in men with a PVR > 300 mL.

2b

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 119

When considering surgery in men with bother3


C
some, predominantly voiding LUTS, PFS may be
performed in men aged > 80 years.
When considering surgery in men with bother3
B
some, predominantly voiding LUTS, PFS should
be performed in men aged < 50 years.
*Upgraded based on Panel consensus.
FVC = frequency volume charts (FVC); LUTS = lower urinary
tract symptoms; PCa = prostate cancer; PFS = pressure flow
studies; PVR = post-void residual.
Figure 2: Assessment algorithm of LUTS in men aged 40 years
or older
Male LUTS

History (+ sexual function)


Symptom Score Questionnaire
Urinalysis
Physical examination
PSA (if diagnosis of PCa will change
the management-discuss with patient)
Measurement of PVR

Look at treatment algorithm

No

Bothersome symptoms

Yes
Abnormal DRE
Suspicion of neurological
disease
High PSA
Abnormal urinalysis

Evaluate according to
relevant
Guidelines or clinical
standard

Treat underlying condition


(if any, otherwise return to
initial assessment)

Significant PVR

US of kidneys
+/- Renal function
assessment

Medical treatment
according to treatment
algorithm

Endoscopy (if test would alter


the choice of surgical modality)
Pressure flow studies (see text
for specific indications)

FVC in cases of
predominant storage
LUTS/nocturia
US assessment of
prostate
Uroflowmetry

Benign conditions of
bladder and/or prostate
with baseline values
PLAN TREATMENT

Surgical treatment
according to treatment
algorithm

120 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

Treatment

Conservative treatment
Watchful waiting is suitable for mild-to-moderate uncomplicated LUTS. It includes education, re-assurance, lifestyle
advice, and periodic monitoring.
Drug treatment
The level of evidence (LE) and the grade of recommendation
(GR) for each treatment option are summarized below.

Recommendations for the conservative and


medical treatment of Male LUTS and follow-up
Men with mild symptoms are appropriate for
watchful waiting.
Men with LUTS should always be offered
lifestyle advice prior to or concurrent with treatment.
a1-blockers can be offered to men with
moderate-to-severe LUTS.
5-ARIs can be offered to men who have
moderate-to-severe LUTS and an enlarged
prostate (> 40 mL)
5-ARIs can prevent disease progression with
regard to acute urinary retention and need for
surgery
Muscarinic receptor antagonists may be used
in men with moderate-to-severe LUTS who have
predominantly bladder storage symptoms.
Carefulness is advised in men with BOO.

LE

GR

1b

1b

1a

1b

1b

1b

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 121

Phosphodiesterase type 5 inhibitors reduce


1a
A
moderate-to-severe (storage and voiding) LUTS
in men with or without erectile dysfunction.
Only tadalafil (5 mg once daily) has been
licensed for the treatment of male LUTS in
Europe.
Vasopressin analogue can be used for the
1b
A
treatment of nocturia due to nocturnal polyuria.
1b
A
Combination treatment with an a1-blocker
together with a 5-ARI can be offered to men
with bothersome moderate-to-severe LUTS,
enlarged prostates, and reduced Qmax (men
likely to develop disease progression).
Combination treatment with an a1-blocker
1b
B
together with a muscarinic receptor antagonist may be used in patients with bothersome
moderate-to-severe LUTS if relief of storage
symptoms has been insufficient with the monotherapy of either drug.
Combination treatment should carefully be pre- 2b
B
scribed in men who may have BOO.
5-ARI = 5 reductase inhibitor; BOO = bladder outlet obstruction; LUTS = lower urinary tract symptoms.

Summary conservative and/or medical treatment

First choice of therapy is behavioural modification, with or


without medical treatment. A flowchart illustrating conservative and medical treatment choices according to evidencebased medicine and patients profiles is provided in Figure 3.

122 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

no

Add Muscarinic
Receptor Antagonist

Residual
storage
symptoms

1-blocker

with or without

Education + Lifestyle Advice

Education + Lifestyle Advice

with or without

Watchful Waiting

no

5-Reductase Inhibitor
1-blocker/PDE5I

with or without

Education + Lifestyle Advice

yes

Muscarinic Receptor
Antagonist

with or without

yes

prostate
volume
> 40 mL?

Education + Lifestyle Advice

yes

storage symptoms
predominant?

no

long-term
treatment?

Nocturnal
polyuria
predominant

no

no

yes

bothersome
symptoms?

Male LUTS

(without indications for surgery)

with or without

Vasopressin Analogue

Education + Lifestyle Advice

yes

Figure 3: Treatment algorithm of male 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).

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 123

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
haematuria 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). Surgery is usually
needed when patients have had insufficient relief in LUTS or
PVR after conservative or medical treatments (relative
operation indications).
Recommendations for surgical treatment of
Male LUTS
M-TURP is the current surgical standard
procedure for men with prostate sizes of
30-80mL and bothersome moderate-to-severe
LUTS secondary of BPO. M-TURP provides subjective and objective improvement rates superior to medical or minimally invasive treatments.
The morbidity of M-TURP is higher than for
drugs or other minimally invasive procedures.
B-TURP achieves short- and midterm results
comparable with M-TURP.
B-TURP has a more favorable perioperative
safety profile compared with M-TURP.
TUIP is the surgical therapy of choice for men
with prostate sizes < 30 mL, without a middle
lobe, and bothersome moderate-to-severe LUTS
secondary to BPO.

LE

GR

1a

1a

1a

1a

1a

124 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

Open prostatectomy or HoLEP is the first choice


of surgical treatment in men with prostate sizes
> 80 mL and bothersome moderate-to-severe
LUTS secondary to BPO needing surgical treatment.
Open prostatectomy is the most invasive
surgical method with significant morbidity.
TUMT and TUNA achieve symptom improvement comparable with TURP, but they are
associated with decreased morbidity and lower
flow improvements.
Durability is in favour of TURP with lower retreatment rates compared to TUMT or TUNA.
HoLEP and 532-nm laser vaporisation of the
prostate are alternatives to TURP in men with
moderate-to-severe LUTS due to BPO leading to
immediate, objective, and subjective improvements comparable with TURP.
The intermediate-term functional results of
532-nm laser vaporisation of the prostate are
comparable with TURP.
The long-term functional results of HoLEP are
comparable with TURP/open prostatectomy.
Diode laser operations lead to short-term
objective and subjective improvement.
ThuVaRP is an alternative to TURP for small- and
medium-size prostates.
ThuVEP leads to short-term objective and
subjective improvement.
With regard to intraoperative safety and
haemostatic properties, diode and thulium
lasers appear to be safe.

1b

1b

1a

1a

1a

1b

1b

1b

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 125

With regard to intraoperative safety, 532-nm


1b
A
laser vaporization is superior to TURP.
532-nm laser vaporization should be considered 3
B
in patients receiving anticoagulant medication
or with a high cardiovascular risk.
Prostatic stents are an alternative to catheteri- 3
C
sation for men unfit for surgery.
Intraprostatic ethanol injections for men with
3
C
moderate-to-severe LUTS secondary to BPO are
still experimental and should be performed only
in clinical trials.
Intraprostatic BTX injections for men with
3
C
bothersome moderate-to-severe LUTS
secondary to BPO or men in urinary retention
are still experimental and should be performed
only in clinical trials.
BPO = benign prostatic enlargement; B-TURP = bipolar TURP;
BTX = botulinum toxin; HoLEP = Holmium laser enucleation;
M-TURP = monopolar TURP; ThuVEP = Tm:YAG vapoenucleation; ThuVaRP = Tm:YAGvaporesection; TUIP: Transurethral
Incision of the Prostate; TUNA = transurethral needle ablation;
TUMT = transurethral microwave therapy; TURP = transurethral resection of the prostate.

Summary surgical treatment

The choice of the surgical technique depends on prostate size,


co-morbidities, ability to undergo anaesthesia, and patients
preference/willingness to accept surgery-associated sideeffects, availability of the surgical armamentarium, and experience of the surgeon. Figure 4 illustrates surgical treatment
choices according to the patient profile.

126 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

TUIP (1)
TURP

< 30 mL

TURP (1)
Laser enucleation
Laser
vaporization
TUMT
TUNA

30 - 80
mL

prostate
volume

low

Male LUTS

Open
prostatectomy (1)
HoLEP (1)
Laser
vaporization
TURP

> 80 mL

can stop
anti-coagulation?

yes

Notice: Readers are strongly recommended to


read the full text that highlights the current
position of each treatment in detail

(1) Current standard/first choice


The alternative treatments are presented in
alphabetical order

yes

High Risk
patients?

with absolute indications for surgery or non-responders toe medical treatment


or those who do not want medical therapy but request active treatment

Laser
vaporization (1)
Laser
enucleation

no

can have
surgery under
anaesthesia?

high

TUMT
TUNA
Stent

no

Figure 4: Treatment algorithm of bothersome 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.

Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 127

Follow-up

Recommended follow-up strategy:


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, PDE5Is, or a combination should be reviewed 4-6
weeks after drug initiation. If patients gain symptomatic
relief, with troublesome side-effects, 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.
patients receiving desmopressin: serum sodium concentration should be measured at day 3 and 7 and 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 side-effects. If patients have symptomatic
relief and there are no side-effects further assessment is
not necessary.
Recommendations for follow-up of Male LUTS LE
Follow-up for all conservative, medical, or opera- 3-4
tive treatment modalities is based on empirical
data or theoretical considerations but not on
evidence-based studies.

GR
C

128 Non-neurogenic Male LUTS including benign prostatic obstruction (BPO)

Readers are strongly recommended to read the full version of


the Guidelines where the efficacy, safety and considerations
for each treatment are presented.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Non-neurogenic Male LUTS including benign prostatic obstruction (BPO) 129

GUIDELINES ON MALE SEXUAL


DYSFUNCTION: Erectile Dysfunction
and Premature Ejaculation
(Text update April 2014)

K. Hatzimouratidis (chair), I. Eardley, F. Giuliano, D. Hatzichristou,


I. Moncada, A. Salonia, Y. Vardi, E. Wespes

Eur Urol 2006 May;49(5):806-15


Eur Urol 2010 May;57(5):804-14
Eur Urol 2012 Sep;62(3):543-52

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.
There is increasing evidence that ED can be an early manifestation of coronary artery and peripheral vascular disease;
thus, ED should not be regarded only as a QoL issue but also
as a potential warning sign of 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, and vascular insufficiency.

130 Male Sexual Dysfunction

Diagnosis and work-up

Basic work-up
The basic work-up (minimal diagnostic evaluation) outlined in
Fig. 1 must be performed in every patient with ED.
Due to the potential cardiac risks associated with sexual
activity, the three 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).
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.
Male Sexual Dysfunction 131

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.
The intracavernous injection test provides limited information about vascular status. However, Duplex ultrasound (US)
provides a simple way of assessing vascular status. Further
vascular investigation is unnecessary if Duplex US is normal,
as indicated by a peak systolic blood flow > 30 cm/s an enddiastolic velocity of < 3 cm/s and a resistance index > 0.8. If
US is abnormal, however, arteriography and DICC should be
performed only in patients who are potential candidates for
vascular reconstructive surgery.

132 Male Sexual Dysfunction

Recommendations for the diagnostic work-up


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.

LE
3

GR
B

Treatment of ED

As a rule, ED can be treated successfully with current treatment options, but cannot be cured, with the exception of:
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 untreated
prostate cancer, unstable cardiac disease and severe LUT
obstruction. 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.
Male Sexual Dysfunction 133

Fig. 1: Minimal diagnostic evaluation (basic work-up) in


patients with ED

Patient with ED (self-reported)

Medical and psychosexual history


(use of validated instruments, e.g. IIEF)
Identify
sexual
problems
other than
ED

Identify
comon
causes of
ED

Identify
reversible
risk factors
for ED

Assess psychosocial
status

Focused physical examination

Penile
deformities

Prostatic
disease

Signs of
hypogonadism

Cardiovascular
and neurological
status

Laboratory tests

Glucose-lipid profile
(if not assessed in the
last 12 months)

Total testosterone
(morning sample).
If indicated, bio-available of
free testosterone

IIEF = International Index for Erectile Function; ED = erectile


dysfunction.
134 Male Sexual Dysfunction

The use of pro-erectile drugs following RP is very important in


achieving erectile function after surgery. Rehabilitation should
start as soon as possible following RP.
Most men with ED will be administered or given 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 satisfaction. A treatment algorithm for ED is given in Fig. 2.

First-line therapy

Oral pharmacotherapy
Three potent, selective PDE5 inhibitors (PDE5Is) 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 is effective following 30-60 min 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 side-effects. Efficacy may be maintained for
up to 12 h. Efficacy rates (erections sufficient for successful
intercourse) are 56%, 77% and 84% in 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
Male Sexual Dysfunction 135

and is adapted according to patient response and side-effects.


Efficacy rates are 67% and 81% in men taking 10 mg and 20 mg
of tadalafil, respectively. Tadalafil also improves erections in
difficult-to-treat subgroups.
Vardenafil (Levitra)
Vardenafil is effective 30 min after 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% in 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 PDE5Is
The choice of a PDE5I 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 PDE5Is
Although PDE5Is 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, dizzi136 Male Sexual Dysfunction

ness, dyspepsia, and nasal congestion. Sildenafil and vardenafil have been associated with visual abnormalities in <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 PDE5Is have demonstrated no increase in myocardial infarction rates. No PDE5I
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 PDE5Is due
to unpredictable hypotension. The duration of interaction
between organic nitrates and PDE5Is varies according to the
PDE5I and nitrate. If a patient develops angina while using a
PDE5I, 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 PDE5I is not worsened, even when the patient is on multiple antihypertensive
agents.
Alpha-blocker interactions
All PDE5Is appear to interact with alpha-blockers, which
under some conditions may result in orthostatic hypotension.
Patients should be stable, on alpha-blocker therapy prior to
initiating combined treatment, and the lowest dose of PDE5Is
should be given initially.
Dosage adjustments
Lower doses of PDE5Is may be required in patients taking
Male Sexual Dysfunction 137

ketoconazole, itraconazole, erythromycin, clarithromycin, and


HIV protease inhibitors (ritonavir, saquinavir). Higher doses of
PDE5Is 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 PDE5Is
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 PDE5I appropriately, there are
several ways of improving efficacy. They include modification
of associated risk factors, treatment of associated hypogonadism, changing to another PDE5I, or continuous use of a PDE5I.
Vacuum erection devices
A vacuum erection device (VED) 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. 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. VED is acceptable for couples in a
stable relationship.

138 Male Sexual Dysfunction

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.
Complications of intracavernosal prostadil 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 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 intra-urethrally 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 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
Male Sexual Dysfunction 139

permanent solution. Prostheses are either malleable (semi


rigid) 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 failures and infections.
With antibiotic prophylaxis, the 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.
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.
When a curable cause of ED is found, it must be
treated first.
PDE5Is are first-line therapy.
Daily administration of PDE5Is may improve
results and restore erectile function.
A vacuum erection device can be used in
patients with stable relationship.
Intracavernous injection is second-line therapy.
Penile implant is third-line therapy.
PDE5I = phosphodiesterase type 5 inhibitor.

140 Male Sexual Dysfunction

LE
1a

GR
A

1b

1b

1a
1b

A
A

1b
4

B
C

Fig. 2: Treatment algorithm for ED


Treatment of erectile dysfunction (ED)

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

PDE5Is

Intracavernous injections
Vacuum devices
Intraurethral alprostadil

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

PDE5I = phosphodiesterase type 5 inhibitor.


Male Sexual Dysfunction 141

PREMATURE EJACULATION

Definition, epidemiology and risk factors


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.
Premature ejaculation has a detrimental effect on self-confidence and relationship with the partner. It may cause mental
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.
142 Male Sexual Dysfunction

Recommendations for the 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 (PROs) have the
potential to identify men with PE. Further
research is needed before PROs can be recommended for clinical use.
Physical examination may be necessary in initial
assessment of PE to identify underlying medical
conditions that may be associated with PE or
other sexual dysfunctions, particularly ED.
Routine laboratory or neurophysiological tests
are not recommended. They should only be
directed by specific findings from history or
physical examination.
IELT = intravaginal ejaculatory latency time.

LE
1a

GR
A

2a

Treatment of PE

In men for whom PE causes few, if any problems, treatment


is limited to psychosexual counselling and education. 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
Male Sexual Dysfunction 143

is the basis of treatment in lifelong PE but dapoxetine is the


only on-demand pharmacological treatment approved for PE
in European countries; all other medications used in PE 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 Fig. 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
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
144 Male Sexual Dysfunction

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 sideeffects 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). 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
Male Sexual Dysfunction 145

such an indication.
Phosphodiesterase type 5 inhibitors
Several recent studies have supported the therapeutic role of
PDE5Is 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.
Guidelines on the treatment of PE
LE
Erectile dysfunction, other sexual dysfunction or 2a
genitourinary infection (e.g. prostatitis) should
be treated first.
Pharmacotherapy should be given as first-line
1a
treatment of lifelong PE.
Pharmacotherapy includes either dapoxetine
1a
on demand (a short-acting SSRI that is the only
approved pharmacological treatment for PE) or
other off-label antidepressants, i.e. daily SSRIs
and clomipramine, that are not amenable to ondemand dosing. With all antidepressant treatment for ED, recurrence is likely after treatment
cessation.
Off-label topical anaesthetic agents can be
1b
offered as a viable alternative to oral treatment
with SSRIs.
Behavioural and sexological therapies have a
3
role in the management of acquired PE. They are
most likely to be best used in combination with
pharmacological treatment.
ED = erectile dysfunction; PE = premature ejaculation;
SSRI = selective serotonin reuptake inhibitor.
146 Male Sexual Dysfunction

GR
B

A
A

Fig. 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
Physical examination

Treatment of premature ejaculation


Patient counselling/education
Discussion of treatment options
If PE is secondary to ED, treat ED first or concomitantly

Pharmacotherapy (recommended as first-line


treatment option in lifelong PE)
o Dapoxetine for on-demand use (the only
approved drug for PE)
o Off-label treatments include chronic daily use
of antidepressants (SSRIs or clomipramine) and
topical anesthetics or oral tramadol on demand
Behavioural therapy, includes stop/start technique,
squeeze and sensate focus
Combination treatment

ED = erectile dysfunction; PE = premature ejaculation;


IELT = intravaginal ejaculatory latency time; SSRI = selective
serotonin receptor inhibitor.

Male Sexual Dysfunction 147

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
148 Male Sexual Dysfunction

GUIDELINES ON
PRIAPISM
A. Salonia, I. Eardley, F. Giuliano, D. Hatzichristou, I. Moncada,
Y. Vardi, E. Wespes, K. Hatzimouratidis

Eur Urol 2014 Feb;65(2):480-9

Definition

Priapism is a pathological condition representing a true disorder of penile erection that persists beyond or is unrelated to
sexual interest or stimulation. Erections lasting up to 4 hours
are defined by consensus as prolonged. Priapism may occur
at all ages.

Classification, epidemiology and pathophysiology

Ischaemic (low-flow or veno-occlusive) priapism


Ischaemic priapism is a persistent erection marked by rigidity
of the corpora cavernosa and by little or no cavernous arterial
inow. The patient typically complains of penile pain and the
examination reveals a rigid erection. Ischaemic priapism is the
most common form of priapism and is considered to be idiopathic in the majority of cases. Ischaemic priapism persisting
beyond 4 hours is considered a compartment syndrome, characterized by pressure within the closed space of the corpora
cavernosa, which severely compromises circulation in the
cavernous tissues. A compartment syndrome requires emergency medical intervention to minimize potential irreversible
consequences, such as corporal fibrosis and permanent erectile dysfunction.
Arterial (high-flow or non-ischaemic) priapism
Arterial priapism is a persistent erection caused by unregulated cavernous arterial inflow. The patient typically reports
Priapism 149

an erection that is not fully rigid and is not associated with


pain. Fully rigid erections under sexual stimulation may occur,
before returning to the previous state of penile tumescence. In
this case, it is not associated with erectile dysfunction.
The most common cause of high-flow priapism is blunt perineal trauma. Priapism often takes up to 2-3 weeks to develop
following the trauma.
Stuttering (recurrent or intermittent) priapism
Stuttering priapism, is a distinct condition characterized by
repetitive, painful, episodes of prolonged erections. Erections
are self-limited with intervening periods of detumescence.
Erectile episodes in stuttering priapism usually resolve more
quickly than in ischaemic priapism.
Sickle cell disease is the most common cause of stuttering
priapism, but the cause may also be idiopathic. Rarely, it is
caused by a neurological disorder.
Conclusions for the epidemiology and
pathophysiology of priapism
Ischaemic priapism is the most common form of
priapism, accounting for more than 95% of all priapism
episodes
Ischaemic priapism is identified as idiopathic in the
vast majority of patients, while sickle cell anaemia is
the most common cause in childhood
Ischaemic priapism occurs relatively often (up to 35%)
after intracavernous injections of papaverine-based
combinations while it is rare (< 1%) after prostaglandin
E1 monotherapy
Priapism is rare in men who have taken
phosphodiesterase type 5 inhibitors with only
sporadic cases reported
150 Priapism

LE
1b

1b

2a

1a

Arterial priapism usually occurs after blunt perineal


trauma
The aetiology of stuttering priapism is the same as
that for the ischaemic priapism. Although sickle cell
disease is the most common cause, priapism can also
be idiopathic or rarely may be due to a neurological
disorder

2
3

Diagnosis

A comprehensive history is the mainstay in priapism diagnosis


and can determine the underlying type of priapism. Ischaemic
priapism is associated with progressive penile pain. The corpora are fully rigid and tender but the glans penis is soft.
Arterial priapism is suspected when there is no pain and
erections are not fully rigid. It can be associated with full erections under sexual stimulation and there is a history of coital
trauma or blunt trauma to the penis.
The onset of post-traumatic high-flow priapism in adults
and children may be delayed by hours to days following the
initial injury. Sexual intercourse is usually not compromised.
The history of stuttering priapism is characterized by recurrent episodes of prolonged erections. Patients seek medical
help when the discomfort interferes with daily life or when
they develop a prolonged episode of ischaemic priapism
requiring emergency medical intervention.

