EUROPEAN UROLOGY 67 (2015) 142–150
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Guidelines
EAU Guidelines on Penile Cancer: 2014 Update
Oliver W. Hakenberg a,*, Eva M. Compérat b, Suks Minhas c, Andrea Necchi d, Chris Protzel a,
Nick Watkin e
a
Department of Urology, University Hospital Rostock, Rostock, Germany; b Department of Pathology, Hôpital La Pitié-Salpétrière, Université Pierre et Marie
Curie University Paris VI, Paris, France; c Department of Urology, University College Hospital, London, UK;
d
Department of Medical Oncology, Fondazione
IRCCS Istituto Nazionale dei Tumori, Milan, Italy; e Department of Urology, St George’s Hospital, London, UK
Article info
Abstract
Article history:
Accepted October 8, 2014
Context: Penile cancer has high mortality once metastatic spread has occurred. Local
treatment can be mutilating and devastating for the patient. Progress has been made in
organ-preserving local treatment, lymph node management, and multimodal treatment
of lymphatic metastases, requiring an update of the European Association of Urology
guidelines.
Objective: To provide an evidence-based update of treatment recommendations based
on the literature published since 2008.
Evidence acquisition: A PubMed search covering the period from August 2008 to
November 2013 was performed, and 352 full-text papers were reviewed. Levels of
evidence were assessed and recommendations graded. Because there is a lack of
controlled trials or large series, the levels of evidence and grades of recommendation
are low compared with those for more common diseases.
Evidence synthesis: Penile squamous cell carcinoma occurs in distinct histologic variants, some of which are related to human papilloma virus infection; others are not.
Primary local treatment should be organ preserving, if possible. There are no outcome
differences between local treatment modes in superficial and T1 disease. Management
of inguinal lymph nodes is crucial for prognosis. In impalpable nodes, invasive staging
should be done depending on the risk factors of the primary tumour. Lymph node
metastases should be treated by surgery and adjuvant chemotherapy in N2/N3 disease.
Conclusions: Organ preservation has become the standard approach to low-stage penile
cancer, whereas in lymphatic disease, it is recognised that multimodal treatment with
radical inguinal node surgery and adjuvant chemotherapy improves outcome.
Patient summary: Approximately 80% of penile cancer patients of all stages can be
cured. With increasing experience in the management of penile cancer, it is recognized
that organ-preserving 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.
# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Keywords:
Penile cancer
Squamous cell carcinoma
Lymph node
Invasive disease
Metastasis
Surgery
Laser
Chemotherapy
Reconstruction
Follow-up
Quality of life
Guidelines
European Association of Urology
* Corresponding author. University of Rostock, Department of Urology, PO Box 10 08 88, D-18055
Rostock, Germany. Tel. +49 381 494 7801; Fax: +49 381 494 7802.
E-mail address: [email protected] (O.W. Hakenberg).
1.
Introduction
Penile cancer can be cured in approximately 80% of cases
but has a poor prognosis once metastatic spread has
occurred. Local treatment can be mutilating and devastating for the psychological well-being of the patient.
Treatment requires careful diagnosis, adequate staging,
and as much organ preservation as possible.
http://dx.doi.org/10.1016/j.eururo.2014.10.017
0302-2838/# 2014 European Association of Urology. Published by Elsevier B.V. All rights reserved.
EUROPEAN UROLOGY 67 (2015) 142–150
The European Association of Urology Guidelines Group
on Penile Cancer has updated this guideline document to
assist medical professionals in the management of this
disease. The penile cancer guidelines were first published in
2001 and updated in 2004 and 2009.
2.
Evidence acquisition
A systematic PubMed search covering the period from
August 2008 to November 2013 retrieved 1602 unique
records, of which 1020 were excluded (exclusion criteria:
case reports, reviews, and non–English language literature).