Priapism 151

Recommendations for the diagnosis of priapism


A comprehensive history is the mainstay in priapism
diagnosis and can help to determine the underlying
type of priapism
Physical examination of the genitalia, the perineum
and the abdomen must be included in the diagnostic
evaluation of priapism. It may help to determine the
underlying type of priapism
Laboratory testing should include a complete blood
count, white blood count with blood cell differential,
platelet count and coagulation profile. Further
laboratory testing should be directed by the history
and clinical and laboratory findings
Colour duplex ultrasonography of the penis and
perineum is recommended for the differentiation
between ischaemic and arterial priapism and for
localization of the site of fistula in arterial priapism
Magnetic resonance imaging of the penis can
predict smooth muscle viability and erectile function
restoration
Selected pudendal arteriogram should be reserved
for the management of arterial priapism when
embolization is undertaken

GR
B

MANAGEMENT OF PRIAPISM

Management of ischaemic (low-flow) priapism


Acute ischaemic priapism is an emergency condition and
rapid intervention is compulsory. In many cases, penile
oedema may persist, with ecchymosis and partial erection,
which could eventually mimic unresolved priapism.
First-line treatments
First-line treatments in ischaemic priapism of more than 4
hours duration are highly recommended before any surgical
152 Priapism

treatment. Conversely, first-line treatments initiated beyond


72 hours may have benefits in relieving the unwanted erection
and associated pain, but have little documented benefit in
terms of potency preservation.
The first intervention consists of corporal aspiration. Blood
aspiration may be performed with intracorporeal access
through the glans or with percutaneous needle access on
either lateral aspect of the proximal penile shaft under local
anaesthesia. It must be continued until fresh red, oxygenated, blood is aspired. It has up to a 30% chance of promoting penile detumescence and thus terminating priapism.
Aspiration is followed by intracavernosal injection of
sympathomimetic agents. The rate of resolution of priapism
with this treatment strategy is up to 80%. Phenylephrine has
been suggested as the drug of choice due to its high selectivity for the alpha-1-adrenergic receptor. Other options include
intracavernosal etilephrine, ephedrine, epinephrine, norepinephrine and metaraminol.
Specific measures for sickle cell disease related priapism
include intravenous hydration, alkalinization with bicarbonate,
administration of oxygen and exchange blood transfusion,
with the aim of increasing the tissue delivery of oxygen.
Second-line treatments
Second-line intervention typically refers to surgical intervention in the form of penile shunt surgery. They should be
considered when conservative management options fail.
Intractable, therapy-resistant, acute ischaemic priapism or
episodes lasting more than 48-72 hours usually result in complete erectile function impairment, along with possible major
penile deformity. In these cases, immediate penile prosthesis
surgery has been recommended.
Priapism 153

Recommendations for the treatment of ischaemic


priapism
Ischaemic priapism is an emergency condition and
rapid intervention is compulsory
The specific aim of any emergent treatment is to
retrieve penile flaccidity, without pain, in order to
prevent eventual chronic damage to the corpora
cavernosa
Management of ischaemic priapism should start as
early as possible (within 4-6 hours) and should follow
a stepwise approach. Erectile function preservation is
directly related to the duration of priapism
The first step in the management of ischaemic
priapism is decompression of the corpora cavernosa
by penile aspiration until fresh red blood is obtained.
In cases of drug-induced priapism after intracavernous
injections of vasoactive agents for the treatment of
erectile dysfunction, blood aspiration can be replaced
by intracavernous injection of a sympathomimetic
drug as the first step
In the case of priapism recurrence after aspiration, the
next step is intracavernous injection of a sympathomimetic drug. Phenylephrine is the recommended
drug because of its favourable safety profile on the
cardiovascular system compared to other drugs.
Phenylephrine is usually diluted in normal saline with
a concentration of 100-500 g/mL and given in 1 mL
doses every 3-5 minutes directly into the corpus
cavernosum, up to a maximum dosage of 1 mg for no
more than 1 hour. Patients at high cardiovascular risk
should be given lower doses. Patient monitoring is
highly recommended

154 Priapism

GR
B
C

In recurrent cases of priapism following aspiration


and intracavernous injection of a sympathomimetic
drug, both interventions should be repeated several
times before considering surgical intervention. No
clear recommendation can be given for the highest
phenylephrine dose
Ischaemic priapism caused by sickle cell anaemia is
treated in the same way as idiopathic ischaemic
priapism. Other supportive measures are recommended (intravenous hydration, oxygen administration
with alkalinization with bicarbonates, blood exchange
transfusions) but these should not delay initial
treatment
Surgical treatment is recommended only when blood
aspiration and intracavernous injection of sympathomimetic drugs have failed or for priapism events
lasting < 72 hours
Distal shunt surgical procedures should be performed
first, followed by proximal procedures in case of failure.
The efficacy of this treatment strategy is questionable
and cavernous biopsy may be considered to diagnose
muscle necrosis. No clear recommendation of one
type of shunt over another can be given
In cases of priapism presenting > 36 hours after onset,
or in cases for which all interventions have failed,
erectile dysfunction is inevitable and the immediate
implantation of a penile prosthesis is recommended.
Implantation of penile prosthesis at a later stage can
be difficult due to severe corporal fibrosis

Management of arterial (high-flow) priapism


The management of arterial priapism is not an emergency
because the penis is not ischaemic. Definitive management
can therefore be considered and discussed with the patient so
Priapism 155

that he understands the risks and complications of treatment.


Recommendations for the treatment of arterial
priapism
The management of high-flow priapism is not an
emergency and definitive management can therefore
be considered
Conservative management includes the use of ice
applied to the perineum or site-specific perineal compression. It may be successful, particularly in children
Selective artery embolization, using temporary or
permanent substances, is the suggested treatment
modality and has high success rates
The recurrence of arterial priapism following
selective artery embolization requires the procedure
to be repeated
The preservation rate of sexual function preservation
rates is about 80%. No definitive statement can be
made on the best substance for embolization in terms
of sexual function preservation
Selective surgical ligation of the fistula should be
reserved as a last treatment option when embolization
has failed

GR
B

Management of stuttering priapism


The primary goal in the management of patients with stuttering priapism is the prevention of future episodes, and this goal
can usually be achieved pharmacologically. The management
of each acute episode is similar to that for ischaemic priapism,
namely aspiration/irrigation in combination with intracavernous injections of alpha-adrenergic agonists.

156 Priapism

Recommendations for the treatment of stuttering


priapism
The primary goal in the management of patients
with stuttering priapism is the prevention of future
episodes, which can generally be achieved pharmacologically. The management of each acute episode is
similar to that for ischaemic priapism
Hormonal therapies (mainly gonadotropin-receptor
hormone agonists or antagonists) and/or antiandrogens may be used for the prevention of future
episodes. They should not be used before sexual
maturation is reached
Phosphodiesterase type 5 inhibitors have a
paradoxical effect in alleviating and preventing
stuttering priapism, mainly in patients with idiopathic
and sickle cell disease associated priapism. Treatment
should be initiated only when the penis is in its flaccid
state
Other systemic drugs (digoxin, alpha-adrenergic
agonists, baclofen, gabapentin, terbutaline) can be
considered, but data are even more limited
Intracavernosal self-injections at home of sympathomimetic drugs can be considered for the treatment
of acute episodes on an interim basis until ischaemic
priapism has been alleviated

GR
B

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Priapism 157

GUIDELINES ON
PENILE CURVATURE
K. Hatzimouratidis (chair), I. Eardley, F. Giuliano, D. Hatzichristou,
I. Moncada, A. Salonia, Y. Vardi, E. Wespes

Eur Urol 2012 Sep;62(3):543-52

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 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.
158 Penile Curvature

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 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.
Ultrasound (US) measurement of the plaques size is inaccuPenile Curvature 159

rate and operator-dependent and is not recommended in everyday clinical practice. Doppler US 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
methodological problems that make it difficult to provide
recommendations in everyday real life.
Recommendations on non-operative treatment LE
for Peyronies disease
Conservative treatment for Peyronies disease is 3
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.

160 Penile Curvature

GR
C

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.
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 does not
reduce penile curvature, plaque size or penile
pain and is 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

1b

1b

1b

1b

1b

2b

Penile Curvature 161

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
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
162 Penile Curvature

in Peyronies disease. The treatment algorithm is presented in


Figure 1.
Recommendations on surgical treatment for
penile curvature
Surgery is indicated when Peyronies disease
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.

LE

GR

2b

2b

2b

Penile Curvature 163

Table 1: Results of surgical treatments for Peyronies disease


(data from different, non-comparable studies)
Tunical shortening
Tunical
procedures
lengthening
procedures
Nesbit
Plication
Grafts
Penile shortening
4.7-30.8% 41-90%
0-40%
Penile straightening 79-100%
58-100%
74-100%
Persistent or
4-26.9%
7.7-10.6%
0-16.7%
recurrent curvature
Post-operative
0-13%
0-22.9%
0-15%
erectile dysfunction
Penile hypoesthesia 2-21%
0-21.4%
0-16.7%
Technical
1
At least 3 Many types
modifications
of grafts and
techniques
used

164 Penile Curvature

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 US)

Stable disease
(no pain, no deformity deterioration,
calcification plaques on US)

Conservative treatment

Surgical treatment

No ED

Yes
Adequate penis length
Curvature < 60
Absence of special
deformities (hour-glass,
hinge)

Nesbit or plication
procedures

Short penis
Curvature > 60
Presence of special
deformities (hour-glass,
hinge)

Tunica lengthening
procedures

ED

Response
to
treatment

No

Penile
prosthesis
(remodelling,
plaque)

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 165

GUIDELINES FOR THE INVESTIGATION


AND TREATMENT OF MALE
INFERTILITY
(Text update March 2013)

A. Jungwirth, T. Diemer, G.R. Dohle, A. Giwercman, Z. Kopa,


C. Krausz, H. Tournaye

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.

Diagnosis

The diagnosis of male fertility should focus on a number of


prevalent disorders (Table 1). Simultaneous assessment of the
female partner is preferable, even if abnormalities are found in
166 Male Infertility

the male, since data show that in 1 out of 4 couples both male
and female partners have pathological findings.
Table 1: Reasons for a reduction in male fertility
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, antisperm
antibodies)
Systemic diseases (diabetes, renal and liver insufficiency,
cancer, hemochromatosis)
Exogenous factors (medications, toxins, irradiation)
Lifestyle factors (obesity, smoking, drugs, anabolic steroids)
Idiopathic (40-50% of cases)
Semen analysis
Semen analysis forms the basis of decisions concerning further treatment. Analysis should be performed in a laboratory
adhering to national quality control standards (Table 2).
Table 2: Lower reference limits (5th centiles and 95%
confidence intervals) for semen characteristics*
Parameter
Lower reference
limit (95% CI)
Semen volume (mL)
1.5 (1.4-1.7)
39 (33-46)
Total sperm number (106 per ejaculate)
Sperm concentration (106 per mL)
15 (12-16)
Male Infertility 167

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
pH
7.2
Peroxidase-positive leukocytes
< 1.0
(106 per mL)
MAR test (motile spermatozoa with
< 50
bound particles, %)
Immunobead test (motile spermatozoa < 50
with bound beads, %)
Seminal zinc (mol/ejaculate)
2.4
Seminal fructose (mol/ejaculate)
13
Seminal neutral glucosidase
20
(mU/ejaculate)
*WHO Manual for Semen Analysis, 5th edn, 2010.
Recommended number of semen analyses
If values are normal, 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), asthenozoospermia (< 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.
168 Male Infertility

Hormonal screening can be limited to determining the levels


of follicle stimulating hormone (FSH), luteinizing hormone
(LH), testosterone and sex hormone binding globulin (SHBG)
in cases of abnormal semen parameters. In men diagnosed
with azoospermia or extreme OAT, it is important to distinguish between obstructive and non-obstructive causes.
Criteria with a reasonable predictive value for 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.
Hypogonadotrophic hypogonadism (low 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 - idiopathic Hypogonadotrophic
Hypogonadism (iHH), Kallmanns syndrome,
Prader-Willi syndrome;
Acquired anomalies - acquired hypothalamic/pituitary
gland diseases (malignant CNS tumours, pituitary
adenoma, hyperprolactinaemia, granulomatous illness,
hemochromatosis);
Exogenous factors - drugs (anabolic steroids, obesity,
irradiation).
Male Infertility 169

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).
White blood cells detected in a semen sample, in combination
with a small ejaculate volume, 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 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
170 Male Infertility

is Klinefelters syndrome (47, XXY), which affects around 14%


of men diagnosed with azoospermia. Klinefelters syndrome is
characterised by hypergonadotrophic hypogonadism which
may be associated with eunuchoid features and/or gynaecomastia. Both testicles are very small due to extensive tubular
sclerosis. In 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
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 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; over 85% of all males diagnosed with
CAVD also test positive for two CFTR-gene mutations when
the entire gene is sequenced. In cases of a homozygous CFTR
mutation carrier with a mutation carrier partner, depending on
the mutations involved, there is a 50% chance of a child with
CF or CAVD. Genetic counselling is mandatory in these cases.
Ultrasonography
Ultrasonography (US) is a useful tool for locating intrascrotal
lesions. Colour Doppler US of the scrotum can detect a variMale Infertility 171

cocele 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
2-5% 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 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
- TESE) 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);
Absence of germ cells (Sertoli cell only syndrome);
Maturation arrest - spermatogenesis arrested at different
stages (spermatogonia, spermatocytes or spermatides);

172 Male Infertility

H
 ypospermatogenesis - all cell types up to spermatozoa
are present, but there is a distinct decline in the number of
reproducing spermatogonia.

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)
may have a positive influence on semen quality but infertile
couples should be advised that current evidence on their
benefit to promote pregnancy is inconclusive. 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 3
times per week, and add HMG or FSH 75-150 IU 3 times per
week, until spermatogenesis occurs;
Hyperprolactinaemia: dopamine agonists.
In patients with anti-sperm antibodies, high-dose steroids are
not recommended because of serious side-effects and questionable benefit.
Male Infertility 173

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 has a oligo- or asthenozoospermia, 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.
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 (20-30%), it is advisable to combine this
procedure with microsurgical epididymal sperm aspiration
(MESA), and cryopreserve the harvested spermatozoa for ICSI.
174 Male Infertility

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/testicular sperm extraction (TESE) 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). In 50-60% 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.
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
Male Infertility 175

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.
Diagnosis is based on the medical history of post-ejaculate
urine. Retrograde ejaculation should also be suspected if the
ejaculate volume is very low (partial retrograde ejaculation).
Treatment of retrograde ejaculation aimes at removing the
cause of the disorder or harvesting spermatozoa from the
urine after orgasm. Anejaculation can be treated by vibrostimulation or electro-ejaculation techniques. It is possible to
induce ejaculation in around 90% of patients with spinal cord
injuries. However, 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. TESE, in-vitro
fertilisation, and ICSI are often required.
Recommendations
Testicular biopsy is the best procedure to define the
histological diagnosis and possibility of finding sperm.
Spermatozoa should be cryopreserved for use in ICSI.
Men with NOA can be offered TESE with cryopreservation of the spermatozoa to be used for ICSI.
To increase the chances of positive sperm retrieval
in men with NOA, TESE (microsurgical or multiple)
should be used.
Testing for microdeletions is not necessary in men
with OA (with normal FSH) when ICSI is used because
spermatogenesis should be normal.

176 Male Infertility

GR
A

A
A

Men with severely damaged spermatogenesis (spermatozoa < 5 million/mL) should be advised to undergo
Yq microdeletion testing for both diagnostic and prognostic purposes. Yq microdeletion also has important
implications for genetic counselling (see below).
If complete AZFa or AZFb microdeletions are detected, micro-TESE is not necessary because it is extremely unlikely that any sperm will be found.
If a man with Yq microdeletion and his partner wish to
proceed with ICSI, they should be advised that microdeletions will be passed to sons, but not to daughters.
Standard karyotype analysis should be offered to all
men with damaged spermatogenesis
(spermatozoa <10 million/mL) who are seeking fertility
treatment by IVF.
Genetic counselling is mandatory in couples with a
genetic abnormality found in clinical or genetic investigation and in patients who carry a (potential) inheritable disease.
When a man has structural abnormalities of the vas
deferens (unilateral or bilateral absence), he and his
partner should be tested for CF gene mutations.
Aetiological treatments for ejaculatory disorders
should be offered before sperm collection and ART is
performed.

B
A

This short booklet text is based on the more comprehensive EAU


guidelines (978-90-79754-71-7), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Male Infertility 177

GUIDELINES ON
MALE HYPOGONADISM
G.R. Dohle (chair), 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 comorbidities, and in men with a poor health status.

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.
178 Male Hypogonadism

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
Main causes
(testicular insufficiency)
Congenital forms
Klinefelter syndrome
Testicular dysgenesis
(cryptorchidism)
Congenital anorchia
Acquired forms
Testicular malignancy
Orchitis
Medications (chemotherapy)
Systemic diseases
Acquired anorchia
Secondary forms
Main causes
(hypothalamic-pituitary
dysfunctions)
Congenital forms
Kallmann syndrome
Idiopathic
hypogonadotrophic
hypogonadism (IHH)

Male Hypogonadism 179

Acquired forms

Late onset hypogonadism


(Combined testicular and
hypothalamic pituitary
insufficiency)
Androgen receptor
insensitivity

Pituitary tumour
(prolactinoma)
Drugs
Systemic disease (renal
failure, haemochromatosis,
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 (Tables 2 and 3),
together with consistently low serum testosterone levels.
Table 2: Signs and symptoms suggesting prepubertal-onset
hypogonadism
Small testes
Cryptorchidism
Gynaecomastia
High voice
Unclosed epiphyses
Linear growth into adulthood
Eunuchoid habitus
Sparse body/facial hair
180 Male Hypogonadism

Infertility
Low bone mass
Sarcopenia
Reduced sexual desire/activity
Table 3: Signs and symptoms associated with late-onset
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
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;
Male Hypogonadism 181

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 or MRI)
of the sellar region and complete endocrine work-up is
requested when a pituitary tumour is suspected.
Recommendations for screening
Screening for testosterone deficiency is only recommended in adult men with consistent and preferably
multiple signs and symptoms, listed in Tables 2 and 3.
Adult men with established severe hypogonadism
should be screened for concomitant osteoporosis.
Total testosterone assessment should be repeated at
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

GR
C

B
A

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.
182 Male Hypogonadism

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).

Male Hypogonadism 183

Table 6: Testosterone preparations for replacement therapy


Formulation Administration Advantages Disadvantages
Testosterone Oral; 2-6 cps
Absorbed
Variable
undecanoate every 6 h
through the
levels of
lymphatic
testosterone
system, with above and
consequent
below the
reduction of
mid-range.
liver involve- Need for
ment
several doses
per day with
intake of fatty
food
Testosterone Intramuscular;
Short-acting Possible
cypionate
one injection
preparation
fluctuation of
every 2-3 weeks
that allows
testosterone
drug withlevels
drawal in case
of onset of
side effects
Testosterone Intramuscular;
Short-acting Possible
enanthate
one injection
preparation
fluctuation of
every 2-3 weeks
that allows
testosterone
drug withlevels
drawal in case
of onset of
side effects

184 Male Hypogonadism

Testosterone
undecanoate

Intramuscular;
Steady-state
one injection
testosterone
every 10-14 weeks levels without
fluctuation

Transdermal
testosterone

Gel or skin
patches; daily
application

Sublingual
testosterone

Sublingual; daily
doses

Buccal
testosterone

Buccal tablet;
two doses per
day

Subdermal
depots

Subdermal
implant every 5-7
months

Long-acting
preparation
that cannot
allow drug
withdrawal
in case of
onset of side
effects
Steady-state Skin irritation
testosterone at the site of
level without application
fluctuation
and risk of
interpersonal
transfer
Rapid absorp- Local irritation and
tion
achievement
of physiological serum
level of testosterone
Rapid absorp- Irritation and
tion and
pain at the
achievement site of appliof physiologi- cation
cal serum
level of testosterone
Long duration Risk of infecand constant tion and
serum testo- extrusion of
sterone level the implants

Male Hypogonadism 185

In patients with secondary hypogonadism, anti-oestrogens or


hormonal stimulation with hCG and FSH or alternatively GnRH
can restore testosterone production.
Recommendations
The patient should be fully informed about expected
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
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 can
only be recommended for hypogonadal patients who
are receiving simultaneous fertility treatment.

Risk factors in testosterone treatment

GR
A

C
 ase reports and small cohort studies point to a possible
correlation between TRT and the onset of breast cancer,
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.

186 Male Hypogonadism

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.
TRT = testosterone replacement therapy; PSA = prostate
specific antigen.

GR
A

Recommendations for monitoring


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.

GR
C

A
C

C
A

Male Hypogonadism 187

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 Hypogonadism

GUIDELINES ON URINARY
INCONTINENCE
(Text update April 2014)

M.G. Lucas (chair), D. Bedretdinova, J.L.H.R. Bosch,


F. Burkhard, F. Cruz, D.J.M.K. de Ridder, A. Nambiar, C.G. Nilsson,
A. Tubaro, R.S. Pickard

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).

ASSESSMENT AND DIAGNOSIS


History and Physical Examination

Take a history to include the following;


Type of incontinence (stress, urgency or mixed)
Timing and severity
Associated urinary symptoms
Obstetric and gynaecological history
Any comorbidities
Medication review
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
Urinary Incontinence 189

Consider early referral to specialist if:


Urinary incontinence associated with pain
Haematuria
History of recurrent urinary tract infection
Previous pelvic surgery or radiotherapy
Constant leak suspicious of fistula
Any voiding difficulty
Suspicion of neurological disease

Questionnaires
Recommendation
Use a validated and appropriate questionnaire when
standardised assessment is required.
* Recommendation based on expert opinion

GR
B*

Voiding diaries
Recommendations
GR
Ask patients to complete a voiding diary to evaluate
A
co-existing storage and voiding dysfunction in patients
with urinary incontinence.
Use a diary duration of between 3 and 7 days.
B

Urinalysis and UTI


Recommendations
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.
* Recommendation based on expert opinion.
190 Urinary Incontinence

GR
A*
A

Post-voiding residual volume


Recommendations
Use ultrasound to measure post-voiding residual.
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.
Consider the presence of voiding dysfunction in
patients whose post-voiding residual is persistently
above 100 mL.
* Recommendation based on expert opinion.