A total of 582 abstracts were assessed, resulting in 352 fulltext papers for panel review. Levels of evidence (LEs) were
assessed and grades of recommendation (GRs) were
assigned [1]. For penile cancer, there is a lack of controlled
trials or large series. The LEs and GRs are low compared with
those for more common diseases.
143
[6]. There is no association between the incidence of penile
cancer and cervical cancer [7].
Phimosis is strongly associated with penile cancer
(odds ratio [OR]: 11.4), but smegma is not a carcinogen
[8]. Other epidemiologic risk factors include cigarette
smoking (4.5-fold increased risk; 95% confidence interval
[CI], 2.0–10.1) and low educational and socioeconomic
status [9]. The incidence of lichen sclerosus (balanitis
xerotica obliterans) in penile cancer is relatively high but is
not associated with adverse features.
Neonatal circumcision reduces the incidence of penile
cancer, but adult circumcision does not. The lowest
incidence is reported for Israeli Jews (0.3 per 100 000 per
year). Circumcision removes about 50% of the tissue from
which penile cancer originates. The protective effect of
neonatal circumcision (OR: 0.41) does not apply to
carcinoma in situ (CIS; OR: 1.0) and is weaker when the
analysis is restricted to men without phimosis (OR: 0.79;
95% CI, 0.29–2).
3.
Evidence synthesis
3.2.
3.1.
Epidemiology and risk factors
It is unknown how often SCC is preceded by premalignant
lesions (Table 1) [10,11]. Distinct histologic variants with
different growth patterns, clinical aggressiveness, and HPV
association have been identified (Tables 1 and 2). Numerous
mixed forms exist.
The TNM classification stratifies T1 into two risk groups
depending on lymphovascular invasion and grade (Table 3).
Lymph node metastasis with extracapsular extension is
staged as pN3 [14]. Retroperitoneal lymph node metastases
are classified as extraregional distant metastases.
Invasion of the corpus spongiosum and the corpora
cavernosa are both staged as pT2, although local recurrence
rate (35% vs 17%) and mortality (30% vs 21%) differ (LE: 2b).
Long-term survival in T2 and T3 as well as N1 and N2
disease does not differ significantly (LE: 2a). In addition, pT3
tumours invading the distal urethra are not associated with
worse outcome.
The majority of penile carcinoma is squamous cell
carcinoma (SCC), but other types occur. It usually originates
from the inner prepuce or the glans. There are several
histologic subtypes. It shares similar pathology with SCC of
other origins.
In Europe and North America, penile cancer has low
incidence (<1 per 100 000) that increases with age, with a
peak during the sixth decade, but it also occurs in younger
men [2,3]. In South America, Southeast Asia, and parts of
Africa, the incidence is much higher, accounting for up to
1–2% of malignancies in men [2].
In the United States, where the overall age-adjusted
incidence rate decreased between 1973 and 2002 from
0.84 to 0.58 per 100 000, it varies by race and ethnicity,
with the highest incidence occurring among Hispanics.
In Europe, incidence has been stable, but increased
incidence has been reported in Denmark and the United
Kingdom [4].
Penile cancer is common in regions with high prevalence
of human papilloma virus (HPV), and this may account for
the geographic variation in incidence. One-third of cases
can be attributed to HPV-related carcinogenesis. No data
link penile cancer to HIV or AIDS.
HPV DNA has been identified in 30–40% of penile cancer
tissue (LE: 2a) with variation among the histologic
subtypes: High HPV prevalence is found in basaloid SCC
(76%), mixed warty-basaloid SCC (82%), and warty penile
SCC (39%). Verrucous and papillary penile SCCs are HPV
negative. HPV is probably a cofactor in the carcinogenesis of
only some variants of penile SCC [5]. The most frequently
found HPV types in penile SCC are HPV 16 (72%), HPV 6 (9%),
and HPV 18 (6%). The risk of penile cancer is increased with
condylomata acuminata (LE: 2b). Better disease-specific
survival has been reported for HPV-positive versus HPVnegative cases (93% vs 78%), but data are conflicting
3.2.1.