GR
A
B
C
B

A*

Urodynamics
Recommendations
GR
(NB: These refer only to neurologically intact adults
with urinary incontinence)
Clinicians carrying out urodynamics in patients with
C
urinary incontinence should:
Ensure that the test replicates the 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
C
be useful in discussing treatment options, although
there is limited evidence that performing urodynamics
will predict the outcome of treatment for urinary
incontinence.
Urinary Incontinence 191

Do not routinely carry out urodynamics when offering


conservative treatment for urinary incontinence.
Perform urodynamics if the findings may change the
choice of invasive treatment.
Do not use urethral pressure profilometry or Leak
Point pressures to grade severity of incontinence or
predict the outcome of treatment.
Urodynamic practitioners should adhere to the standards laid out in the ICS document Good Urodynamic
Practice.

B
B
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 standardise pad testing,
there remain differences in the way patients are instructed to
undertake activity during the test.
Recommendations
Use a pad test when quantification of urinary incontinence is required.
Use repeat pad test after treatment if an objective
outcome measure is required.

GR
C
C

Imaging
Recommendations
Do not routinely carry out imaging of the upper or
lower urinary tract as part of the assessment of
urinary incontinence.
Do not include bladder (detrusor) wall thickness
measurement in the routine assessment of urinary
incontinence.
192 Urinary Incontinence

GR
A

CONSERVATIVE MANAGEMENT

Conventional medical practice encourages the use of simple,


relatively harmless, interventions before resort to those associated with higher risks.

Medical conditions associated with incontinence

These conditions include:


cardiac failure
chronic renal failure
diabetes
chronic obstructive pulmonary disease
neurological disease including stroke and 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
Take a drug history from all patients with urinary
incontinence.
For women taking oral conjugated equine oestrogen
as hormone replacement therapy who develop or
worsen UI, suggest discussion of alternative hormone
replacement therapies with the relevant clinician.
Advise women who are taking systemic oestradiol
who suffer from UI, that stopping the oestradiol is
unlikely to improve their incontinence.
Review any new medication associated with the development or worsening of urinary incontinence.

GR
A
A

Urinary Incontinence 193

Constipation

Several studies have shown strong associations between


constipation, urinary incontinence and overactive bladder.
Constipation can be improved by behavioural and medical
treatments.
Recommendation
For adults with urinary incontinence, treat co-existing
constipation.

GR
C

Containment (pads etc)


Recommendations
Ensure that adults with urinary incontinence and/
or their carers are informed regarding available treatment options before deciding on containment alone.
Suggest use of disposable insert pads for women and
men with light urinary incontinence.
In collaboration with other healthcare professionals
help adults with moderate/severe urinary incontinence to select the individually best containment
regimen considering pads, external devices and
catheters, and balancing benefits and harms.
Choice of pad from the wide variety of different
absorbent materials and designs available should be
made with consideration of the individual patients
circumstance, degree of incontinence and preference.
* Based on expert opinion.

Lifestyle Changes

GR
A*

A*
A*

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
194 Urinary Incontinence

weight loss, fluid restriction, reduction of caffeine or alcohol


intake, limiting heavy activity and stopping smoking.
Recommendations
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
Offer supervised intensive PFMT, lasting at least 3
months, as a first-line therapy to women with stress
urinary incontinence or mixed urinary incontinence.
PFMT programmes should be as intensive as possible.
Offer PFMT to elderly women with urinary incontinence.
Consider using biofeedback as an adjunct in women
with stress urinary incontinence.
Offer instruction on PFMT to men undergoing radical
prostatectomy to speed recovery of incontinence.

GR
A

A
B
A
B

Urinary Incontinence 195

Offer bladder training as a first-line therapy to adults


A
with urgency urinary incontinence or mixed urinary
incontinence.
Offer timed voiding to adults with incontinence, who
A
are cognitively impaired.
Do not offer electrical stimulation with surface elecA
trodes (skin, vaginal, anal) alone for the treatment of
stress urinary incontinence.
Consider offering electrical stimulation as an adjunct B
to behavioural therapy in patients with urgency UI.
Do not offer magnetic stimulation for the treatment of B
incontinence or overactive bladder in adult women.
Do not offer PTNS to women or men who are seeking A
a cure for urgency urinary incontinence.
Offer, if available, P-PTNS as an option for improveB
ment of urgency urinary incontinence in women, but
not men, who have not benefitted from antimuscarinic
medication.
Support other healthcare professionals in use of reha- A
bilitation programmes including prompted voiding for
care of elderly care-dependent people with urinary
incontinence.
PFMT = pelvic floor muscle training; P-PTNS = percutaneous
posterior tibial nerve stimulation; PTNS = posterior tibial nerve
stimulation.

196 Urinary Incontinence

Conservative therapy in mixed urinary incontinence


Recommendations
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.

GR
C
B

DRUG TREATMENT OF URINARY INCONTINENCE


Antimuscarinics
Recommendations
Offer IR or ER formulations of antimuscarinic drugs
as initial drug therapy for adults with urgency urinary
incontinence.
If IR formulations of antimuscarinic drugs are unsuccessful for adults with urgency urinary incontinence,
offer ER formulations or longer-acting antimuscarinic
agents.
Consider using transdermal oxybutynin if oral
antimuscarinic agents cannot be tolerated due to dry
mouth.
Offer and encourage early review (of efficacy and side
effects) of patients on antimuscarinic medication for
urgency urinary incontinence (< 30 days).
IR = immediate release; ER = extended release.

GR
A

Urinary Incontinence 197

Adrenergic drugs in the elderly


Recommendations
In older people being treated for urinary incontinence,
every effort should be made to employ non- pharmacological treatments first.
Use antimuscarinic drugs with caution in elderly
patients who are at risk of, or have, cognitive dysfunction.
In older people who are being prescribed antimuscarinic drugs for control of UI, consider modifications
to other medications to help reduce anticholinergic
load.
Check mental function in patients on antimuscarinic
medication if they are at risk of cognitive dysfunction.

GR
C

Adrenergic drugs
Recommendation
GR
Offer mirabegron to people with urgency urinary
B
incontinence, but warn patients receiving mirabegron
that the possible long-term side effects remain uncertain.

Duloxetine
Recommendations
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.

198 Urinary Incontinence

GR
A
B*

Duloxetine should be initiated using dose titration


because of high adverse effect rates.
* Downgraded based on expert opinion.

Oestrogen
Recommendations
Offer post-menopausal women with urinary incontinence vaginal oestrogen therapy particularly if other
symptoms of vulvovaginal atrophy are present.
Do not offer oral (systemic) oestrogen replacement
therapy as treatment for urinary incontinence.
Offer vaginal oestrogen therapy to post-menopausal
women with urinary incontinence, and vaginal atrophy.
Vaginal oestrogen therapy should be long-term and in
an appropriate dose.

GR
A

A
A
C

Desmopressin
Recommendations
GR
Offer desmopressin to patients requiring occasional
B
short-term relief from urinary incontinence and inform
them that this drug is not licensed for this indication.
Do not use desmopressin for long-term control of uri- A
nary incontinence.

Urinary Incontinence 199

Drug treatment in mixed urinary incontinence


Recommendations
Treat the most bothersome symptom first in patients
with mixed urinary incontinence.
Offer antimuscarinic drugs to patients with urgencypredominant mixed urinary incontinence.
Consider duloxetine for patients with mixed urinary
incontinence unresponsive to other conservative
treatments and who are not seeking cure.

GR
C
A*
B

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
procedures 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

Surgery for uncomplicated stress urinary incontinence


in women
Recommendations
Offer the mid-urethral sling (self-fixing, retropubic,
transobturator or single incision) to women with
uncomplicated stress urinary incontinence as the
preferred surgical intervention whenever available.

200 Urinary Incontinence

GR
A

Warn women who are being offered a retropubic insertion of midurethral 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 who are being offered a single-incision
sling that long-term efficacy remains uncertain.
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.
Offer colposuspension (open or laparoscopic) or
autologous fascial sling to women with stress urinary
incontinence if mid-urethral sling cannot be considered.
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.
Inform older women with stress urinary incontinence
about the increased risks associated with surgery,
including the lower probability of success.
Inform women that any vaginal surgery may have an
impact on sexual function.
Women who suffer from multiple risk factors should
be warned that they are less likely to have a successful
outcome from surgery for stress urinary incontinence.
Only offer new devices, for which there is no level 1
evidence base, as part of a structured research programme.

A
C

A*

Urinary Incontinence 201

Only offer adjustable mid-urethral sling as a primary


A*
surgical treatment for stress urinary incontinence as
part of a structured research programme.
Do not offer bulking agents to women who are seeking A
a permanent cure for stress urinary incontinence.
* Recommendation based on expert opinion

Surgery for complicated stress urinary incontinence in


women
Recommendations
GR
The choice of surgery for recurrent stress urinary
C
incontinence should be based on careful evaluation of
the individual patient including video-urodynamics.
Warn women with recurrent stress urinary incontiC
nence, that the outcome of a surgical procedure, when
used as a second-line treatment, is generally inferior
to its use as a first-line treatment, both in terms of
reduced efficacy and increased risk of complications.
Consider secondary synthetic sling, colposuspension C
or autologous sling as first options for women with
complicated stress urinary incontinence.
Implantation of AUS or ACT for women with comC
plicated stress urinary incontinence should only be
offered in expert* centres.
Warn women receiving AUS or ACT that, even in
C
expert centres, there is a high risk of complications,
mechanical failure or a need for explantation.
AUS = artificial urinary sphincter; ACT = adjustable compression therapy.
* expert centres refers to the comments on surgeon volume in
the introduction to the surgical chapter.

202 Urinary Incontinence

Recommendations for women requiring surgery


for bothersome POP who have symptomatic or
unmasked stress urinary incontinence
Offer simultaneous surgery for POP and stress urinary
incontinence.
Warn women of the increased risk of adverse events
with combined surgery compared to prolapse surgery
alone.
Recommendations for women requiring surgery for
bothersome POP without symptomatic or unmasked
stress urinary incontinence
Warn women that there is a risk of developing de novo
stress urinary incontinence after prolapse surgery.
Inform women that the benefit of prophylactic stress
urinary incontinence surgery is uncertain.
Warn women that the benefit of surgery for stress
urinary incontinence may be outweighed by the
increased risk of adverse events with combined surgery compared to prolapse surgery alone.
Attempt to unmask occult SUI by a prolapse reduction
stress test.
Symptomatic urethral diverticula should be completely surgically removed.
POP = pelvic organ prolapse; SUI = stress urinary
incontinence.
* based on expert opinion.

GR

A
A

GR

A
C
A

A*

Urinary Incontinence 203

Recommendations for surgery in men with stress


GR
urinary incontinence
Only offer bulking agents to men with mild post-pros- C
tatectomy incontinence who desire temporary relief of
incontinence symptoms.
Do not offer bulking agents to men with severe postC
prostatectomy incontinence.
Offer fixed slings to men with mild-to-moderate post- B
prostatectomy incontinence.
Warn men that severe incontinence, prior pelvic radio- C
therapy or urethral stricture surgery, may worsen the
outcome of fixed male sling surgery.
Offer AUS to men with moderate-to-severe post-pros- B
tatectomy incontinence.
Implantation of AUS or ACT for men should only be
C
offered in expert centres.
Warn men receiving AUS or ACT that, even in expert
C
centres, there is a high risk of complications, mechanical failure or a need for explantation.
Do not offer non-circumferential compression device C
(ProACT) to men who have had pelvic radiotherapy.
AUS = artificial urinary sphincter; ACT = artificial compression
device.

204 Urinary Incontinence

Surgical interventions for Refractory Detrusor


Overactivity
Intravesical injection of onabotulinumtoxinA
Recommendations
Offer onabotulinumtoxinA (100 units) intravesical
injections to patients with urgency urinary incontinence refractory to antimuscarinic therapy.
Warn patients of the limited duration of response, the
possible prolonged need to self-catheterise (ensure
that they are willing and able to do so) .

GR
A

Sacral nerve stimulation


Recommendation
If available, offer sacral nerve modulation to patients,
who have urgency urinary incontinence refractory to
conservative therapy.

GR
A

Cystoplasty/Urinary Diversion
Recommendations
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.

GR
C

Urinary Incontinence 205

Only offer urinary diversion to patients who have failed C


less invasive therapies for the treatment of urinary
incontinence and who will accept a stoma.
Warn patients undergoing augmentation cystoplasty
C
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 C
have undergone augmentation cystoplasty or urinary
diversion.

Surgery in patients with mixed urinary incontinence


Recommendations
Treat the most bothersome symptom first in patients
with 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
A

Surgery for UI in the elderly


Recommendation
Inform older women with urinary incontinence about
the increased risks associated with surgery (including
BTX injection), together with the lower probability of
benefit.

GR
B

Urinary Fistula*
Recommendations
General
Surgeons undertaking complex pelvic surgery should
be competent at identifying, preserving and repairing
the ureter.
206 Urinary Incontinence

GR
C

Do not routinely use ureteric stents as prophylaxis


against injury during routine gynaecological surgery.
Suspect ureteric injury or fistula in patients following
pelvic surgery if a fluid leak or pelvicalyceal dilatation
occurs postoperatively or if drainage fluid contains
high levels of creatinine.
Suspect uretero-arterial fistula in patients presenting
with haematuria with a history of relevant surgery.
Use three dimensional imaging techniques to diagnose and localise urinary fistulae.
Manage upper urinary tract fistulae by conservative
or endoluminal technique where such expertise and
facilities exists.
Surgical principles
Surgeons involved in fistula surgery should have
appropriate training, skills, and experience to select an
appropriate procedure for each patient.
Attention should be given as appropriate to skin care,
nutrition, rehabilitation, counselling and support prior
to and following fistula repair.
if a vesicovaginal fistula is diagnosed within six weeks
of surgery, consider indwelling catheterisation for a
period of up to 12 weeks after the causative event.
Tailor the timing of fistula repair to the individual
patient and surgeon requirements once any oedema,
inflammation, tissue necrosis, or infection are
resolved.
Where concurrent ureteric re-implantation or augmentation cystoplasty are required, the abdominal
approach is necessary.

B
C

C
C
B

Urinary Incontinence 207

Ensure that the bladder is continuously drained folC


lowing fistula repair until healing is confirmed (expert
opinion suggests: 10-14 days for simple and/or postsurgical fistulae; 14-21 days for complex and/or postradiation fistulae).
Where urinary and/or faecal diversions are required,
C
avoid using irradiated tissue for repair.
Use interposition grafts when repair of radiation asso- C
ciated fistulae is undertaken.
In patients with intractable urinary incontinence from C
radiation-associated fistula, where life expectancy is
very short, consider performing ureteric occlusion.
Repair persistent ureterovaginal fistula by an abdomi- C
nal approach using open, laparoscopic or robotic techniques according to availability and competence.
Consider palliation by nephrostomy tube diversion and C
endoluminal distal ureteric occlusion for patients with
ureteric fistula associated with advanced pelvic cancer and poor performance status.
Urethrovaginal fistulae should preferably be repaired
C
by a vaginal approach.
*These recommendations are derived from summarisation of
the ICUD 2013 review and have not been fully validated by the
EAU guidelines panel methodology.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-71-7), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
208 Urinary Incontinence

continued on page 210

Urinary Incontinence 209

Initial assessment
History
Physical examiniation
Questionnaire optional
Voiding dairy
Urinalysis
Post void residual
if voiding diculty
Pad test if quantication
of leakage is desired
C

A
A
C
B
A

Women presenting with urinary


incontinence

Further
assessment

Haematuria
Pain
Recurrent UTI
Grade 3 or symptomatic prolapse
Previous pelvic radiotherapy
Previous surgery for UI
Pelvic mass
Suspicion of stula

continued on page 211

210 Urinary Incontinence


Mixed
incontinence

* Based on expert op opinion.

Advise on bowels, drugs, co-morbidity, fluid intake


Advise on weight loss
Offer pads or other containment device if needed
Consider topical vaginal oestrogen for post-menopausal women
Offer desmopressin for short term symptom relief
Offer timed or prompted voiding in elderly /care-dependent people

Stress
incontinence

Consider P-PTNS
B

Anti-muscarinics
A
or mirabegron
B

C
A
A*
A
B
B

Urgency
incontinence

No response

individualised behavioural and physical therapies including pelvic floor muscle training

Discuss management

Urinary Incontinence 211

Stress
predominant

Re-evaluate patient and consider


second-line surgery
A

Failure

Offer fascial sling or


colposuspension if MUS
unavailable
A

Offer MUS
A

Stress
incontinence

Mixed
incontinence

Urgency
incontinence

Discuss bladder augmentation or


urinary diversion
A

Advise onabotulinumtoxin A
or
sacral nerve stimulation
A

Urgency
predominant

Offer urodynamics if findings may change choice of surgery

Failed conservative or drug therapy

Surgical treatment
in women

continued on page 213

212 Urinary Incontinence

Initial assessment
History
Physical examiniation
Questionnaire optional
Voiding dairy
Urinalysis
Post void residual
if voiding diculty
Pad test if quantication
of leakage is desired
C

A
A
C
B
A

Men presenting with urinary


incontinence

Further
assessment

Haematuria
Pain
Recurrent UTI
Previous pelvic radiotherapy
Abnormal DRE
Findings suspicious of voiding
dysfunction

continued on page 214

Urinary Incontinence 213

Mixed
incontinence

* Based on expert op opinion.

Advise on bowel function, drugs, co-morbidity, fluid intake


Advise on weight loss
Offer pads or other containment device if needed
Offer desmopressin for short term symptom relief
Offer timed or prompted voiding in elderly /care-dependent people

Stress
incontinence

Consider P-PTNS
B

Anti-muscarinics
A
or mirabegron
B

C
A
A*
B
B

Urgency
incontinence

No response

individualised behavioural and physical therapies including pelvic floor muscle training

Discuss management options

214 Urinary Incontinence


Stress
predominant

Mixed
incontinence

** Available evidence on
onabutulinumtoxinA and sacral nerve
stimulation refers mainly to women.

Consider fixed sling for men with PPI


B

Offer AUS to men with PPI depending on


severity
B

Stress
incontinence

Discuss bladder augmentation or


urinary diversion
A

Advise onabotulinumtoxin A
or
sacral nerve stimulation
A**

Urgency
predominant

Urgency
incontinence

Perform urodynamics, cystoscopy and consider imaging of lower urinary tract


to exclude bladder outlet obstruction
if the result would alter the choice of surgery

Failed conservative or drug therapy

Surgical treatment
in men with UI

GUIDELINES ON
UROLOGICAL INFECTIONS
(Text update April 2014)

M.Grabe (chair), R. Bartoletti, T.E. Bjerklund-Johansen, M. ek,


K.G. Naber, R.S. Pickard, P. Tenke, F. Wagenlehner, B. Wullt

Introduction

Urinary tract infections (UTIs) pose a serious health problem


for patients with high cost to society. UTIs are also the most
frequent healthcare associated infections.
E. coli is the predominate pathogen in uncomplicated
UTIs whilst Enterobacteriaceae and Enterococcus spp are
predominate in patients with urological diseases. Microbial
resistance is developing at an alarming rate with countryspecific resistance rates related to the amount of antibiotics
used. Particularly of concern 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, UTIs and male genital tract


infections are classified into entities defined by the predominant clinical symptoms (Table 1).

Urological Infections 215

Table 1: Traditional classification of urinary tract and male


genital infections
Uncomplicated lower UTI (cystitis)
Uncomplicated pyelonephritis
Complicated UTI with or without pyelonephritis
Urosepsis
Urethritis
Prostatitis, epididymitis, orchitis
The definitions of bacteriuria are listed in Table 2.
Table 2: Relevant bacterial growth in adults
1.  103 uropathogens/mL in midstream urine in acute
uncomplicated cystitis in women.
2.  104 uropathogens/mL in midstream urine in acute
uncomplicated pyelonephritis in women.
3.  105 uropathogens/mL in midstream urine in women or
104 uropathogens/mL in 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.
Pyuria
The diagnostic requirement for pyuria is 10 white blood cells
per high-power field (HPF) (x400) in the re-suspended sediment 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 assessment of
haemoglobin and nitrites.
Asymptomatic bacteriuria
Asymptomatic bacteriuria is defined as two positive urine
cultures taken more than 24 hours apart containing 105
216 Urological Infections

uropathogens/mL of the same bacterial strain (in a patient


without any clinical symptoms).
Urethritis
Symptomatic urethritis is characterised by alguria and purulent discharge.
Classification of prostatitis/chronic pelvic pain syndrome
(CPPS)
It is recommended to use the classification according to
NIDDK/NIH (Table 3).
Table 3: Classification of prostatitis according to NIDDK/
NIH
I
Acute bacterial prostatitis (ABP)
II
Chronic bacterial prostatitis (CBP)
III
Chronic pelvic pain syndrome (CPPS)
IIIA Inflammatory CPPS: WBC in EPS/voided
bladder urine-3 (VB3)/semen
IIIB Non-inflammatory CPPS: no WBC/EPS/VB3/semen
IV
Asymptomatic inflammatory prostatitis (histological
prostatitis)
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.
Consider Chlamydia trachomatis infection in the younger
male population.