Pathology and classification
Biopsy and histology
The diagnosis of penile cancer is often without doubt, but in
doubtful cases and if nonablative treatment is planned,
histologic verification is mandatory. Small lesions should be
totally included, and bigger lesions should have at least
Table 1 – Premalignant penile lesions (precursor lesions)
Lesions sporadically associated with SCC of the penis:
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-Löwenstein)
Erythroplasia of Queyrat
Bowen’s disease
Paget’s disease (intradermal ADK)
SCC = squamous cell carcinoma.
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EUROPEAN UROLOGY 67 (2015) 142–150
Table 2 – Histologic subtypes of penile carcinomas, their frequency, and outcome
Subtype
Frequency, % of cases
Prognosis
Common SCC
Basaloid carcinoma
Warty carcinoma
Verrucous carcinoma
Papillary carcinoma
Sarcomatoid carcinoma
Mixed carcinoma
Pseudohyperplastic carcinoma
Carcinoma cuniculatum
Pseudoglandular carcinoma
Warty-basaloid carcinoma
48-65
4–10
7–10
3–8
5–15
1–3
9–10
<1
<1
<1
9–14
Adenosquamous carcinoma
<1
Mucoepidermoid carcinoma
Clear cell variant of penile carcinoma
<1
1–2
Depends on location, stage, and grade
Poor prognosis, frequently early inguinal nodal metastasis
Good prognosis, metastasis rare
Good prognosis, no metastasis
Good prognosis, metastasis rare
Very poor prognosis, early vascular metastasis
Heterogeneous group
Foreskin, related to lichen sclerosus, good prognosis, metastasis not reported
Variant of verrucous carcinoma, good prognosis, metastasis not reported
High-grade carcinoma, early metastasis, poor prognosis
Poor prognosis, high metastatic potential [12] (higher than in warty, lower than
in basaloid SCC)
Central and perimeatal 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 [13]
HPV = human papilloma virus; SCC = squamous cell carcinoma.
three or four blocks. Lymph nodes and surgical margins
have to be totally included. The pathology report has to
include the histologic variant, grade, perineural and
vascular invasion, and surgical margins.
With an average biopsy size of 0.1 cm, there is difficulty
in evaluating the depth of invasion in 91% [11]. Although
a punch biopsy may be sufficient, an excisional biopsy
is preferable. The width of negative surgical margins
should follow a grade-based risk-adapted strategy, and a
5-mm tumour-free tissue margin is considered sufficient
[15].
3.2.2.
Prognostic factors
Perineural and lymphatic invasion and grade are prognostic
predictors. Grading has been shown to be highly observer
dependent [16]. Some types of penile SCC have good
prognosis: verrucous, papillary, warty, pseudohyperplastic,
and carcinoma cuniculatum. These types are locally
destructive but metastasize rarely. High-risk variants are
the basaloid, sarcomatoid, adenosquamous, and poorly
differentiated types, which metastasize early. An intermediate-risk group comprises the usual SCCs, mixed forms,
and the pleomorphic form of warty carcinomas. Carcinomas
limited to the foreskin have better prognosis.
3.2.3.
Molecular biology
Sparse data link chromosomal abnormalities in penile SCC
to biological behaviour. DNA copy number alterations are
comparable to those found in SCC of other origins. Lower
copy and alteration numbers have been linked to poor
survival. Alterations in the locus 8q24 seem to play a major
role [17].
Epigenetic alterations of CpG island methylation in
CDKN2A have been found. This encodes for two tumoursuppressor proteins (p16INK4A and p14ARF). Moreover, 62%
of invasive penile cancers display allelic loss of p16, and this
has been linked to lymph node metastasis and prognosis
[18]. Allelic loss of the p53 gene occurs in 42% [19] and has
been linked to poor prognosis [20].
3.3.