Diagnosis

UTI (general)
A disease history, physical examination and dipstick urine
analysis, including white and red blood cells and nitrite reacUrological Infections 217

Table 4: Recommendations for antimicrobial therapy in urology


Diagnosis

Most frequent pathogen/species

Cystitis
acute,
sporadic and
uncomplicated

E. coli
Klebsiella
Proteus
Staphylococci

Pyelonephritis
acute,
uncomplicated
(usually febrile)

E. coli
Proteus
Klebsiella
Other enterobacteria
Staphylococci

UTI with
complicating
factors (febrile)

E. coli
Enterococci
Pseudomonas
Staphylococci

Nosocomial UTI

Klebsiella
Proteus

Pyelonephritis
severe
acute,
complicated

Enterobacter
Other enterobacteria
(Candida)

218 Urological Infections

Initial, empirical antimicrobial therapy

Therapy duration

Nitrofurantoin
Fosfomycin trometamol
Pivmecillinam
Alternative:
TMP-SMX1
Fluoroquinolone2,3

(5-)7 days
1 dose
(3-)5 days

Fluoroquinolone2
Cephalosporin (group 3a)
Alternatives:
Aminopenicillin/BLI
Aminoglycoside

7-10 days

Fluoroquinolone2
Aminopenicillin/BLI
Cephalosporin (group 2)
Cephalosporin (group 3a)
Aminoglycoside

3-5 days after


defervescence
or control/
elimination of
complicating
factor

In case of failure of initial therapy


within 1-3 days or in clinically
cases:
Anti-Pseudomonas active:
Fluoroquinolone, if not used initially
Acylaminopenicillin/BLI
Cephalosporin (group 3b)
Carbapenem
Aminoglycoside
In case of Candida:
Fluconazole
Amphotericin B

3 days
(1-)3 days

Urological Infections 219

Prostatitis
acute, chronic
Epididymitis
Ureaplasma:
Acute
Urosepsis

E. coli
Other enterobacteria
Pseudomonas
Enterococci
Chronic:
Staphylococci
Chlamydia
Ureaplasma
E. coli
Other enterobacteria
After urological
interventions - multiresistant pathogens:
Pseudomonas
Proteus
Serratia
Enterobacter

1Only

in areas with resistance rate < 20% (for E. coli).


with mainly renal excretion (see text).
3Avoid Fluoroquinolones in uncomplicated cystitis whenever possible.
2Fluoroquinolone

BLI = beta-lactamase inhibitor; UTI = urinary tract infection.


tion, is recommended for routine diagnosis. A urine culture
is recommended in all types of UTI before treatment, except
for sporadic episodes of uncomplicated UTI (cystitis) in premenopausal women, in order to adjust antimicrobial therapy
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.

220 Urological Infections

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


defervescence or
control/
elimination
of complicating
factor

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 221

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 only be recommended
for patients with recurrent UTI, after counselling and other
prevention methods have failed. The regimens shown in Table
5 have a documented effect in preventing recurrent UTI in
women.
Special situations
UTI in pregnancy
A urine culture is recommended. Asymptomatic bacteriuria
and cystitis are treated with a 3-5 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.
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.
222 Urological Infections

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
recognised 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
Dose
Agent1
Standard regimen
Nitrofurantoin
50 mg/day
Nitrofurantoin macrocrystals
100 mg/day
TMP-SMX
40/200 mg/day or
three times weekly
TMP
100 mg/day
Fosfomycin trometamol
3 g/10 day
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; UTI = urinary tract
infection.

Urological Infections 223

Follow-up of patients with UTI

For routine follow-up after uncomplicated UTI and pyelonephritis in women, dipstick urine analysis 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, a urological evaluation should be 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 recommended after
two episodes of UTI in girls and one episode in boys.
Recommended investigations are ultrasound 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
(2010). For the treatment of gonorrhoea, the following antimicrobials can be recommended:
First choice
Ceftriaxone 1 g im
as a single dose
(im with local anaesthetic)
Azithromycin 1g orally as
a single dose

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:
224 Urological 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.
Combination therapy with antibiotics and -blockers:
Urodynamic studies have shown increased urethral closing
pressure in patients with chronic prostatitis. Combination
Urological Infections 225

Table 6: Recommendations for peri-operative antibacterial

Procedure
Pathogens
Prophylaxis

(expected)
(standard)
Diagnostic procedures
Transrectal biopsy of the
Enterobacteriaceae All patients
(Anaerobes)
prostate1

Cystoscopy
Enterobacteriaceae No
Urodynamic study
Enterococci

Staphylococci
Ureteroscopy
Enterobacteriaceae No

Enterococci

Staphylococci
Endourological surgery and SWL
SWL
Enterobacteriaceae No

Enterococci


Ureteroscopy for
Enterobacteriaceae No
uncomplicated distal stone Enterococci

Staphylococci

Ureteroscopy of proximal
Enterobacteriaceae All patients
or impacted stone and
Enterococci
percutaneous stone
Staphylococci
extraction

TUR of the prostate
Enterobacteriaceae All patients

Enterococci



226 Urological Infections

prophylaxis in urology
Antibiotics

Remarks

Fluoroquinolones
TMP SMX
Metronidazole2
TMP SMX
Cephalosporin 2nd
generation
TMP SMX
Cephalosporin 2nd
generation

Single dose effective in low


risk. Consider prolonged
course in risk patients
Consider in risk patients

TMP SMX
Cephalosporin 2nd or
3rd generation
Aminopenicillin/BLI3
TMP SMX
Cephalosporin 2nd or
3rd generation
Aminopenicillin/BLI
TMP SMX
Cephalosporin 2nd or
3rd generation
Aminopenicillin/BLI
(Fluoroquinolones)
TMP SMX
Cephalosporin 2nd or
3rd generation
Aminopenicillin/BLI

In patients with stent or


nephrostomy tube or other
risk factor

No studies

Consider in risk patients

Short course,
Length to be determined
Intravenous suggested at
operation
Low-risk patients and
small-size prostate
require no prophylaxis

Urological Infections 227

TUR of bladder tumour


Enterobacteriaceae No

Enterococci


Open or laparoscopic urological surgery4
Clean operations
Skin-related
No

pathogens,

e.g. staphylococci

Catheter-

associated

uropathogens
Clean-contaminated
Enterobacteriaceae Recommended
(opening of urinary tract)
Enterococci

Staphylococci

Clean-contaminated/
Enterobacteriaceae All patients
contaminated (use of bowel Enterococci
segments):
Anaerobes

Skin-related

bacteria
Implant of prosthetic
Skin-related
All patients
devices
bacteria,

e.g. staphylococci

BLI = beta-lactamase inhibitor; TMP SMX = trimethoprim with or
resection.
1Increased resistance of faecal flora recorded (see text).
2No evidence for the use of mettronidazole in prostate core biopsies.
3Gram-negative bacteria excluding Pseudomonas aeruginosa.
4Classifications of surgical field contamination (CDC).
228 Urological Infections

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

Single peri-operative
course

Cephalosporin 2nd or
3rd generation
Metronidazole

As for colonic surgery

Cephalosporin 2nd or
3rd generation
Penicillin
(penicillinase stable)
without sulphamethoxale (co-trimoxazole); TUR = transurethral

Urological Infections 229

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 aim of antimicrobial prophylaxis in urological surgery is


to reduce the load of bacteria at the site of surgery and thus
to prevent symptomatic or febrile urogenital infections, such
as acute pyelonephritis, prostatitis, epididymitis and urosepsis, as well as serious wound infections in conjunction with
surgery. In recent years increased resistance of the faecal
flora, especially against fluoroquinolones, has been recorded
which may impact on prophylaxis mode. It is recommended to
assess the risk, i.e. prior to prostate biopsy. The basic recommendations for short-term peri-operative antibacterial prophylaxis in standard urological interventions are listed in table 6.
230 Urological Infections

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.
Urological Infections 231

GUIDELINES ON NEURO-UROLOGY
(Text update April 2014)

J. Pannek (co-chair), B. Blok (co-chair), D. Castro-Diaz,


G. del Popolo, J. Groen, G. Karsenty, T.M. Kessler, G. Kramer,
M. Sthrer

Eur Urol 2009 Jul;56(1):81-8

Introduction

Neuro-urological disorders can cause a variety of long-term


complications; the most dangerous being damage of renal
function. Treatment and intensity of follow-up examinations
are based on the type of neuro-urological disorder and the
underlying cause.

Terminology

The terminology used and the diagnostic procedures outlined


in this document follow the published by the International
Continence Society (ICS).

Risk factors and epidemiology

All central and peripheral neurological disorders carry a high


risk of causing functional disturbances of the urinary tract.

Classification

A functional classification for motor function based on


urodynamic and clinical findings is proposed (Figure 1).

232 Neuro-Urology

Fig. 1: The EAU-Madersbacher classification system*


Detrusor

Over-
active

Overactive

Over-
active

Over-
active

Underactive Normo-active
Urethral sphincter

Underactive

Overactive

Detrusor


Under-
active

Underactive

Under-
active

Normo-
active

Normo-active Overactive
Urethral sphincter

Normoactive

Underactive

*Adapted from Madersbacher et al.

Timing of diagnosis and treatment

Early diagnosis and treatment are essential in both congenital


and acquired neuro-urological disorders, even in the presence
of normal neurological reflexes. Neuro-urological disorders
can be the presenting feature of neurological pathology and
early intervention can prevent irreversible deterioration of the
lower and upper urinary tract.
Patient assessment
Diagnosis of neuro-urological disorders should be based on a
comprehensive assessment of neurological and non-neuroNeuro-Urology 233

logical 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.

234 Neuro-Urology

Fig. 2: The neurological status of a patient with neuro-urological symptoms 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.


Neuro-Urology 235

Urodynamic tests
Bladder diaries are considered a valuable diagnostic tool
in patients with neuro-urological disorders. A bladder diary
should be recorded for at least 2-3 days. Uroflowmetry and US
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 neuro-urological disorder.
Recommendations for urodynamics and uro-neurophysiology
Recommendations
The recording of a bladder diary is advisable.
Non-invasive testing is mandatory before invasive
urodynamics is planned.
Urodynamic investigation is necessary to document
LUT (dys-) function and same session repeat measurement is crucial for clinical decision making.
Video-urodynamics is the gold standard for invasive
urodynamics in patients with neuro-urological symptoms. If this is not available, then a filling cystometry
continuing into a pressure flow study should be
performed.
A physiological filling rate and body-warm saline must
be used.
Specific uro-neurophysiological tests are elective procedures.
LUT = lower urinary tract.

GR
B
A
A

A
C

Video-urodynamics combines filling cystometry and pressure


flow studies with radiological imaging. Currently, video-urodynamics is considered to provide the most comprehensive
information evaluating neuro-urological disorders.
236 Neuro-Urology

Table 2: Characteristic findings in neuro-urological


disorders*

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
Bladder outlet obstruction
Detrusor Sphincter Dyssynergia (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.
Recommendations for history taking and physical
examination
History taking
An extensive general history is mandatory, concentrating on past and present symptoms and conditions for
urinary, bowel, sexual, and neurological functions, and
on general conditions that might impair any of these.
Special attention should be paid to the possible existence of alarm signs, such as pain, infection, haematuria, fever, etc, that warrant further specific diagnosis.
A specific history should be taken for each of the four
mentioned functions.
Physical examination
Individual patient handicaps should be acknowledged
in planning further investigations.

GR*

Neuro-Urology 237

The neurological status should be described as comA


pletely as possible. Sensations and reflexes in the urogenital area must all be tested.
The anal sphincter and pelvic floor functions must be A
tested extensively.
Urinalysis, blood chemistry, bladder diary, residual and A
free flowmetry, incontinence quantification and urinary tract imaging should be performed.
Quality of life should be assessed when evaluating
B
LUT symptoms in neurogenic patients and when treating neurogenic bowel dysfunction.
The available validated tools are Qualiveen, a specific B
long-form and short-form tool for spinal cord lesion
and multiple sclerosis patients and VAS for symptom
bother. In addition, generic (SF-36) or specific tools for
incontinence (I-QOL) questionnaires can be used.
* All grade A recommendations are based on panel consensus.
LUT = lower urinary tract; VAS = Visual Analogue Scale.

Treatment

The primary aims when treating neuro-urological disorders


and their priorities are:
1. Protection of the upper urinary tract;
2. Improvement of urinary continence;
3. Restoration of (parts of) the LUT function;
4. Improvement of the patients QoL.
Further considerations are the patients disability, costeffectiveness, technical complexity, and possible
complications.
Conservative treatment
Assisted bladder emptying
Triggered reflex voiding is not recommended as there is a risk
of pathologically elevated bladder pressures. Only in the case
238 Neuro-Urology

of absence, or surgically reduced, outlet obstruction it may be


an option.
Caution: 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.
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.
Medical therapy
A single, optimal, medical therapy for patients with neurourological symptoms is not yet available. Muscarinic receptor
antagonists are the first-line choice for treating neuro-urological disorders.
Recommendations on drug treatments
For NDO, antimuscarinic therapy is the
recommended first-line medical treatment.
Alternative routes of administration (i.e.,
transdermal or intravesical) of antimuscarinic
agents may be used.
Outcomes for NDO may be maximized by
considering a combination of antimuscarinic
agents.
To decrease bladder outlet resistance,
a-blockers should be prescribed.
For underactive detrusor, no parasympathicomimetics should be prescribed.

LE
1a

GR
A

1b

1b

1a

Neuro-Urology 239

In neurogenic stress urinary incontinence, drug


treatment should not be prescribed.
NDO = neurogenic detrusor overactivity.

Recommendations for minimal invasive treatment


Intermittent Catheterization
LE
Intermittent catheterization - whenever possible 3
aseptic technique - should be used as a standard treatment for patients who are unable to
empty their bladder.
Patients must be well instructed in the tech3
nique and risks of IC.
The catheter size should be 12-16 Fr.
4
Whenever possible, indwelling transurethral and 3
suprapubic catheterization should be avoided.
IC = intermittent catheterization.
Recommendations for minimal-invasive treatment
Botulinum toxin injection in the detrusor is the most
effective minimally invasive treatment to reduce
neurogenic detrusor overactivity.
Sphincterotomy is the standard treatment for detrusor
sphincter dyssynergia.
Bladder neck incision is effective in a fibrotic bladder
neck.

240 Neuro-Urology

GR
A

A
B
A

GR
A

A
B

Recommendations for surgical treatment


In order to treat refractory detrusor overactivity, bladder augmentation is recommended.
Detrusor myectomy is an acceptable alternative.
In female patients with neurogenic stress
urinary incontinence who are able to selfcatheterise, placement of an autologous
urethral sling should be used.
In male patients with neurogenic stress urinary
incontinence, artificial urinary sphincter should
be used.

LE
3

GR
A

Urinary tract infections (UTI)


Patients with neuro-urological disorders, especially those with
spinal cord injury, may have other signs and symptoms in
addition to, or instead of, traditional signs and symptoms of a
UTI in able-bodied individuals.
Guidelines on the treatment of UTI
Asymptomatic bacteriuria in patients with
neuro-urological disorders should not be
treated.
The use of long-term antibiotics in recurrent
UTIs should be avoided.
In patients with recurrent UTI, treatment of
neuro-urological symptoms should be optimised
and foreign bodies (e.g. stones, indwelling catheters) should be removed from the urinary tract.
In patients with neuro-urological disorders, UTI
prophylaxis must be individualized since there is
no optimal prophylactic measure available.

LE
4

GR
A

2a

Neuro-Urology 241

Sexual (dys)function and Fertility


Patients with neurological disease often suffer from sexual
dysfunction (ED), which frequently impairs quality of life.
Guidelines on Male ED and Fertility
LE
GR
In neurogenic ED, oral PDE5Is are the recom1b
A
mended first-line medical treatment.
In neurogenic ED, intracavernous injections of
3
A
vasoactive drugs (alone or in combination) are
the recommended second-line medical treatment.
In neurogenic ED, mechanical devices such as
3
B
vacuum devices and rings can be effective and
may be offered to patients.
In neurogenic ED, penile prostheses should be
4
B
reserved for selected patients.
Vibrostimulation and transrectal electroejacula- 3
B
tion are effective methods of sperm retrieval.
In men with SCI, MESA, TESE or ICSI may be
3
B
used after failed vibrostimulation and/or
transrectal electroejaculation.
In men with SCI above T6, it is essential to
3
A
counsel patients at risk and fertility clinics
about the potentially life-threatening condition
of autonomic dysreflexia.
ED = erectile dysfunction; ICSI = intracytoplasmic sperm
injection; MESA = microsurgical epididymal sperm aspiration;
PDE5is = phosphodiesterase type 5 inhibitors; SCI = spinal
cord injury; TESE = testicular sperm extraction.
There is no effective medical therapy for the treatment of neurogenic sexual dysfunction in women (GR: A). In women with
a neurological disease, the management of fertility, pregnancy
and delivery requires a multidisciplinary approach tailored to
242 Neuro-Urology

an individual patients needs and preferences (GR: A).


Follow-up
Neurogenic lower urinary tract dysfunction is often unstable
and the symptoms may vary considerably, even within a relatively short period. Regular follow-up is, therefore, necessary.
Guidelines for follow-up
In high-risk patients, the upper urinary tract
should be assessed at least every six months.
In high-risk patients, physical examination, and
urine laboratory should take place every year.
Any significant clinical changes should instigate
further, specialized, investigation.
Urodynamic investigation is a mandatory baseline diagnostic and in high-risk patients, should
be done at regular intervals.

LE
4

GR
A

Summary

Neuro-urological disorders present 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.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Neuro-Urology 243

GUIDELINES ON
UROLOGICAL TRAUMA
(Text update April 2014)

D.J. Summerton (chair), N. Djakovic, N.D. Kitrey, F.E. Kuehhas,


N. Lumen, E. Serafetinides, D.M. Sharma

Eur Urol 2010 May;57(5):791-803


Eur Urol 2012 Oct;62(4):628-39

Introduction

Genito-urinary trauma is seen in both sexes and in all age


groups, but is more common in males. Traumatic injuries are
classified according to the basic mechanism into penetrating
and blunt.
Penetrating trauma is further classified according to the
velocity of the projectile:
1. High-velocity projectiles (e.g. rifle bullets - 800-1000m/sec).
2. Medium-velocity (e.g. handgun bullets - 200-300 m/sec).
3. Low-velocity items (e.g. knife stab).
High-velocity weapons inflict greater damage because the bullets transmit large amounts of energy to the tissues,
resulting in damage to a much larger area then the projectile
tract itself. In lower velocity injuries, the damage is usually
confined to the track of the projectile.
Blast injury is a complex cause of trauma because it
commonly includes both blunt and penetrating trauma, and
may also be accompanied by a burn injury.

Initial evaluation and treatment

The first priority is stabilisation of the patient and treatment of


244 Urological Trauma

associated life-threatening injuries. A direct history is obtained


from the patient (if conscious) or from witnesses/emergency
personnel (if patient unconscious and/or seriously injured).
In penetrating injuries, assess size of the weapon in stabbings, and the type and caliber of the weapon used in gunshot
wounds. The medical history should be as detailed as possible.
It is important to recognise the high risk of hepatitis B and C
infection in trauma patients and take appropriate precautions.
In any penetrating trauma, tetanus vaccination should be
considered according to the patients vaccination history and
nature of the wound.

Renal Trauma

Renal injuries (RI) account for 1-5% of all trauma and in 10% of
all abdominal trauma cases.
Table 1: Injury severity scale for the kidney*#
Grade Description
1
Contusion or non-expanding subcapsular
haematoma, no laceration
2
Non-expanding perirenal haematoma, cortical
laceration < 1 cm deep without extravasation
3
Cortical laceration > 1 cm without urinary
extravasation
4
Laceration: through corticomedullary junction
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.

Urological Trauma 245

Diagnosis

H
 aemodynamic stability should be assessed upon
admission.
History: time and setting of incident, past renal surgery,
known renal abnormalities.
Lab: gross haematuria, dipstick urine analysis, serial haematocrit, baseline serum creatinine.
In 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.
Ultrasound (US) may be helpful during the primary evaluation or follow-up of recuperating patients.
Angiography can be used for diagnosis and simultaneous
selective embolization of bleeding vessels if necessary.

Treatment

Indications for renal exploration include:


haemodynamic instability
exploration for associated injuries
expanding or pulsatile peri-renal haematoma identified
during laparotomy
grade 5 vascular injury (Figs. 1 and 2)
Interventional radiology is indicated in patients with active
bleeding from renal injury but without other indications for
immediate abdominal operation.

246 Urological Trauma

Observation,
bed rest,
serial Ht,
antibiotics

Observation

Grade 3

Angiography and
selective angioembolisation

Grade 1 2

Associated injuries requiring laparotomy

Observation,
bed rest,
serial Ht, antibiotics

Vascular

Rapid deceleration
injury or major
associated injuries

Microscopic haematuria

Angiography and
selective angioembolisation

Grade 4 -5
Parenchymal

Contrast enhanced
spiral CT scan with
delayed images

Gross haematuria

Stable

Determine haemodynamic stability

Normal IVP

Renal exploration
(reconstruction or
nephrectomy)

Abnormal IVP, Pulsatile


or expanding haematoma

Emergency laparotomy/One-shot IVP

Unstable

Observation

Suspected adult blunt renal trauma

Fig. 1: Evaluation of blunt renal trauma in adults

Urological Trauma 247

248 Urological Trauma

Observation,
bed rest, serial
Ht, antibiotics

Grade 1 2

Grade 4 -5

Unstable

Associated injuries requiring laparotomy

Grade 3

Contrast enhanced spiral


CT scan with delayed
images

Stable

Determine haemodynamic stability

Suspected adult penetrating renal trauma

Observation

Normal IVP

Renal exploration
(reconstruction or
nephrectomy)

Abnormal IVP,
Pulsatile or expanding
haematoma

Emergency laparotomy/One-shot IVP

Fig. 2: Evaluation of penetrating renal trauma in adults

Post-operative care, follow-up and complications

R
 epeat imaging is recommended in cases of suspected
complications,cases of fever, flank pain, or falling
haematocrit.
Nuclear scintigraphy is useful for documenting functional
recovery.
First follow up should be at approximately 3 months after
major renal injury with hospitalisation and should include:
physical examination, urinalysis, individualised radiological investigation, blood pressure measurement and serum
determination of renal function.
Long-term follow-up should be decided on a case-by-case
basis.
Complications following renal trauma require a thorough
radiographic evaluation.
Medical management and minimally invasive techniques
should be the first choice for the management of complications.

Iatrogenic renal injuries (IRI)







I RIs are procedure-dependent (1.8-15%).


Significant injury requiring intervention is rare.
Most common injuries are vascular.
Renal allografts are more susceptible.
Injuries occurring during surgery are rectified immediately.
Symptoms suggestive of a significant injury require investigation.
Patients with minor injuries should be treated conservatively.
Severe or persistent injuries require intervention with
embolization.
In stable patients, a second embolisation should be
considered in case of failure.

Urological Trauma 249

Ureteral Trauma

Ureteral injuries are quite rare - most are iatrogenic. They


are often missed intra-operatively, usually involve the lower
ureter, and may result in severe sequelae. Risk factors include
advanced malignancy, prior surgery or irradiation - i.e. conditions which alter the normal anatomy. External ureteral trauma usually accompanies severe abdominal and pelvic injuries.
Gunshot wounds account for the majority of penetrating
ureteral trauma, while motor vehicle accidents account for
most of blunt injuries.

Diagnosis

A
 high index of suspicion of ureteral injury should be maintained because the majority of cases are diagnosed late
and predispose the patient to pain, infection, and renal
function impairment.
Haematuria is an unreliable indicator.
Extravasation of contrast material in CT is the hallmark
sign of ureteral trauma, and in unclear cases, a retrograde
or antegrade urography is required for confirmation.

Treatment

P
 artial injury can be managed with ureteral stenting or
urinary diversion by a nephrostomy.
In complete injuries, ureteral reconstruction following temporary urinary diversion is required.
The type of repair procedure depends on the site of the
injury (table 1), and it should follow the principles outlined
in table 2.
Proximal and mid-ureteral injuries can often be managed
by primary uretero-ureterostomy, while a distal injury is
often treated with ureteral reimplantation.

250 Urological Trauma

Ureteral reconstruction options by site of injury


Site of injury
Upper ureter

Mid ureter

Lower ureter
Complete

Reconstruction options
Uretero-ureterostomy
Transuretero-ureterostomy
Uretero-calycostomy
Uretero-ureterostomy
Transuretero-ureterostomy
Ureteral reimplantation and a Boari flap
Ureteral reimplantation
Ureteral reimplantation with a psoas hitch
Ileal interposition graft
Autotransplantation

Principles of surgical repair of ureteral injury


Debridement of necrotic tissue
Spatulation of ureteral ends
Watertight mucosa-to-mucosa anastomosis with absorbable
sutures
Internal stenting
External drain
Isolation of injury with peritoneum or omentum

Bladder Trauma

Bladder injuries can be due to external (blunt or penetrating)


or iatrogenic trauma. Iatrogenic trauma is caused by external
laceration or internal perforation (mainly during TURB). Blunt
bladder injuries are strongly associated with pelvic fractures.
Bladder injuries are classified as extraperitoneal, intraperitoneal or combined.

Urological Trauma 251

Diagnosis
Clinical signs and symptoms

External trauma
Cardinal sign: gross haematuria.
Others: abdominal tenderness, inability to void, bruises
over the suprapubic region, and abdominal distension (in
case of urinary ascites).
Penetrating bladder injury: entrance and exit wounds in
lower abdomen or perineum.
Bloody urethrorrhagia: suspect concomitant urethral injury.
Iatrogenic trauma
External perforation: extravasation of urine, visible laceration, clear fluid in the surgical field, appearance of the bladder catheter, and blood and/or gas (in case of laparoscopy)
in the urine bag.
Internal perforation: fatty tissue or bowel between detrusor
muscle fibres, inability to distend the bladder, low return of
irrigation fluid and/or abdominal distension.
Postoperative symptoms of unrecognised bladder perforation: haematuria, lower abdominal pain, abdominal
distension, ileus, peritonitis, sepsis, urine leakage from the
wound, decreased urinary output, and increased serum
creatinine.

Imaging

Cystography (conventional or CT-cystography)


Fill the bladder with at least 350 mL of dilute contrast
material.
CT cystography preferred in case of other possible abdominal injuries or causes of abdominal pain.
Standard evaluation for external trauma and in case of suspicion of an iatrogenic bladder injury in the postoperative
setting.
252 Urological Trauma

I mperative in case of gross haematuria combined with


pelvic fracture.
Cystoscopy
To detect intra-operative bladder injuries.
Recommended after minimally invasive synthetic suburethral sling operations by retropubic route and major
gynaecologic operations.
Optional after any other type of sling procedure or transvaginal mesh procedure.

Treatment

Surgical repair (two-layer vesicorraphy)


Penetrating injury.
Blunt intraperitoneal injury.
Blunt extraperitoneal injury with internal osteosynthetic
fixation of pelvic fracture.
(large) Iatrogenic internal intraperitoneal injury.
Intra-operative recognised injury.
In case of bladder neck involvement, bony fragment(s) in
the bladder, concomitant rectal injury and/or bladder wall
entrapment.
Conservative treatment (urinary catheter)
Postoperative recognised extraperitoneal perforation.
Blunt extraperitoneal perforation.
Iatrogenic internal extraperitoneal perforation.
Small internal intraperitoneal perforation in absence of
ileus and peritonitis. Placement of an intraperitoneal drain
is optional.

Urethral Trauma

I njuries to the anterior urethra (AU) are caused by trauma


during sexual intercourse (associated with penile fracture),
penetrating trauma, placement of penile constriction
Urological Trauma 253

bands, and from iatrogenic trauma e.g. endoscopic instruments, catheterisation.


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.

Diagnosis

B
 lood at the external urethral meatus is the most common
clinical sign, and indicates the need for further diagnostic
work up.
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 may indicate disruption.
Blood at the vaginal introitus is present in more than 80%
of female patients with pelvic fractures and co-existing urethral injuries.
Rectal examination may reveal a high riding prostate.
However, this is an unreliable finding. Blood on the examination finger is suggestive of a rectal injury associated with
pelvic fracture urethral bleeding or urinary extravasation
can cause penile and scrotal swelling and hematoma.
Retrograde urethrography is the gold standard for evaluating urethral injury and urethral catheterisation should be
avoided until the urethra is imaged.
In an unstable patient, however, an attempt can be made to
pass a urethral catheter (gently, by someone with urological experience). If this is not possible, a suprapubic cath254 Urological Trauma

eter is inserted and a retrograde urethrogram is performed


later.
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 treatment is suggested:
Anterior urethral injuries are treated by primary urethral
repair only if associated with penile fracture or in penetrating wounds. Blunt trauma should be treated in the acute
management by suprapubic cystosomy or urethral catheterisation. After the patient has recovered from any associated injuries, and the urethral injury has stabilized, delayed
management is used after 3 to 6 months. Short and flimsy
strictures are managed by optical urethrotomy or urethral
dilatation. Denser strictures require urethral reconstruction.
Posterior urethral injuries are treated by primary open
repair only in stable patients with penetrating wounds. In
all other cases a suprapubic cystostomy is performed. In
stable patients with blunt trauma associated with complete urethral rupture an open surgery is only necessary
in the acute phase when complicated by bladder neck or
rectal injuries. In all other cases a suprapubic cystostomy is
the appropriate acute management.
If delayed management is conducted, it consists of
endoscopic realignment or delayed urethroplasty.
Urethral strictures following partial ruptures can be
treated by optical urethrotomy.

Iatrogenic Urethral Trauma

M
 ost commonly caused by urethral instrumentation, and
results in stricture formation.
Due to their variable location and severity, they often
Urological Trauma 255

require different management strategies.


S
 hort and flimsy strictures can be treated by urethrotomy.
If the stricture is longer or denser, urethroplasty should be
considered.

Genital Trauma

Of all genito-urinary injuries, one-third to two-thirds involve


the external genitalia and is much more common in males
- due to anatomical differences and increased frequency
of road traffic accidents, physical sports, violent crime, and
war-fighting. 80% is blunt trauma, 20% is due to penetrating
injuries.

Diagnosis

U
 rinalysis should be performed.
Macro- and or microhaematuria require a retrograde urethrogram in males, and consideration of cystoscopy in
females.
In women with genital injuries and blood at the vaginal
introitus, further gynaecologic investigation to exclude
vaginal injury.
In cases of suspected sexual abuse gynecological and
forensic support and advice is necessary and the emotional situation and privacy of the patient must be respected.

Blunt Penile Trauma

U
 sually results from trauma to the erect penis during sexual intercourse or masturbation.

Penile Fracture

S
 udden cracking or popping sound, pain and immediate
detumescence.
Local swelling of the penile shaft is seen and this may
extend to the lower abdominal wall.
The rupture of the tunica may be palpable.
256 Urological Trauma

T
 horough history and examination confirms diagnosis
Imaging (US or magnetic resonance imaging [MRI]) may be
useful.

Treatment

S
 ubcutaneous haematoma, without associated rupture of
the cavernosal tunica albuginea does not require surgical
intervention. Nonsteroidal analgesics and ice-packs are
recommended.
In penile fracture, early surgical intervention with closure of
the tunica albuginea is recommended.
Intra-operative flexible cystoscopy is useful to diagnose
urethral injury and to further localise tunical damage
Conservative management of penile fracture is not recommended.

Penetrating Penile Trauma

R
 arely seen in isolation.
Due to gunshot/knife injury, animal or human bites, assault
and industrial or self-inflicted mutilation.
Non-operative management is recommended in small
superficial injuries with intact Bucks fascia.
More significant injuries require surgical exploration and
debridement of necrotic tissue.
In extended injuries of the penis, primary alignment of
the disrupted tissues may allow for acceptable healing
because of the robust penile blood supply.
In avulsion of the penis, resuscitate the patient and
attempt re-implantation of the penis (if not too badly
damaged) - ideally microsurgical.

Blunt Scrotal Trauma

M
 ay result in testicular dislocation, haematocoele, testicular rupture and/or scrotal haematoma.
Dislocation of the testicle is rare. Treat by manual replaceUrological Trauma 257

ment and secondary orchidopexy. If manual reposition cannot be performed, immediate orchidopexy is indicated.
If haematocele is smaller than three times the size of the
contralateral testis - conservative management.
If large haematocele - explore.
If testicular rupture suspected, explore, evacuate clot and
any necrotic testicular tubules and close the tunica albuginea.

Penetrating Scrotal Trauma

S
 urgical exploration with conservative debridement of nonviable tissue.
Primary reconstruction of testis and scrotum can be performed in most cases.
In complete disruption of the spermatic cord, realignment
without vaso-vasostomy may be considered.
In extensive destruction of the tunica albuginea, mobilisation of a free tunica vaginalis flap can be performed for
testicular closure.
If reconstruction cannot be achieved, orchiectomy is indicated.
In IED blast injury, the extensive loss of genital tissue often
requires complex and staged reconstructive surgical procedures.

Genital Trauma in Females

I n blunt trauma to the external genitalia, imaging studies of


the pelvis with US, CT, or MRI should be performed.
Vulvar haematomas usually do not require surgical intervention, but in massive vulvar haematoma or haemodynamically unstable patients, surgical intervention, lavage
and drainage is indicated.
In vulvar laceration, suturing after conservative debridement is indicated with concomitant primary repair of any
associated vaginal injuries.
258 Urological Trauma

Polytrauma, Damage Control and Mass Casualty Events

Urological trauma is often associated with significant and


higher priority injuries in the polytraumatised patient. Damage
control principles govern the management of the severely
injured patient and urologists need to understand their role in
the context of polytrauma.
Damage control is a three-phase approach - rapid control of
haemorrhage and wound contamination, resuscitation in the
intensive care unit, and delayed definitive surgery.
Procedures should be directed at the rapid control of bleeding, debridement of dead and devitalised tissue, and minimising urinary extravasation by simple diversionary measures.
A mass casualty event is one in which the number of injured
people is significantly higher than the number of healthcare
providers available. Examples include the collapse of buildings
or bridges, earthquakes, floods, tsunamis, train collisions, aircraft catastrophes, civilian terrorism.
Triage sorts 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
other, more salvageable patients, timely care. These
patients are given minimal or no treatment, and reevaluated when resources become available. There is no absolute
Urological Trauma 259

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 should be
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.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6) available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
260 Urological Trauma

GUIDELINES ON PAIN MANAGEMENT &


PALLIATIVE CARE
(Text update March 2013)

A. Paez Borda (chair), V. Fonteyne, E.G. Papaioannou,


F. Charnay-Sonnek

This pocket version aims to synthesise the important clinical


messages described in the full text and is presented as
a series of algorithms and graded action based recommendations, which follow the standard for levels of evidence
used by the EAU (see Introduction chapter).

Pain Management & Palliative Care 261

Cancer pain treatment in urology


Pain in patient with urological cancer

Pain assessment using OPQRSTUV and physical assessment (pain area, pain type, pertinent history, risks of addiction, associated
symptoms-nausea, vomiting, constipation, dyspnoea, tingling, urinary retention)

Mild pain (score 1-3)


Paracetamol
NSAIDs at the lowest
effective dose (need
for periodical pain
assessment)
Consider gastric
protection in long
term NSAIDs use
Weak opioids (codeine
or tramadol) at low
doses in combination
with non-opioids

Moderate pain (score 4-6)

Opioid nave patient


Morphine 5 mg x
6 per os and 2.5-5
mg every hr prn
for breakthrough
pain. For elderly
or debilitated
consider starting
dose of 2.5 mg x 6
Hydromorphone
1 mg x 6 per os
with 0.5-1 mg
every hr prn.
For elderly and
debilitated 0.5 mg
x 6
Oxycocone 2.5 mg
x 6 per os with 2.5
mg every hr prn for
breakthrough pain

In case of inadequate
pain control

Severe pain (score 7-10)

Patient in opiod
treatment
Increase the
regular and
breakthrough
doses by 25%
Titrate dose every
24hrs
Make frequent
assessments and
opioid titration
until pain is
controlled.

If pain persists

Opioid nave patient


Morphine 5-10 mg
x 6 per os and 5
mg prn every 1hr,
or
Hydromorphone 1-2
mg x 6 per os and
1mg prn every 1hr,
or
Morphine 2.5-5 Mg
x 6 sc and 2.5 Mg sc
prn every 30 min,
or
Hydromorphone
0.5-1 mg x 6 sc and
0.5 mg sc prn every
30 min.

If pain persists consider opioid switching


Consult a palliatve care specialist

Severe pain crisis

Consult a palliative care specialist

iv access present

Opioid-nave patient
Morphine 5-10 mg
every 10 min until pain
is relieved

Patient on opioids
Give the usual per os
morphine dose iv every
10 min until pain is
relieved

No iv access present

Opioid-nave patient
Morphine 5-10 mg sc
every 20-30 min until
pain is relieved

Titrate dose by 25% every 1-2 doses until pain is relieved

262 Pain Management & Palliative Care

Patient in opiod
treatment
Increase the regular
and breakthrough
doses by 25%.
Titrate dose every
24hrs.

Patient on opioids
Give the usual per
os morphine dose sc
every 20-30 min until
pain is relieved

Act accordinlgy
Drain, insert catheter
Stockings
Treat constipation or obstructive
ileus (if present)
Palliative hormonal therapy

Multiple painful
lesions

Consider radioisotopes

Document number and location


(scintigraphy)
Start hormone therapy (and
analgesics if painful, see
addendum)

METASTASES

If pain persists, consider


bisphosphonates/denosumab

Consider limited field


radiotherapy

Single painful lesions

Soft tissue invasion


Bladder outlet obstruction
Ureteric obstruction
Lymphoedema
Ileus
Hematuria

LOCAL
IMPAIRMENT

Prostate cancer

Consider decompressive surgery

Paraplegia < 48h


Life expectancy > 3 months

Start iv dexamethasone
8 mg/12 hours

SPINAL CORD
COMPRESSION

Consider radiotherapy

Paraplegia > 48h


Life expectancy < 3 months

Pain management in prostate cancer patients

Pain Management & Palliative Care 263

Prostate cancer pain management


Recommendations
LE
GR
Systemic pain management
WHO analgesic ladder step 1: NSAID or para1a
A
cetamol
Opioid administration
Opioids use (see Cancer pain treatment in
1a
A
urology)
Access to breakthrough analgesia
1b
A
Tricyclic antidepressant and/or anticonvulsant
1a
A
in case of neuropathic pain
Pain due to painful or unstable bony metastases (single
lesions)
External beam irradiation
1b
A
Pain due to painful bony metastases (widespread, opioid
refractory)
Radioisotopes (89Sr or 153Sm-EDTMP)
2
B
Bisphosphonates
1b
A
Denosumab
1b
A

264 Pain Management & Palliative Care

Pain management in bladder cancer patients


Bladder cancer

LOCAL
IMPAIRMENT

METASTASES

Document number and location


(scintigraphy)

Bladder outlet obstruction


Ureteric obstruction
Bowel invasion
Soft tissue invasion

Act accordingly (TURBT, insert catheter or percutaneous


nephrostomy, treat obstructive ileus if present)
Consider pallative pelvic exenteration for selected cases of
advanced disease
Consider chemotherapy for selected cases of advanced disease
Consider local radiotherapy for selected cases of advanced disease

Single lesions

Multiple lesions

Consider single-fraction
radiotherapy

Consider hemi-body irradation


Consider radioisotopes

Pain management in upper urinary tract cancer patients


Upper urinary tract cancer

Local impairment

Ureteric obstruction
Invasion of surrounding areas
Soft tissue invasion

Nephroureterectomy
Consider extended operations (nephroureterectomy+bowel/
spleen/abdominal wall muscle resection) for selected cases of
advanced disease
Consider chemotherapy for locally advanced and/or metastatic
cancer

Bone metastases

Document number and location


(scintigraphy)

Single lesions

Consider single-fraction
radiotherapy

Multiple lesions

Consider hemi-body irradation


Consider radioisotopes

Pain Management & Palliative Care 265

Transitional cell carcinoma pain management


Recommendations
Always disclose bladder outlet obstruction as
source of local pain
In locally advanced bladder cancer, palliative
cystectomy or exenteration might be an option
for symptom relief.
Use radiotherapy to reduce pain and symptoms
of locally advanced bladder cancer.
Use radiotherapy to reduce pain due to bone
metastases.

LE
-

GR
GCP

1a

1b

Pain management in renal cell carcinoma patients


Renal cell carcinoma

Local impairment

Metastases

Ureteric obstruction
Invasion of surrounding areas
(posterior abdominal wall, nerve roots,
bowel, spleen, liver)
Soft tissue invasion

Document number and location


(scintigraphy)

Bone

Nephrectomy
Consider extended operations (nephroureterectomy+bowel/
spleen/abdominal/wall muscle resection) for selected cases of
painful advanced disease

Consider radiotherapy
Consider radioisotopes

266 Pain Management & Palliative Care

Brain

Consider radiosurgery

Renal cell carcinoma pain management


Recommendations
GR
Obstruction of the upper urinary tract due to haemGCP
orrhage and subsequent formation of blood clots is
effectively treated by radical nephrectomy in nonmetastatic tumour.
If the patient is physically fit for surgery, this should be GCP
done to increase the QoL, e.g., palliative nephrectomy
in cases of metastatic tumour.
GCP = good clinical practice.

Pain management in patients with adrenal carcinoma


Pain management in patients with malignant
pheochromocytoma
Malignant pheochromocytoma

Soft tissue and/or bone


metastases

131

I-MIBG

Symptomatic treatment

Consider palliative
radiotherapy

Pain Management & Palliative Care 267

Pain management in patients with adrenocortical


carcinomas

Adrenocortical carcinoma

Soft tissue and/or bone


metastases

Symptomatic treatment

Consider palliative
radiotherapy

Adrenal carcinoma
Recommendations malignant phaeochromocytoma
131I-MIBG may reduce pain
Radiation therapy can induce partial remission
Recommendations adrenocortical carcinoma
Surgical removal of the primary tumour and
local lymph nodes can decrease pain
Radiotherapy can be effective for palliation and
pain management

268 Pain Management & Palliative Care

LE

GR

2b
3

B
C

2b

Pain management in penile cancer patients


Penile cancer
Pain in early stages: disclose voiding dysfunction
secondary to invasion of corpus spongiosum

Pain due to local impairment

Bladder outlet obstruction


Ureteric obstruction
Bowel invasion
Soft tissue invasion

Pain due to
lymphoedema

Pain due to metastases

Wraps, pressure stockings or


pneumatic pumps

Consider partial/total penectomy


approach with a multimodal regimen:
chemotherapy,
radiotherapy and surgical resection

Act accordingly (TURP, insert


catheter or percutaneous
nephrostomy, treat obstructive ileus
if present)
Consider palliative pelvic
exenteration under certain
circumstances

If erosion of femoral vessels is


anticipated, insert prophylactic
endoluminal vascular stent

Penile cancer pain management


Recommendations
Advanced penile cancer must be approached
with a multimodal treatment regimen that
includes neoadjuvant chemotherapy, radiotherapy and surgical resection
Radiotherapy might decrease pain from fixed
nodes and bone metastases

LE
2b

GR
B

Pain Management & Palliative Care 269

Pain management in testicular cancer patients


Testicular cancer

Pain due to local impairment

Orchiectomy

Pain due to metastases

Chemotherapy regimes + analgesia


Consider ureteral stenting or percutaneous nephrostomy
if hydronephrosis
Consider urgent spinal cord decompression if vertebral
metastases and neurological symptoms

Testicular cancer pain management


Recommendations
LE
Systemic chemotherapy is effective for the back 2b
or flank pain due to retroperitoneal lymphadenopathy
Back pain and neurological symptoms due to
3
spinal cord compression may require urgent
surgery

270 Pain Management & Palliative Care

GR
B

PAIN MANAGEMENT AFTER UROLOGICAL


OPERATIONS
Postoperative pain management
Acute postoperative pain

Exclude medical/surgical emergency

Refer to appropriate level of treatment

Access pain level

No pain

Pain level reassessment


and evaluation every
4-6 hrs unless patient
expresses discomfort

Mild (VAS score 1-3)

Moderate (VAS score 4-6)

Severe (VAS score 7-10)

(SWL, transurethral,
percutaneous endoscopic,
transvaginal procedures)

(Laparoscopic, minor operations


of the scrotum/penis and the
inguinal approach)

(Open surgery - perineal,


transperitoneal, suprapubic,
retropubic extraperitoneal
laparotomy, retroperitoneal
approach, flank incision,
thoracoabdominal approach)

P
aracetamol 500 mg-1g x 4 iv
and/or NSAIDs (diclofenac
50 mg x3 iv, ketorolac 10-30 mg
x 4 iv, lornoxicam 4-8 mg x 2 iv,
parecoxib 40 mg x 2 iv) and/or
metamizole 500-1000 mg x 4 iv
or paracetamol 500-1000 mg
plus codeine 30-60 mg x 4
orally.