Diagnosis and staging
Physical examination should include palpation of the penis
and the inguinal regions. Ultrasound or magnetic resonance
(MR) with an artificial erection can give information about
infiltration of the corpora [21,22]. Penile carcinoma is often
clinically obvious but can be hidden under a phimosis.
In clinically normal inguinal nodes, the likelihood of the
presence of micrometastatic disease is approximately 25%.
Current imaging techniques are not reliable in detecting
these micrometastases. Ultrasound (7.5 MHz), computed
tomography (CT), MR imaging (MRI), or F 18 fluorodeoxyglucose positron emission tomography/CT (18F-FDG-PET/CT)
scans cannot detect micrometastases reliably [23–25]. An
exception can be made for obese patients in whom palpation
is unreliable.
The diagnostic management with normal inguinal nodes
should be guided by pathologic risk factors including
lymphovascular invasion, stage, and grade [26,27]. Nomograms are unreliable. Invasive lymph node staging is required
in patients at intermediate or high risk of lymphatic spread.
With enlarged inguinal lymph nodes, the presence of
lymph node metastases is very likely. Physical examination
should note the number of nodes and whether these are
fixed or mobile. Staging for pelvic nodes and systemic
disease should be done with abdominopelvic CT and chest
x-ray or CT [28–30] (LE: 2b). 18F-FDG-PET/CT can confirm
metastases in palpable inguinal lymph nodes [25].
There is no tumour marker for penile cancer. The SCC
antigen is increased in <25% and does not predict metastatic
disease but possibly predicts disease-free survival in lymph
node–positive patients [31].
3.4.
Treatment of the primary tumour
The aims of treatment are radical tumour removal with as
much organ preservation as possible. Local recurrence in
itself has little influence on long-term survival, so organpreservation strategies are justified [32].
EUROPEAN UROLOGY 67 (2015) 142–150
Table 3 – 2009 TNM clinical and pathological classification of
penile cancer [14]
Clinical classification
T: Primary tumour
TX
Primary tumour cannot be assessed
T0
No evidence of primary tumour
Tis
Carcinoma in situ
Ta
Non-invasive carcinoma
T1
Tumour invades subepithelial connective tissue
T1a Tumour invades subepithelial connective tissue without
lymphovascular invasion and is not poorly differentiated
or undifferentiated (T1G1-2)
T1b Tumour invades subepithelial connective tissue with
lymphovascular invasion or is poorly differentiated
or undifferentiated (T1G3-4)
T2
Tumour invades corpus spongiosum and/or corpora cavernosa
T3
Tumour invades urethra
T4
Tumour invades other adjacent structures
N: Regional lymph nodes
NX
Regional lymph nodes cannot be assessed
N0
No palpable or visibly enlarged inguinal lymph node
N1
Palpable mobile unilateral inguinal lymph node
N2
Palpable mobile multiple unilateral or bilateral inguinal
lymph nodes
N3
Fixed inguinal nodal mass or pelvic lymphadenopathy,
unilateral or bilateral
M: Distant metastasis
M0
No distant metastasis
M1
Distant metastasis
Pathologic classification
The pT categories correspond to the clinical T categories. The pN
categories are based upon biopsy or surgical excision.
pN: Regional lymph nodes
pNX
Regional lymph nodes cannot be assessed
pN0
No regional lymph node metastasis
pN1
Intranodal metastasis in a single inguinal lymph node
pN2
Metastasis in multiple or bilateral inguinal lymph nodes
pN3
Metastasis in pelvic lymph node(s), unilateral or bilateral or
extranodal extension of any regional lymph node metastasis
pM: Distant metastasis
pM0
No distant metastasis
pM1
Distant metastasis
G: Histopathologic grading
GX
Grade of differentiation cannot be assessed
G1
Well differentiated
G2
Moderately differentiated
G3-4
Poorly differentiated/undifferentiated
There are no controlled trials comparing different
treatment modalities. The existing evidence must generally
be regarded as low. Penile preservation appears to be
superior in functional and cosmetic outcomes. Histologic
diagnosis with local staging must be obtained when
nonsurgical treatment modalities are considered (GR: C).