P
aracetamol 500 mg-1g x 4 iv
and/or NSAIDs (diclofenac
50 mg x3 iv, ketorolac 10-30 mg
x 4 iv, lornoxicam 4-8 mg x 2 iv,
parecoxib 40 mg x 2 iv) and/or
metamizole 500-1000 mg x 4 iv
or paracetamol 500-1000 mg
plus codeine 30-60 mg x 4
orally.
Pethidine 50-100 mg x 6 iv or
tramadol 50-100 mg x 6 iv or
morphine 5 mg starting dose x
4-6 times per day sc/im or 2 mg
starting dose x 6 iv.

P
aracetamol 500 mg-1g x 4 iv
and/or NSAIDs (diclofenac
50 mg x3 iv, ketorolac 10-30 mg
x 4 iv, lornoxicam 4-8 mg x 2 iv,
parecoxib 40 mg x 2 iv) and/or
metamizole 500-1000 mg x 4 iv
PCA with morphine iv
(0.5-2.5 mg bolus, 10-15 min
lockout)
PCEA with morphine 100200g demand dose, lockout
interval 10-15 min and
continuous rate 300-600g/h
ropivacaine 0.2% 2 ml
demand dose, and continuous
rate 5 ml/h or bupivacaine
0.125% 2 ml demand dose and
continuous rate 4 ml/h.

In case of persistent pain


pethidine 50-100 mg iv or
tramadol 50-100 mg iv prn.

In case of persistent pain add or


increase morphine dose by 2 mg
bolus in 1 hr increments

In case of persistent pain extra


morphine 2-5 mg iv or morphine
1-5 mg 10-15ml bupivacaine
0.125% or ropivacaine 0,2% bolus
epidurally in 1 hr increments.

PCA = patient controlled analgesia; PCEA = patient controlled


epidural analgesia; PRN = as needed.

Pain Management & Palliative Care 271

Recommendations pain treatment after different urological


operations
Extracorporeal shock wave lithotripsy
LE
GR
Administer NSAIDs or midazolam 30-45 min
2b
B
before SWL procedure to reduce the need for
opioids
Transurethral procedures
LE
GR
Postoperative analgesics with spasmolytic
3
C
effect or mild opioids are preferable.
Antimuscarinic drugs could be helpful in reduc- 3
B
ing discomfort resulting from the indwelling
catheter.
Antimuscarinic drugs may reduce the need for
3
B
opioids.
Laparoscopic and robotic procedures
LE
GR
Low intra-abdominal pressure and good desuf- 1b
A
flation at the end of the procedure reduces
postoperative pain.
NSAIDs are often sufficient for postoperative
2a
B
pain control.
NSAIDs decrease the need for opioids.
1b
B
NSAIDs = non-steroidal anti-inflammatory drugs; SWL = extracorporeal shock wave lithotripsy.
Recommendations pain management after open surgery
Minor operations of the scrotum/penis and the LE
inguinal approach
For postoperative pain control, multimodal anal- 3
gesia with a combination of NSAIDs or paracetamol plus local anaesthetics should be used.
If possible, avoid opioids for outpatients.
3
272 Pain Management & Palliative Care

GR
B

Transvaginal surgery
NSAIDs are often sufficiently effective after
2a
minor or moderate surgery.
NSAIDs decrease the need for opioids.
1b
Transperitoneal laparotomy
Consider continuous epidural infusion of a com- 1b
bination of opioids and local anaesthetic. Once
the patient is able to take oral analgesics use
metamizole, paracetamol codeine or tramadol.
Retroperitoneal approach - flank incision thoracoabdominal approach
Consider continuous epidural infusion of a com- 1b
bination of opioids and local anaesthetic. Once
the patient is able to take oral analgesics use
metamizole, paracetamol codeine or tramadol.
NSAIDs = non-steroidal anti-inflammatory drugs; PCA =
patient-controlled analgesia; PCEA = patient-controlled
epidural analgesia.

B
B
A

Pain Management & Palliative Care 273

Summary of recommendations for postoperative pain management in adults


Recommendation
Preoperative assessment and preparation of
patients allow more effective pain management.
Adequate postoperative pain assessment can
lead to more effective pain control and fewer
complications.
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.
The use of paracetamol is recommended for
postoperative pain management because it
reduces consumption of opioids.
Administer paracetamol as a single therapy to
alleviate mild postoperative pain without major
adverse effects.
The use of intravenous patient controlled
analgesia is recommended because it provides
superior postoperative analgesia, improving
patient satisfaction and decreasing risk of respiratory complications.
Administer adjuncts in appropriate doses and
monitored care to improve analgesic efficacy
and reduce opioid-related side effects.
Administer clonidine preoperatively or epidurally postoperatively to reduce opioid
Requirements.

274 Pain Management & Palliative Care

LE
1a

GR
A

2a

2a

1b
2a

B
B

1b

2a

1b

1a

1a

Gabapentin can be administered before as well 1a


A
as after surgery to decrease pain severity and
need for analgesic supplementation.
Epidural analgesia, especially PCEA, provides
1b
A
superior postoperative analgesia, reducing
complications and improving patient satisfaction, and is therefore preferable to systemic
techniques.
NSAIDs = non-steroidal anti-inflammatory drugs; PCEA =
patient-controlled epidura.
Recommendations special populations
Special populations
Ambulatory surgical patients
For postoperative pain control in outpatients,
multimodal analgesia with a combination of
NSAIDs or paracetamol plus local anaesthetics
should be used.
If possible, avoid opioids.
Geriatric patients
Multimodal and epidural analgesia are preferable for postoperative pain management in
elderly patients because these techniques are
associated with fewer complications.
Obese patients
Postoperative use of opioids should be avoided
in obese patients unless absolutely necessary.
An epidural local anaesthetic in combination
with NSAIDs or paracetamol is preferable.
Perioperative pain management in children
Apply EMLA locally to alleviate venipuncture
pain in children.

LE

GR

2b

2b

2b

2b

1b

Pain Management & Palliative Care 275

Dosage and method of delivery of some important


analgesics
Dosage and delivery of NSAIDs
Drug

Daily dose

Route of
administration
Conventional NSAIDs (non-selective COX inhibitors)
Ketorolac
10-30 mg four times daily Orally or iv
Ibuprofen
400 mg three times daily Orally
Ketoprofen
50 mg four times daily
Orally or iv
Diclofenac
75 mg twice daily
Orally or iv
50 mg three times daily
Orally or iv
100 mg twice daily
Rectally
COX-2 selective inhibitors
Meloxicam
15 mg once per day
Orally
Lornoxicam
4-8 mg twice daily
Orally or iv
Celecoxib
200 mg once per day
Orally
Parecoxib
40 mg once or twice daily iv form only
Etoricoxib
90-120 mg once daily
Orally

Dosage and delivery of paracetamol, metamizole and its


combinations with opioids
Drug

Method of
administration
Paracetamol Orally
Paracetamol iv
Metamizole
Metamizole

Orally
iv

276 Pain Management & Palliative Care

Single dose Maximal dose


(mg)
(mg/day)
500-1000
4000 (50 mg/
kg)
1000
4000 (50 mg/
kg)
500-1000
4000
1000-2500 5000

Paracetamol Opioid
Paracetamol
1g
Paracetamol
600-650 mg
Paracetamol
500 mg
Paracetamol
300 mg
Paracetamol
650 mg

Codeine 60 mg

Times
per day
Four

Codeine 60 mg

Four

Codeine 30 mg

Four

Codeine 30 mg

Four

Dextropropoxyphene
65 mg
Paracetamol Tramadol 75-100
600-650 mg mg
Paracetamol Oxycodone 5 mg
325 mg

Four

Route of
administration
Orally or rectally
Orally or rectally
Orally or rectally
Orally or rectally
Orally

Four

Orally

Four

Orally

Dose and delivery of opioids


Drug

Method of
Common
administration single dose
(mg)
Tramadol
Orally
50
Tramadol
iv
50-100
Dihydrocodeine Orally
60-120
Piritramid
sc/im
15-30
Pethidine
Orally
25-150
Pethidine
Rectally
100
Pethidine
sc/im
25-150
Pethidine
iv
25-100
Morphine*
Orally
Starting
with 10

Maximal
dose (mg)
400-600
400-600
240
120
500
500
500
500
No maximal
dose

Pain Management & Palliative Care 277

Morphine*

Rectally

Starting
No maximal
with 10
dose
Morphine*
sc/im
Starting
No maximal
with 5
dose
Morphine*
iv
Starting
No maximal
with 2
dose
Morphine*
Iv (PCA)
0.5-2.5 mg
No maximal
bolus
dose
10-15 min
lockout
*Strong opioids have no real upper dose limit (except
buprenorphine). The dose must be titrated in correlation
with pain relief and depending on the individual strength of
unwanted effects such as respiratory depression. A simple
way of calculating the daily dose of morphine for adults (20-75
years) is: 100 - patients age = morphine per day in mg.
PCA = patient-controlled analgesia.
Common equi-analgesic doses for parenteral and oral administration of opioids*
Drug
Parenteral (mg)
Oral (mg)
Morphine
10
30
Fentanyl
0.1
Pethidine
75
300
Oxycodone
15
20-30
Dextropropoxyphene 50
Tramadol
37.5
150
Codeine
130
200
*All listed opioid doses are equivalent to parenteral morphine
10 mg. The intrathecal opioid dose is 1/100, and
the epidural dose 1/10 of the dose required systemically.

278 Pain Management & Palliative Care

PALLIATIVE CARE
Protocols for communicating with patients about major
topics in palliative care
Establishing goals
of medical care

Communicating
bad news

Withdrawing
treatment

Create the right setting: plan what to say, allow adequate time, and determine who else should be present at the meeting

Establish what the patient knows:


clarify the situation and context in
which the discussion about goals is
occurring

Establish what the patient knows:


clarify what the patient can
comprehend; reschedule the talk if
necessary

Establish and review the goals of


care

Explore what the patient is hoping


to accomplish: help distinguish
between realistic and unrealistic
goals

Establish how much the patient


wants to know: recognise and
support preferences; people handle
information in different ways

Establish the context of the


current discussion: discuss what
has changed to precipitate the
discussion

Suggest realistic goals: explore how


goals can be achieved and work
through unrealistic expectations

Share the information: avoid


jargon, pause frequently, check for
understanding, use silence; do not
minimise the information

Discuss specific treatment in the


context of the goals of care: talk
about whether the treatment will
meet the goals of care

Discuss alternatives to the


proposed treatment: talk about
what will happen if the patient
decides not to have the treatment
Respond empathetically to feelings: be prepared for strong emotions and allow time for response, listen, encourage
description of feelings, allow silence

Make a plan and follow through:


discuss which treatments will be
undertaken to meet the goals,
establish a concrete plan for followup, review and revise the plan
periodically as needed

Follow up: plan for next steps,


discuss potential sources of
support, share contact information,
assess the patients safety and
support, repeat news at future
visits

Plan for the end of the treatment:


document a plan for withdrawal of
treatment and give it to the patient,
the patients family, and members
of the health care team

Adapted from the Education on Palliative and End-of-life Care


Project.
Curriculum Emanuel LL, von Gunten CF, Ferris FD, eds.
The Education in Palliative and End-of-life Care (EPEC)
Curriculum: The EPEC Project, 1999, 2003.

Pain Management & Palliative Care 279

Recommendations treatment of physical symptoms


Dyspnoea and respiratory symptoms
Benzodiazepines can be considered when
opioids and non-pharmacological measures fail
to control breathlessness.
Cancer anorexia-cachexia syndrome
Nutritional support is ineffective
Oral thalidomide (50 mg/day, 2 weeks) seems
effective
Vomiting
Dexamethasone is not effective in
metoclopramide-refractory nausea.
Patients with a high risk of vomiting induced
by chemotherapy are effectively treated with a
combination of dexamethasone and 5-HT3 and
neurokinin 1 receptor antagonists.
In patients with moderate risk of vomiting
induced by chemotherapy, palonosetron
combined with dexamethasone is
recommended.
Patients receiving radiotherapy and
experiencing emesis can be effectively treated
with combined 5-HT3 receptor antagonist and
dexamethasone.
Fatigue
For anaemic patients erythropoietin and
darbopoetin have provided improvement.
Methylphenidate 10-40 mg/day, can reduce
fatigue and depression.
Restlessness
Neuroleptics cannot be recommended for
treatment of terminal restlessness.
280 Pain Management & Palliative Care

LE
1a

GR
A

1b
1b

A
A

1b

1a

1a

1a

1b

1b

Agitated delirium
Haloperidol (5-10 mg, intravenous) can be useful 2a
Constipation
No clear recommendations as to the use of a
1a
particular laxative can be made.
Anxiety
It is therefore not possible to draw conclusions 4
about the effectiveness of pharmacotherapy in
this setting.

C
A

Recommendations treatment of psychological aspects


Fear
LE
Distress must be recognised, measured, treated 2b
and monitored at all stages of the disease.
Depression
Efforts should be made to detect hidden depres- 2b
sion.
*Recommendation based on expert opinion.

GR
A

B*

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-71-7), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Pain Management & Palliative Care 281

GUIDELINES ON CHRONIC PELVIC PAIN

(Partial text update April 2014)

D. Engeler (chair), A.P. Baranowski, J. Borovicka, A. Cottrell,


P. Dinis-Oliveira, S. Elneil, J. Hughes, E.J. Messelink,
A. van Ophoven, Y. Reisman, A.C. de C. Williams

Eur Urol 2004;46(6):681-9


Eur Urol 2010;57(1):35-48
Eur Urol 2013;64(3):431-9
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).
Figure 1: Predisposing factors & causes associated with central en peripheral mechanisms
Predisposing factors
genetics
psychological state
recurrent somatic trauma

Causes
surgery
trauma
infection

Peripheral nerve injury

Peripheral sensitisation

Abnormal peripheral
afferent signalling

Increased peripheral
afferent signalling

Central sensitisation
Abnormal central
afferent signalling

Abnormal central
efferent signalling

Abnormal central
processing

Consequences include:
sensory problems

Consequences include:
changes in organ function

Psychological, behavioural and


sexual consequences

Regional and systemic changes


Referred pain, viscero-visceral hyperalgesia, viscero-somatic hyperalgesia. Trophic, autonomic, endocrine and
immunological responses

282 Chronic Pelvic Pain

Algorithm 1: Diagnosing and treating CPP


Chronic Pelvic Pain

History

Physical
examination
yes

Symptom of a well
known disease

Treat according to
specific disease
guidelines

Specific disease associated


pelvic pain
Pelvic pain syndrome

no

Organ specific symptoms


present

no

Go to:
Pain management
(Alg. 2)

yes

urology

gynaecology

gastroenterology

neurology

sexology

pelvic floor

see
chapter 3

see
chapter 4

see
chapter 5

see
chapter 6

see
chapter 7

see
chapter 9

Algorithm 2: Pain management


Multidisciplinary approach

Holistic* approach

Sexology

Psychology

Physiotherapy

Pain medicine

See chapter 7

See chapter 8

See chapter 9

See chapter 10

*The term holistic means consideration of the complete person, physically, psychologically, socially, and spiritually, in the
management and prevention of disease.

Chronic Pelvic Pain 283

Table 1: Classification of chronic pelvic pain syndromes


Axis I
Region

Axis II
System

Axis III
End-organ as pain syndrome as identified
from Hx, Ex and Ix

Chronic Specific
pelvic
disease
pain
associated
pelvic pain

Urological

Prostate
Bladder
Scrotal
Testicular
Epididymal
Penile
Urethral
Postvasectomy
Vulvar
Vestibular
Clitoral
Endometriosis associated
CPPS with cyclical exacerbations
Dysmenorrhoea
Irritable bowel
Chronic anal
Intermittent chronic anal
Pudendal pain syndrome
Dyspareunia
Pelvic pain with sexual dysfunction
Any pelvic organ

OR
Pelvic pain
syndrome
Gynaecological

Gastrointestinal

Peripheral nerves
Sexological
Psychological
Musculo-skeletal

Pelvic floor muscle


Abdominal muscle
Spinal
Coccyx

Hx = History; Ex= Examination; Ix = Investigation.

284 Chronic Pelvic Pain

Axis IV
Axis V
Axis VI
Axis VII
Referral
Temporal
Character
Associated
character- characteristics
symptoms
istics
Suprapubic
ONSET
Aching
UROLOGICAL
Inguinal
Acute
Burning
Frequency
Urethral
Chronic
Stabbing
Nocturia
Penile/clitoral
Electric
Hesitance
Perineal
ONGOING
Dysfunctional flow
Rectal
Sporadic
Urge
Back
Cyclical
Incontinence
Buttocks
Continuous
Thighs
GYNAECOLOGICAL
TIME
Menstrual
Filling
Menopause
Emptying
Immediate post
GASTROINTESTINAL
Late post
Constipation
Diarrhoea
TRIGGER
Bloatedness
Provoked
Urge
Spontaneous
Incontinence
NEUROLOGICAL
Dysaesthesia
Hyperaesthesia
Allodynia
Hyperalegesie

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

SEXUOLOGICAL
Satisfaction
Female dyspareunia
Sexual avoidance
Erectile dysfunction
Medication
MUSCLE
Function impairment
Fasciculation
CUTANEOUS
Trophic changes
Sensory changes

Chronic Pelvic Pain 285

Figure 2: Phenotyping and assessment of CPP


Phenotyping

Assessment

Urology

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)
Specific diseases with similar symptoms must be
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
with symptoms according to the above definition
should be diagnosed with PPS.
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.

286 Chronic Pelvic Pain

GR
A

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 synGR


drome (PPS)
Consider multimodal and phenotypically directed
B
treatment options for PPS.
Alpha-blockers are recommended for patients with a
A
duration of PPS < 1 year.
Single use of antimicrobial therapy (quinolones or
A
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 longB
term side effects have to be considered.
Allopurinol is not recommended for use in PPS.
B
Phytotherapy might be used in patients with PPS.
B
Consider high-dose pentosan polysulphate to improve A
symptoms and quality of life in PPS.
Pregabalin is not recommended for use in PPS.
A
Perineal extracorporeal shock wave therapy might be B
considered for the treatment of PPS.
Electro-acupuncture might be considered for the
B
treatment of PPS.
Posterior tibial nerve stimulation might be considered B
for the treatment of PPS.
TUNA of the prostate is not recommended for the
B
treatment of PPS.
For PPS with significant psychological distress, psyB
chological treatment focussed on PPS should be
attempted.
TUNA = transurethral needle ablation; NSAIDs = non-steroidal
anti-inflammatory drugs.
Chronic Pelvic Pain 287

Figure 3: Assessment and treatment of PPS


Assessment

Treatment

Urine culture

Grade A
recommended

Alpha-blockers when duration is < 1 year

Uroflowmetry

Single use antibiotics (6 weeks) when duration


is < 1 year

Transrectal
US prostate

High dose Pentosan polysulfate to improve QoL


and symptoms

NIH-CPSI
scoring list

Grade B
recommended

NSAIDs. Be aware of long-term side effects


Phytotherapy
Perineal extracorporeal shock wave therapy

Phenotyping

Electroacupuncture

Pelvic floor
muscle testing

Percutaneous tibial nerve stimulation (PTNS)


Psychological treatment focused on the pain
Not recommended

Allopurinol

[B]

Pregabalin

[A]

TransUrethral Needle Ablation (TUNA)

[B]

US = Ultrasound

BLADDER PAIN SYNDROME


Table 2: ESSIC classification of types of BPS according to the results
of cystoscopy with hydrodistension and biopsies
Not
done

Cystoscopy with hydrodistension


Normal
Glomerulationsa
Hunners
lesionb

Biopsy
Not done
XX
1X
2X
3X
Normal
XA
1A
2A
3A
Inconclusive XB
1B
2B
3B
Positivec
XC
1C
2C
3C
aCystoscopy: glomerulations grade 23
bLesion per Falls definition with/without glomerulations
cHistology showing inflammatory infiltrates and/or detrusor
mastocytosis and/or granulation tissue and/or intrafascicular
fibrosis.
288 Chronic Pelvic Pain

Recommendations: assessment and diagnosis


bladder pain syndrome (BPS)
Specific diseases with similar symptoms must be
excluded. It is therefore recommended to adapt diagnostic procedures to each patient and aim at identifying them.
After primary exclusion of specific diseases, patients
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.

GR
A

A
A

Recommendations: treatment bladder pain syndrome GR


(BPS)
Offer subtype and phenotype-oriented therapy for the
treatment of BPS.
Multimodal behavioural, physical and psychological
techniques should always be considered alongside
oral or invasive treatments of BPS.
Opioids might be used in BPS in disease flare-ups.
Long-term application solely if all treatments failed.
Corticosteroids are not recommended for long-term
treatment.
Offer hydroxyzine for the treatment of BPS.
Consider cimetidine as valid oral option before
invasive treatments.

A
A

C
C
A
B

Chronic Pelvic Pain 289

Administer amitriptyline for use in BPS.


Offer oral pentosanpolysulphate sodium for the treatment of BPS.
Treatment with oral pentosanpolysulphate sodium plus
subcutaneous heparin is recommended especially in low
responders to pentosanpolysulphate sodium alone.
Antibiotics can be offered when infection is present or
highly suspected.
Prostaglandins are not recommended. Insufficient
data on BPS, adverse effects considerable.
Cyclosporin A might be used in BPS 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 for oral treatment of
BPS.
Administer intravesical lidocain plus sodium bicarbonate prior to more invasive methods.
Administer intravesical pentosanpolysulphate sodium
before more invasive treatment alone or combined with
oral pentosanpolysulphate sodium.
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.
Administer intravesical DMSO before more invasive
measures.
Consider intravesical bladder wall and trigonal injection of
BTX-A if intravesical instillation therapies have failed.
290 Chronic Pelvic Pain

A
A
A

C
C
B
C
C
C
A
A

C
B
B
A
C

Administer submucosal injection of BTX-A plus hydrodistension if intravesical instillation therapies have
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.
Bladder distension is not recommended as a treatment 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 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.
DMSO = dimethyl sulphoxide.

A
A
C
C
C
B
B
B
B
C
C
B
A

Chronic Pelvic Pain 291

Figure 4: Diagnosis and therapy of BPS


Assessment

Treatment

Urine culture

Grade A
recommended

Uroflowmetry

Intravesical: PPS, DMSO, onabotulinum toxin A


plus hydrodistension

Cystoscopy with
hydrodistension
Bladder biopsy

Grade B
recommended

Micturition diary

Oral: Cimetidine, cyclosporin A


Intravesical: hyaluronic acid, chondroitin sulphate
Electromotive drug administration for intravesical
drugs

Pelvic floor
muscle testing

Neuromodulation, bladder training, physical


therapy

Phenotyping
ICSI score list

Standard: Hydroxyzine, Amitriptyline,


Pentosanpolysulphate

Psychological therapy
Not recommended
Other comments

292 Chronic Pelvic Pain

Bacillus Calmette Gurin


Intravesical Chlorpactin
Data on surgical treatment are largely variable
Coagulation and laser only for Hunners lesions

Algorithm 3: Treatment of BPS Type 3 C


Bladder Pain Syndrome

Hunners lesion at cystoscopy

yes

no

TUR / laser

Adequate:

Inadequate:

* Retreat when
necessary

* Start other
treatment

* Oral agents
* TENS
* Complementary
medicine
Inadequate relief:
* start Intravesical
therapy
Still inadequate response:
* Refer to specialist
pain management unit

SCROTAL PAIN SYNDROME


Recommendations: treatment of scrotal pain syndrome

GR

Start with general treatment options for chronic pelvic pain (see Chapter 10 full text).

Inform about the risk of postvasectomy pain when


counselling patients planned for vasectomy.

To reduce the risk of scrotal pain, open instead of


laparoscopic inguinal hernia repair is recommended.

Chronic Pelvic Pain 293

It is recommended that during inguinal hernia repair


all the nerves in the spermatic cord are identified.

For patients who are treated surgically, microsurgical


denervation of the spermatic cord is recommended.

For patients who do not benefit from denervation it is


recommended to perform epididymectomy.

We recommend that orchiectomy should not be


done, unless all other therapies, including pain management assessment, have failed.

Figure 5: Assessment and treatment of scrotal pain syndrome


Assessment

Treatment

Semen culture

Grade A
recommended

Uroflowmetry

General treatment options for chronic pelvic


pain - see Chapter 10 full text
Microsurgical denervation of the spermatic cord

Ultrasound
scrotum
(see full text)

Inform patients undergoing vasectomy about the


risk of pain
For surgeons: open hernia repair yields less
scrotal pain

Pelvic floor
muscle testing

For surgeons: identify all nerves during hernia


repair

Phenotyping
Grade B
recommended

Epididymectomy, in case patient did not benefit


from denervation

Grade C
recommended

In case all other therapies, including pain


management assessment, have failed,
orchiectomy is an option.

Other
comments

Ultrasound has no clinical implications on the


further treatment although physicians tend to
still use ultrasound to reassure the patient

294 Chronic Pelvic Pain

URETHRAL PAIN SYNDROME


Recommendations: treatment of urethral pain syndrome
Start with general treatment options for chronic pelvic
pain (see Chapter 10 full text).
It is recommended that patients with urethral pain
syndrome are treated in a multidisciplinary and multimodal programme.
When patients are distressed, it is recommended to
refer them for pain-relevant psychological treatment
to improve function and quality of life.

GR
A
B

Figure 6: Assessment and treatment of urethral pain syndrome


Assessment

Treatment

Uroflowmetry

Grade A
recommended

General treatment options for chronic pelvic


pain - see Chapter 10 full text

Grade B
recommended

Treat in a multidisciplinary and multimodal


programme

Micturition
diary
Pelvic floor
muscle testing

Pain-relevant psychological treatment to improve


QoL and function

Phenotyping
Other comments

Data on urethral pain are very sparse and of


limited quality

Chronic Pelvic Pain 295

GYNAECOLOGICAL ASPECTS OF CHRONIC PELVIC


PAIN
Recommendations: gynaecological aspects in 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 7: Assessment and treatment of gynaecological


aspects in chronic pelvic pain
Assessment

Treatment

Gynaecological
examination

Grade A
recommended

Laparoscopy to rule out treatable causes

Grade B
recommended

Hormonal therapy in well defined states

Ultrasound
Laparoscopy
(see text)

Multidisciplinary approach in persistent


disease states
Psychological treatment for refractory
chronic vulvar pain

296 Chronic Pelvic Pain

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 A and electrogalvanic stimulation can
be considered in the chronic anal pain syndrome.
Percutaneous tibial nerve stimulation can be considered in the chronic anal pain syndrome.
Sacral neurostimulation should be considered in the
chronic anal pain syndrome.
Inhaled salbutamol should be considered in the intermittent chronic anal pain syndrome.

GR
A
A
B
B
C
C

Figure 8: Assessment and treatment of anorectal pain syndrome


Assessment

Treatment

Endoscopy

Grade A
recommended

Biofeedback treatment

Grade B
recommended

Botulinum toxin A in women with pelvic pain

Other comments

Sacral neuromodulation should be considered

Pelvic floor
muscle testing
Anorectal
manometry
Rectal balloon
expulsion test
MRIdefecography

Electrogalvanic stimulation
Percutaneous tibial nerve stimulation

Inhaled salbutamol should be considered in


intermittent anal pain syndrome

Chronic Pelvic Pain 297

Algorithm 4: Diagnosis of 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
* Physical therapy
* PTNS
* SNS

PTNS = percutaneous tibial nerve stimulation; SNS = sacral


nerve 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 utilised.
298 Chronic Pelvic Pain

GR
A
B

Figure 9: Assessment and treatment of peripheral nerve pain


syndrome
Assessment

Treatment

Extended
neurological
tests

Grade A
recommended

Refer to an expert when a peripheral nerve


problem is suspected

Grade B
recommended

Imaging may be of help

Extended
history on
nature of pain
Standardised
questionnaires

Neurophysiology may be of help


Treatment is as for any other nerve injury

SEXOLOGICAL ASPECTS OF CHRONIC PELVIC PAIN


Recommendations: sexological aspects in chronic
pelvic pain
Patients presenting with symptoms suggestive for
chronic pelvic pain syndrome should be screened for
abuse, without suggesting a causal relation with the
pain.
The biopsychosocial model should be applied in
the evaluation of the effect of chronic pelvic 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.
Offer behavioral strategies to the patient and his/her
partner to cope with sexual dysfunctions.
Training of the pelvic floor muscles is recommended
to improve quality of life and sexual function.

GR
B

B
B

Chronic Pelvic Pain 299

Figure 10: Assessment and treatment of sexologial aspects in


chronic pelvic pain
Assessment

Treatment

History of
sexual
functioning

Grade A
recommended

Refer to sexologist when sexual dysfunction


or trauma is present

Grade B
recommended

Screen for sexual abuse

History of
negative
experiences
Ask about
abuse
Psychiatric
history
History of
relationship

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

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.
Ask the patient what he/she thinks may be wrong to
cause pain, to allow the opportunity to inform and
reassure as appropriate.
Try psychological interventions in combination with
medical and surgical treatment, or alone.

300 Chronic Pelvic Pain

GR
A

Figure 11: Assessment and treatment of psychological


aspects of chronic pelvic pain
Assessment

Treatment

Psychological
history

Grade A
recommended

Investigate
pain-related
beliefs and
behavior

Interpret psychological distress in the context


of pain
Psychological interventions as adjuvant to
other modalities

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
The use of the ICS classification on pelvic floor muscle
function and dysfunction is recommended.
In patients with chronic pelvic pain syndrome it is
recommended to actively look for the presence of
myofascial trigger points.
Apply pelvic floor muscle treatment as first line treatment in patients with chronic pelvic pain syndrome.
In patients with an overactive pelvic floor biofeedback
is recommended as therapy adjuvant to muscle exercises.
When myofascial triggerpoints are found treatment by
pressure or needling is recommended.

GR
A
B

B
A

Chronic Pelvic Pain 301

Figure 12: Assessment and treatment pelvic floor function


Assessment

Treatment

Palpation of
the muscles

Grade A
recommended

Testing of
pelvic floor
function

Use biofeedback in combination with muscle


exercises
Treat myofascial triggerpoints using pressure
or needling

Pelvic floor
muscle EMG
Test for
myofascial
trigger points

Grade B
recommended

Look actively for the presence of myofascial


trigger points
Apply pelvic floor muscle therapy as first line
treatment

History of all
the involved
organs
Standardised
questionnaires

Use the International Continence Society


classification of dysfunction

Other comments

The role and options of a physiotherapist may


differ between countries

GENERAL TREATMENT OF CHRONIC PELVIC PAIN


Recommendations for use of opioids in chronic/non-acute
urogenital 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.

302 Chronic Pelvic Pain

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 opioid, 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.

Chronic Pelvic Pain 303

Recommendations: medical and interventional treatment of


chronic pelvic pain
Agent
Pain Type
LE GR Comment
Paracetamol
Somatic pain 1a A
Evidence
based on
arthritic pain
with good
benefit
NSAIDs
Pelvic pain
1a A
Good eviwith inflamdence for their
matory
use
process (e.g.
dysmenorrhoea)
Antidepressants
Neuropathic 1a A
Effective.
including tricyclic pain
No specific
antidepressants,
evidence for
duloxetine and
chronic pelvic
venlafaxine
pain
Anticonvulsants
Neuropathic 1a A
Effective
gabapentin, prepain, fibrogabalin
myalgia
Gabapentin
Women with 2b B
Effective
chronic pelvic pain
Topical capsaicin Neuropathic 1a A
Some evipain
dence of
benefit
Opioids
Chronic non- 1a A
Beneficial in a
malignant
small number
pain
of patients

304 Chronic Pelvic Pain

Nerve blocks

Have a role as
part of a broad
management
plan
TENS
1b B
There is no
good evidence for or
against the
use of TENS.
Data covered
chronic pain
not just CPP
and was insufficient regarding long-term
treatment
effects.
Neuromodulation Pelvic pain
3
C
Role developing with
increasing
research.
NSAIDs = non-steroidal anti-inflammatory drugs;
TENS = transcutaneous electrical nerve stimulation.

Chronic Pelvic Pain 305

Figure 13: General analgesic treatment of chronic pelvic pain


Assessment

Treatment

General
history

Grade A
recommended

Medications
used

NSAIDs when inflammation is present


Antidepressants (including TCA) in
neuropathic pain

Allergic
reactions

Anticonvulsants in neuropathic pain


Topical Capsaicin in neuropathic pain

Use of alcohol
Daily activities
that will be
affected

Paracetamol in somatic pain

Opiods in chronic non-malignant pain


Grade B
recommended

Gabapentin in women with CPP

Other comments

Nerve blocks as part of a broad management [C]


plan
Neuromodulation may become an option,
increasing research

306 Chronic Pelvic Pain

[C]

Algorithm 5: General management of CPP


Pain described in neuropathic or
central pain terms
yes

no

First-line management trial using

Simple analgesics

1. Amitriptyline
2. Gabapentin

Alternatives:
1. Nortriptyline or Imipramine
2. Pregabalin
Review

Review

Adequate
analgesia:

Inadequate
response:

Adequate
analgesia:

Inadequate
response:

review regularly

consider adding
another first line
agent

discharge back to
primary care
physician

refer to specialist
pain management
unit

sustained eect:
consider dose
reduction

rotate agents
Still inadequate:
refer to specialist
pain management
unit

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-74-8), available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Chronic Pelvic Pain 307

GUIDELINES ON UROLITHIASIS
(Limited update April 2014)

C. Trk (chair), T. Knoll (vice-chair), A. Petrik, K. Sarica, C. Seitz,


A. Skolarikos, M. Straub

Classification of stones

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).
Table 1: X-ray characteristics
Radiopaque
Poor radiopaque
Calcium oxalate
Magnesium
dihydrate
ammonium phosphate
Calcium oxalate
Apatite
monohydrate
Calcium phosCystine
phates

Radiolucent
Uric acid

Ammonium urate
Xanthine
2,8-dihydroxyadenine
Drug-stones

308 Urolithiasis

Table 2: Stones classified according to their aetiology


Non infection Infection
Genetic
Drug stones
stones
stones
stones
Calcium
Magnesium
Cystine
e.g. indinavir
oxalates
ammonium
(see extended
phosphate
document)
Calcium
Carbonate
Xanthine
phosphates
apatite
Uric acid
Ammonium
2,8-dihydroxyurate
adenine
Table 3: Stones classified by their composition
Chemical composition
Mineral
Calcium oxalate monohydrate
whewellite
Calcium-oxalate-dihydrate
wheddelite
Uric acid dihydrate
uricite
Ammonium urate
Magnesium ammonium phosphate
struvite
Carbonate apatite (phosphate)
dahllite
Calcium hydrogenphosphate
brushite
Cystine
Xanthine
2,8-dihydroxyadenine
Drug stones

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.

Urolithiasis 309

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 and
bariatric surgery)
Sarcoidosis
Genetically determined stone formation
Cystinuria (type A, B, AB)
Primary hyperoxaluria (PH)
Renal tubular acidosis (RTA) type I
2,8-dihydroxyadenine
Xanthinuria
Lesch-Nyhan-Syndrome
Cystic fibrosis
Drugs associated with stone formation (see Chapter 11
extended text)

310 Urolithiasis

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 appropriate imaging.
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 non-contrast
enhanced computed tomography (NCCT) is considered, but
KUB can differentiate between radiolucent and radiopaque
stones and serve for comparison during follow-up.

Evaluation of patients with acute flank pain


Recommendation
NCCT should be used to confirm stone diagnosis in patients with acute flank pain, because it
is superior to IVU.

LE
1a

GR
A

Urolithiasis 311

Some drug stones like indinavir stones are 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*

Biochemical work-up

Each emergency patient with urolithiasis needs a succinct


biochemical work-up of urine and blood besides imaging
studies; no difference is made between high- and low-risk
patients.
Recommendations: Basic analysis emergency stone patient
Urine
GR
Urinary sediment/dipstick test out of spot urine sam- A*
ple for: red cells / white cells / nitrite / urine pH level by
approximation.
Urine culture or microscopy.
A
Blood
Serum blood sample creatinine / uric acid / ionized
A*
calcium / sodium / potassium / CRP.
Blood cell count.
A*
If intervention is likely or planned: Coagulation test
A*
(PTT and INR).
*Upgraded following panel consensus.
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
312 Urolithiasis

more specific analytical programme (see section on Metabolic


Evaluation below).
Analysis of stone composition should be performed in all firsttime stone formers (GR: A) and will need redoing if changes
are expected. 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
GR
prevention of recurrent renal colic
First choice: start with an NSAID, e.g.
1b
A
diclofenac*, indomethacin or ibuprofen.**
Second choice: hydromorphine, pentazocine
4
C
and tramadol.
Use a-blockers to reduce recurrent colic.
1a
A
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).
** Recommended to counteract recurrent pain after renal
colic (see extended document section 5.3).
If analgesia cannot be achieved medically, drainage, using
stenting or percutaneous nephrostomy, or stone removal,
should be performed.

Management of sepsis in the obstructed kidney

The obstructed, infected kidney is a urological emergency.


Urolithiasis 313

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.
Recommendations - Further Measures
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.

Stone relief

GR
A*

When deciding between active stone removal and conservative treatment using MET, it is important to consider the
individual circumstances of a patient that may affect treatment decisions.

314 Urolithiasis

Observation of ureteral stones


Recommendations
LE
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
observation*.
*see also Section MET.

GR
A

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
Kidney stones should be treated in case of growth, formation of de novo obstruction, associated infection,
and acute and/or chronic pain.
Comorbidity and patient preference need to be taken
into consideration when making treatment decisions.
If kidney stones are not treated, periodic evaluation is
needed.
* Upgraded following panel consensus.

GR
A

C
A

Medical expulsive therapy (MET)

For patients with ureteral stones that are expected to pass


spontaneously, NSAID tablets or suppositories and -blockers
may help to reduce inflammation and the risk of recurrent
pain.

Urolithiasis 315

Recommendations for MET


LE
GR
For MET, a-blockers are recommended.
A
Patients should be informed about the attendA*
ant risks of MET, including associated drug side
effects, and should be informed that it is administered as off-label**.
Patients, who elect for an attempt at spontaA
neous 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
A*
position and to assess for hydronephrosis.
*Upgraded following panel consensus.
**MET using -blockers in children and during pregnancy cannot be recommended due to the limited data in this specific
population.
Statements

LE

There is good evidence that MET accelerates sponta- 1


neous passage of ureteral stones and fragments generated with SWL limits pain.
No recommendation for the use of corticosteroids in
1b
combination with a-blockers in MET can be made, due
to limited data.
SWL = shock wave lithotripsy.

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.

316 Urolithiasis

Percutaneous irrigation chemolysis


Recommendations
GR
In percutaneous chemolysis, at least two nephrostoA
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.

Methods of percutaneous irrigation chemolysis

Percutaneous irrigation chemolysis is rarely used; it may be


an option for infection stones (using 10% Hemiacidrin at a pH
of 3,5 -4) and for uric acid and cystine stones (using THAM
[Trihydroxymethylaminomethan], 0.3 or 0.6mol/L, pH 8.5-9.0).
For uric acid stones oral chemolysis is preferred.

Oral chemolysis

Oral chemolitholysis is efficient for uric acid calculi only. The


urine pH should be adjusted to between 6.5 and 7.2.
Recommendations
The dosage of alkalising medication must be modified
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
required at regular intervals during the day. Morning
urine must be included.

GR
A

Urolithiasis 317

Careful monitoring of radiolucent stones during/after


therapy is imperative.
The physician should clearly inform the patient of the
significance of compliance.

A
A

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 (UTIs);
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.
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
Routine stenting is not recommended as part of 1b
SWL treatment of ureteral stones.
SWL = shock wave lithotripsy.

318 Urolithiasis

GR
A

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 energy setting with step-wise
power (and SWL sequence) ramping prevents renal injury.
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.
Urolithiasis 319

Recommendation
In case of infected stones or bacteriuria,
antibiotics should be given prior to SWL.
SWL = shock wave lithotripsy.

LE
4

GR
C

Medical expulsive therapy (MET) after SWL can expedite


expulsion and enhance stone-free rates.

Percutaneous nephrolitholapaxy (PNL)


Recommendations
Ultrasonic, ballistic and Ho:YAG devices are recommended 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.

GR
A*

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.
Recommendation - Preoperative 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.
320 Urolithiasis

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 retrograde transurethral manipulation, and easier anaesthesia. Disadvantages
are limited manoeuvrability of instruments and the need of
appropriate equipment.
Nephrostomy and stents after PNL
Recommendation
In uncomplicated cases, tubeless (without
nephrostomy tube) or totally tubeless (without
nephrostomy tube and without ureteral stent)
PNL procedures provide a safe alternative.

LE
1b

GR
A

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 (antiplatelet 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 321

Contraindications
Apart from general considerations, e.g. with general anaesthesia or untreated UTIs, 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 with miniaturized instruments is especially suitable
for female patients with distal ureteral stones. 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.
Stone disintegration and extraction
The aim of endourological intervention is complete stone
removal. Smash and go strategies should be limited to the
treatment of large renal stones. For flexible URS (RIRS) only
322 Urolithiasis

baskets made of Nitinol are suitable.


Recommendations
LE
Stone extraction using a basket without endo4
scopic visualisation of the stone (blind basketing) should not be performed.
Ho:YAG laser lithotripsy is the preferred method 3
for (flexible) URS.
*Upgraded following panel consensus.

GR
A*

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.
Recommendations
In uncomplicated URS, a stent need not be
inserted.
An -blocker can reduce stent-related symptoms

LE
1a

GR
A

1a

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
Urolithiasis 323

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

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).

324 Urolithiasis

Recommendations
Laparoscopic or open surgical stone removal
may be considered in rare cases where SWL,
URS, and percutaneous URS fail or are unlikely
to be successful.
When expertise is available, laparoscopic surgery 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 recommended for large impact stones or when endoscopic lithotripsy or SWL have failed.

LE
3

GR
C

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);
comorbidity;
choice of treatment.
The suspected stone composition might influence the choice
of treatment modality.
Urolithiasis 325

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 2-3 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
Urine culture or urinary microscopy is mandatory
before any treatment is planned and urinary infection
should be treated ahead of stone removal.
In patient at high risk for complications (due to antithrombotic therapy) in the presence of an asymptomatic caliceal stone, active surveillance should be
offered.
Temporary discontinuation, or bridging of antithrombotic therapy in high-risk patients, should be decided
in consultation with the internist.
Antithrombotic therapy should be stopped before
stone removal after weighting the thrombotic risk.
If stone removal is essential and antithrombotic
therapy cannot be discontinued, retrograde (flexible)
ureterorenoscopy is the preferred approach since it is
associated with less morbidity.
*Upgraded based on panel consensus.

GR
A*

B
A*

Radiolucent uric acid stones, but not sodium urate or ammonium urate stones, can be dissolved by oral chemolysis.
326 Urolithiasis

Selection of procedure for active removal of renal


stones**
Fig. 1: Treatment algorithm for renal calculi
Kidney stone

(all but lower pole stone 10-20 mm)

> 20 mm

1. PNL
2. RIRS or SWL

10-20 mm

SWL or Endourology*

< 10 mm

1. SWL or RIRS
2. PNL

Lower pole stone

> 20 mm and < 10 mm: like above

Yes

10-20 mm

SWL or Endourology

Favourable
factors for
SWL***
No

1. Endourology
2. SWL

* 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.
Urolithiasis 327

Selection of procedure for active stone removal of


ureteral stones (GR: A*)
Stone location and size
Proximal ureter < 10 mm
Proximal ureter > 10 mm

First choice
Second choice
SWL
URS
URS (retrograde or antegrade)
or SWL
Distal ureter < 10 mm
URS or SWL
Distal ureter > 10 mm
URS
SWL
*Upgraded following panel consensus.
Recommendation
Percutaneous antegrade removal of proximal 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.
SWL = shock wave lithotripsy; URS =ureterorenoscopy.

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.

328 Urolithiasis

LE
1b

GR
A

Residual stones
Recommendations
LE
GR
Identification of biochemical risk factors and
1b
A
appropriate stone prevention is particularly
indicated in patients with residual fragments or
stones.
Patients with residual fragments or stones
4
C
should be followed up regularly to monitor disease course.
After SWL and URS, MET is recommended using 1a
A
an a-blocker to improve fragment clearance.
For well-disintegrated stone material in the
1a
B
lower calix, an inversion therapy with simultaneous mechanical percussion manoeuvre under
enforced diuresis may facilitate stone clearance.
SWL = shock wave lithotripsy; URS = ureterorenoscopy; MET =
medical expulsion therapy.
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
US is the method of choice for practical and
safe evaluation of pregnant women.
Conservative management should be the firstline treatment for all non-complicated cases
of urolithiasis in pregnancy (except those that
have clinical indications for intervention).

LE
1a

GR
A
A

Urolithiasis 329

If intervention becomes necessary, placement


3
of an internal stent, percutaneous nephrostomy,
or ureteroscopy are treatment options.
URS is a reasonable alternative to avoid long2a
term stenting/drainage.
Regular follow-up until final stone removal is
necessary due to higher encrustation tendency
of stents during pregnancy.
URS = ureterorenoscopy; US = ultrasound.
Pregnancy remains an absolute contraindication for SWL.

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.
Recommendations
GR
Ultrasound evaluation is the first choice for imaging in A*
children and should include the kidney, filled bladder
and adjoining portions of the ureter.
If US does not provide the required information, KUB
B
radiography (or NCCT) should be performed.
In all paediatric patients all efforts should be made to A
collect stone material for analysis, followed by
complete metabolic evaluation.
*Upgraded from B following panel consensus.
KUB = kidney ureter bladder; NCCT = non-contrast enhanced
computed tomography; US = ultrasound.

330 Urolithiasis

Table 5: Stones in exceptional situations


Caliceal diverticulum
stones

Horseshoe kidneys

Stones in pelvic kidneys

Stones in transplanted
kidneys
Stones formed in urinary
division

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 well-disintegrated stone material remains in
the original position.
Can be treated in line with
the stone treatment options
described above.
Passage of fragments after SWL
might be poor.
SWL, RIRS or laparoscopic surgery
For obese patients, the options
are SWL, PNL, RIRS or open
surgery
PNL, (flexible) URS, SWL.
Metabolic evaluation based on
stone analysis
Individual management
necessary.
For smaller stones SWL is
effective.
PNL and antegrade flexible URS
frequently used .

Urolithiasis 331

Stones formed in a continent reservoir

Present a varied and often difficult problem.


Each stone problem must be
considered and treated individually.
Stones in patients with
All methods apply based on indineurogenic bladder disvidual situation.
order
Careful patient follow up and
preventive strategies are important.
In myelomeningocele-patients,
latex allergy is common, appropriate measures needed.
Patients with obstrucPNL followed by percutaneous
tion of the ureteropelvic
endopyelotomy or open/laparojunction which needs cor- scopic surgery, or URS together
rection
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.

332 Urolithiasis

Metabolic evaluation and recurrence prevention

Stone prevention is based on a reliable stone analysis and


basic analysis as mentioned above. Every patient should be
assigned to the low- or high risk group for stone formation. For
both groups general preventive measures apply:
Fluid intake (drinking
advice)

Fluid amount: 2.5-3.0 L/day


Circadian drinking
Neutral pH beverages
Diuresis: 2.0-2.5 L/day
Specific weight of urine: < 1010
Nutritional advice for Balanced diet*
a balanced diet
Rich in vegetable and fibre
Normal calcium content: 1-1.2 g/day
Limited NaCl content: 4-5 g/day
Limited animal protein content: 0.81.0 g/kg/day
Lifestyle advice to
BMI: 18-25 kg/m2 (adults)
Stress limitation measures
normalise general
Adequate physical activity
risk factors
Balancing of excessive fluid loss
For patients assigned to the high risk group of stone formers
specific laboratory analysis of blood and urine including two
consecutive 24-hour urine samples are necessary. For the
specific metabolic work-up, the patient should stay on a selfdetermined diet under normal daily conditions and should ideally be stone free for at least 20 days, better 3 months. These
findings are the basis for further recommendations:

Urolithiasis 333

Recommendations for a specific diet


Hyperoxaluria
Oxalate restriction
High sodium excretion Restricted intake of
salt
Small urine volume
Increased fluid intake
Urea level indicating a Avoid excessive intake
high intake of animal
of animal protein
protein

LE
2b
1b

GR
B
A

1b
1b

A
A

Recommendations for specific pharmacological treatment


Urinary risk factor
Suggested treatment LE
GR
Hypercalciuria
Thiazide + potassium
1a
A
citrate
Hyperoxaluria
Oxalate restriction
2b
A
Enteric hyperoxaluria
Potassium citrate
3-4 C
Calcium supplement
2
B
Oxalate absorption
3
B
Hypocitraturia
Potassium citrate
1b
A
Sodium bicarbonate
1b
A
when intolerance to
potassium citrate
Hyperuricosuria
Allopurinol
1b
A

Calcium oxalate stones

(Hyperparathyreoidism excluded by blood examination)

334 Urolithiasis

Alcaline Citrate
9-12 g/d
or
Sodium
Bicarbonate
1.5 g tid2,4

5-8 mmol/d2

> 5 mmol/d

Calcium > 500


mg/d1
200-400 mg/d

Alcaline
Citrate
9-12 g/d

Hydrochlorothiazide
Initially 25 mg/d
Up to 50 mg/d

Pyridoxine
Initial 5 mg/kg/d
Up to 20 mg/kg/d

> 1 mmol/d

Hyperoxaluria

< 2.5 mmol/d

Hypercitraturia

> 8 mmol/d

Hypercalcuria

24 h urine collection

Basic evaluation

Calcium oxalate stone

Alkaline Citrate
9-12 g/d
or
Sodium
Bicarbonate
1.5 g tid2
PLUS
Allopurinol
100 mg/d

> 4 mmol/d

Alkaline Citrate
9-12 g/d
PLUS
Allopurinol
100-300 mg/d4

Magnesium
200-400 mg/d3

< 3 mmol/d

Hypomagnesuria

Hyperuricosuria and
Hyperuricemia > 380 mol

Hyperuricosuria

Fig. 2: Diagnostic and therapeutic algorithm for calcium


oxalate stones

Urolithiasis 335

336 Urolithiasis

Hydrochlorothiazide
initially 25 mg/d
up to 50 mg/d

Hypercalciuria
> 8 mmol/d

Exclude UTI

Adjust urinary pH
between 5.8 and 6.2 with
L-methionine
200-500 mg 3 times daily

Exclude RTA

Elevated calcium
exclude HPT

Exclude RTA

Hydrochlorothiazide
initially 25 mg/d
up to 50 mg/d

Hypercalciuria
> 8 mmol/d

Exclude HPT

Basic evaluation

Basic evaluation

Urinary pH > 5.8

Brushite stones

Carbonate apatite
stones

Calcium phosphate
stones

Calcium phosphate stones

Fig. 3: Diagnostic and therapeutic algorithm for calcium


phosphate stones

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.

Uric acid and ammonium urate stones


Fig 4: Diagnostic and therapeutic algorithm for uric acid and
ammonium urate stones.
Urate containing stones

Urid acid stone

Ammonium urate stone

Basic evaluation

Basic evaluation

Uric acid arrest


Urine pH < 6

Alcaline citrate
9-12 g/d2
Or
Sodium
bicarbonate
1.5 g tid

> 4.0 mmol/d

Allopurinol
100 mg/d

Dose depends on
targeted urine pH

Prevention
urine pH 6.2-6.8

Urine
pH > 6.5

Hyperuricosuria

> 4.0 mmol/d


and
Hyperuricemia
> 380 mol

Allopurinol
100-300 mg/d

UTI

Antibiotics

L-methionine
200-500 mg tid
Target urine-pH
5.8-6.2
Correction of
factors
predisposing
amm.urate stone
formation

Chemolytholisis
urine pH 6.5-7.2

Urolithiasis 337

Fig 5: Metabolic management of cystine stones.

Cystine stones

Basic evaluation

Appropriate hydration
with > 3.5 L/d in adults and
1.5 L/m2 body surface in
children
AND
Adjust urine pH
between 7.5. and 8.5
with
alkaline citrates or
sodium bicarbonate

Cystine excretion
< 3 mmol/d

Cystine excretion
> 3 mmol/d

possible add. treatment


with Tiopronin
(depending on recurrence)

Additional treatment with


Tiopronin 250 mg/d up to
2000 mg/d max. dos

338 Urolithiasis

Struvite and infection stones


Recommendations Therapeutic measure
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
3,4

GR
A*

3
3
3

B
B
B

1b

LE
3

GR
B

Cystine stones
Therapeutic measures
Urine dilution
High fluid intake recommended so that 24-h urine
volume exceeds 3 L.
Intake should be 150 mL/h.
Alkalinisation
For cystine excretion < 3 mmol/day: potassium
citrate 310 mmol 2 or 3 times daily, to achieve
pH > 7.5.
Complex formation with cystine
For patients with cystine excretion > 3 mmol/day,
or when other measures are insufficient:
tiopronin, 2502000 mg/day.
Captopril, 75150 mg/day, remains a second-line
option if tiopronin is not feasible or unsuccessful.

Urolithiasis 339

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.

Drug stones

Drug stones are induced by pharmacological treatment. Two


types exist:
stones formed by crystallised compounds of the drug;
stones formed due to unfavourable changes in urine composition under drug therapy.
Treatment includes general preventive measures and the
avoidance of the respective drugs
Investigating a patient with stones of unknown composition
Investigation
Medical history

Diagnostic imaging

Blood analysis

340 Urolithiasis

Rationale for investigation


Stone history (former stone events,
family history)
Dietary habits
Medication chart
Ultrasound in case of a suspected
stone
Unenhanced helical CT
(Determination of the Houndsfield
unit provides information about the
possible stone composition)
Creatinine
Calcium (ionized calcium or total
calcium + albumin)
Uric acid

Urinalysis

Urine pH profile (measurement


after each voiding, minimum 4
daily)
Dipstick test: leucocytes, erythrocytes, nitrite, protein, urine pH,
specific weight
Urine culture
Microscopy of urinary sediment
(morning urine)
Cyanide nitroprusside test (cystine
exclusion)

Further examinations depend on the results of the investigations listed above.

This short booklet text is based on the more comprehensive EAU


guidelines (ISBN 978-90-79754-65-6) available to all members of the
European Association of Urology at their website,
http://www.uroweb.org.
Urolithiasis 341

GUIDELINES ON
RENAL TRANSPLANTATION
(Text update March 2009)

G. Karam (chair), 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
Deceased donors
In all countries without presumed consent law,
increase efforts to recruit donors through an opting-in
register or by carrying donor cards.
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.
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.

342 Renal Transplantation

GR
C

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 willing to donate.
Paired kidney exchange, if permitted by national law.

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 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,
Renal Transplantation 343

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.
Recommendations for brain dead donors
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
during life.
A donor organ affected by a potentially transmissible
pathology (infections, neoplasias) must be carefully
evaluated considering the risk/benefits for the
recipient.
344 Renal Transplantation

GR

C
B

A good-quality organ must be guaranteed to the recipi- C


ent 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
Living-donor transplantation is associated with higher
success rates than deceased-donor transplantation.
The surgeon is responsible for making sure the donor
is medically and psychologically suitable, the donated
organ is healthy, and success in the recipient is likely.
Always leave the donor with the better kidney. The
transperitoneal approach carries a higher risk of
splenic and intestinal complications.
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.

GR
B
B

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.

Renal Transplantation 345

Recommendations for pre-transplant therapy


In the abnormal urogenital tract, meticulous pre-transplant 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).

346 Renal Transplantation

GR
B

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.
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.

C
B

B
C

Renal Transplantation 347

Recurrence of the original renal disease is common,


C
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
Determine ABO blood group and HLA-A, -B, and -DR
phenotypes of all candidates awaiting transplantation.
To avoid hyper-acute rejection (HAR), cross-matching
must be performed before transplantation.

GR
B
B

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.

348 Renal Transplantation

Recommendations for immunosuppressive therapy


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 side-effects,
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.
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.

GR
A
A

A
A

A
A

Renal Transplantation 349

Recommendations for other immunosuppressive therapies


mTOR inhibitors (sirolimus, everolimus)
GR
Acute rejection can be effectively prevented by inhibi- A
tors 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 inhibiA
tors with MPA and steroids is not sufficient to prevent
acute rejection compared to a standard regimen.
Prophylactic surgical measures must be used when
A
mTOR inhibitors are given in the perioperative period
because of impaired wound healing.
mTOR inhibitors are an alternative to CNIs if there are A
severe CNI-related side-effects.
Blood levels of sirolimus and everolimus must be regu- A
larly monitored.
T-cell depleting induction therapy
Potential life-threatening side-effects include a higher B
incidence of severe opportunistic infections and malignancy, particularly post-transplant lymphoproliferative
disease.
T-cell depleting therapy has not resulted in improved
B
outcomes overall.
T-cell depleting therapy should not be routinely used in B
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 CNIA
and steroid-sparing regimens.

Complications

Hyper-acute rejection (HAR) is rare and usually occurs within


350 Renal Transplantation

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 confirmed, 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.
Renal Transplantation 351

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.

This short booklet 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.
352 Renal Transplantation

GUIDELINES ON
PAEDIATRIC UROLOGY
(Limited update April 2014)

S. Tekgl (chair), H.S. Dogan, P. Hoebeke, R. Kocvara,


J.M. Nijman (vice-chair), 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 are
separated, then the space is filled with urine during voiding,
causing the foreskin to balloon outward.

Paediatric Urology 353

Treatment

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
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
Agglutination of the foreskin does not respond to steroid
treatment.
Paraphimosis
It is characterised by retracted foreskin with the constrictive
ring localised at the level of the sulcus. A dorsal incision of the
constrictive ring may be required, or circumcision is carried
out immediately or in a second session.

CRYPTORCHIDISM

Clinical management is determined by classification into palpable and non-palpable testes.

Diagnosis

Physical examination is the only method of differentiating


palpable and non-palpable testes. There is no benefit from
ultrasonography (US), computed tomography (CT), magnetic
resonance imaging (MRI) or CT angiography (CTA).

Surgical treatment

Surgery differs for palpable or non-palpable testes.


354 Paediatric Urology

Orchidopexy (inguinal approach) is used for palpable testis


(up to 92% success). Inguinal surgical exploration should be
attempted for non-palpable testes. Laparoscopy can be used
for testis removal or orchidolysis and orchiopexy.

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
likely to develop testicular malignancy, independent of treatment choice.
Recommendations for cryptorchidism
Boys with retractile testes do not need medical
or surgical treatment, but require close followup until puberty.
Surgical orchidolysis and orchidopexy should be
concluded at the age of 12 months, or 18 months
the latest.
In case of non-palpable testes and no evidence
of disorders of sex development, laparoscopy
still represents the gold standard because it
has almost 100% sensitivity and specificity in
identifying an intraabdominal testis as well as
the possibility for subsequent treatment in the
same session.
Hormonal therapy, either in an adjuvant or neoadjuvant setting, is not standard treatment.
Patients have to be evaluated on an individual
basis.
For an intra-abdominal testis in a 10-year-old
boy or older, with a normal contralateral testis,
removal is an option because of the theoretical
risk of a later malignancy.

LE
2

GR
A

1b

Paediatric Urology 355

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, US should be performed.
Contralateral disease should be excluded.

Surgical treatment

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 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.
356 Paediatric Urology

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.
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
Paediatric Urology 357

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

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.
Fig. 1 gives an algorithm for the management of hypospadias.

358 Paediatric Urology

Onlay, TIP
GAP, TIP, Mathieu,
MAGPI, advancement

Two-stage,
tube-onlay

Urethral plate
preserved
Urethral plate
cut

No chordee
Chordee

Proximal
Distal

Reconstruction required

Diagnosis at birth

Paediatric urologist

Exclude D.S.D.

No reconstruction

Fig. 1: Algorithm for the management of hypospadias

D.S.D. = disorders of sexual differentiation; GAP = glans


approximation procedure; TIP = tubularized incised plate urethroplasty; MAGPI = meatal advancement and glanuloplasty
incorporated.
Paediatric Urology 359

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
Mean SD (cm)
Newborns
3.5 0.4
0-5 months
3.9 0.8
6-12 months
4.3 0.8
1-2 y
4.7 0.8
2-3 y
5.1 0.9
3-4 y
5.5 0.9
4-5 y
5.7 0.9
5-6 y
6.0 0.9
6-7 y
6.1 0.9
7-8 y
6.2 1.0
8-9 y
6.3 1.0
9-10 y
6.3 1.0
10-11 y
6.4 1.1
Adults
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.
Testicular catch-up growth and improvement in sperm parameters after varicocelectomy has been reported in adolescents.
360 Paediatric Urology

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.

Surgical treatment

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.
Fig. 2 shows an algorithm for the diagnosis of varicocele in
children and adolescents, and Fig. 3 shows an algorithm for its
treatment.

Paediatric Urology 361

Fig. 2: Algorithm for the diagnosis of varicocele in children and


adolescents
Varicocele in children
and adolescents
Physical examination
in the upright position

Ultrasound
investigation

Grade I - Valsalva positive


Grade II - Palpable
Grade III - Visible

Venous reflux detected on


Doppler US
Size of the testes

Fig. 3: Algorithm for the treatment of varicocele in children and adolescents


Varicocele in children
and adolescents

Surgery:
Indication
Type

Conservative treatment:
Indication
Follow-up

Small testis (growth arrest)


Additional testicular
pathology
Bilateral palpable
varicocele
Pathological spermiogram
Symptomatic varicocele

Symmetrical testes
Normal spermiogram
(in older adolescents)

Microsurgical lymphaticsparing repair (microscopic


or laparoscopic)

Measurement of testicular
size (during adolescence)
Repeated sperm analysis
(after adolescence)

362 Paediatric Urology

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.
Fig. 4 presents an algorithm for the diagnosis and treatment of
monosymptomatic nocturnal enuresis.

Paediatric Urology 363

Fig. 4: Algorithm for the diagnosis and treatment of


monosymptomatic nocturnal enuresis
Nocturnal enuresis
Initial assessment

Monosymptomatic
Nocturnal enuresis

Education

Voiding diary or
direct questioning
Voiding habits
Wetting episodes
Bowel function

Urinalysis

Daytime wetting
Urge syndrome
Lower tract dysfunction
Infection
Other

Supportive therapy
Alarm or desmopressin

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, and
screening for lower urinary tract dysfunction [LUTD]), physical
examination including blood pressure measurement, urinaly364 Paediatric Urology

sis (assessing proteinuria), urine culture, and serum creatinine


in patients with bilateral renal parenchymal abnormalities.
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 VCU 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 VCU to detect reflux is
optional.
When cases identified by prenatal US become symptomatic
with UTIs, further evaluation with VCU 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. VCU is recommended if there is evidence of renal
scarring on US or a history of UTI.
In older children who are toilet-trained, there is no added
value in screening for VUR.
UTI = urinary tract infecting; VCU = 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
Paediatric Urology 365

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.
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.

366 Paediatric Urology

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.
Paediatric Urology 367

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. 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.

368 Paediatric Urology

This short booklet text is based on the more comprehensive EAU/


ESPU Paediatric Urology Guidelines (ISBN 978-90-79754-71-7),
available at their website, http://www.uroweb.org.
Paediatric Urology 369

Table 2: Management and follow-up according to


different risk groups
Risk
Groups

Presentation

High

Symptomatic male
or female patients
after toilet-training
with high-grade reflux
(grades IV/V), abnormal
kidneys and LUTD
High
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

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
abnormal kidneys
cases of breakthrough
infections or persistent
reflux

370 Paediatric Urology

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 VCU 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

Paediatric Urology 371

Moderate Symptomatic male or


female patients after
toilet-training, with
high-grade reflux and
normal kidneys with
LUTD

Initial treatment is
always for LUTD.
Intervention may be
considered in cases
of breakthrough infections or persistent
reflux

Moderate Symptomatic male or


female patients after
toilet-training with lowgrade reflux, abnormal
kidneys with or without
LUTD
Moderate All symptomatic
patients with normal
kidneys, with low-grade
reflux, with LUTD
Low
All symptomatic
patients with normal
kidneys, with low-grade
reflux, with no LUTD
Low
All asymptomatic
patients with normal
kidneys with low-grade
reflux

Choice of treatment
is controversial.
Endoscopic treatment
may be an option.
LUTD treatment should
be given if needed.
Initial treatment is
always for LUTD

No treatment or CAP

No treatment or CAP in
infants

PNH = prenatal diagnosed hydronephrosis.

372 Paediatric Urology

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 reevaluation 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 Follow-up for UTI


should be informed about risk
of infection
If no treatment is given, parents Follow-up for UTI
should be informed about risk
of infection

Paediatric Urology 373

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-by-case 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.