Treatment of the primary tumour and of the regional
nodes can be done as staged procedures.
3.4.1.
Treatment of superficial noninvasive disease
For CIS, topical chemotherapy with imiquimod or 5fluorouracil (5-FU) is a first-line treatment with low toxicity
and a complete response rate of up to 57% [33]. It requires
close follow-up and should not be repeated in case of
failure. Other options are laser ablation or total or partial
glans resurfacing (complete removal of the glandular
epithelium and split skin grafting). Histologic verification
is required because up to 20% of cases have been reported to
have invasive disease [34].
145
For small invasive lesions (Ta/T1a), a penis-preserving
strategy is recommended (GR: C). Circumcision should be
performed and may be sufficient for tumours confined to
the prepuce.
Intraoperative assessment of surgical margins by frozen
section is recommended (GR: C) [35]. Total removal of the
glans (glansectomy) and prepuce has the lowest local
recurrence rates among the treatment modalities for small
penile lesions (2%) [35], and a negative surgical margin of
5 mm is adequate [35,36].
Treatment choice should depend on tumour size,
histology, stage and grade, localization relative to the
meatus, and patient preference. Laser ablation can be done
with a neodymium:yttrium-aluminium-garnet (Nd:YAG)
laser or a carbon dioxide (CO2) laser [37], and visualisation
may be enhanced by photodynamic diagnosis. Local
recurrence rates for laser treatment of CIS/T1 are 14–23%
with a CO2 laser and 10–48% with an Nd:YAG laser
[37]. Other studies using a variety of laser treatments have
reported similar results [38]. Local recurrence rates of 0–6%
for total or partial glans resurfacing [34,39,40] and 7–8% for
glansectomy [35,41] have been reported.
Evidence is insufficient to suggest a difference regarding
outcomes of different penis-sparing strategies that appear
to have good oncologic results. Organ-sparing treatments
including reconstructive surgery improve quality of life, but
the risk of local recurrence is higher than with partial
penectomy (5–12% vs 5%). Local recurrence after organsparing surgery has only a small effect on long-term
survival.
3.4.2.
Radiation therapy for T1/T2 disease
Radiotherapy gives good results in T1–2 lesions <4 cm in
diameter [42,43] (LE: 2b), given as external radiotherapy
(60 Gy) combined with a brachytherapy boost or as
brachytherapy only [42,43]. Brachytherapy achieves local
control rates of 70–90% [42–44]. Local recurrence rates are
higher than after partial penectomy, but salvage surgery can
achieve local control [45]. Complications are not uncommon, with urethral stenosis in 20–35% and glans necrosis in
10–20%; with brachytherapy, metal stenosis occurs in >40%
(LE: 3).
3.4.3.
Management of regional lymph nodes
Management of regional lymph nodes is decisive for longterm patient survival. Cure can be achieved in regional
lymph node disease. Radical inguinal lymphadenectomy
(ILND) is the treatment of choice (GR: B), but multimodal
treatment with chemotherapy is often indicated.
Lymphatic spread can be uni- or bilateral from any
primary penile cancer [46]. The superficial and deep
inguinal lymph nodes are the first nodal group reached,
with the nodes of the medial superior and central inguinal
zones most commonly affected [47]. The second regional
groups are the ipsilateral pelvic lymph nodes. Pelvic
nodal disease does not seem to occur without ipsilateral
inguinal disease, and crossover metastatic spread has never
been reported. Para-aortic and paracaval nodes are classified as systemic metastatic disease.
146
EUROPEAN UROLOGY 67 (2015) 142–150
Early ILND in clinically node-negative patients gives
superior survival compared with therapeutic ILND when
regional nodal recurrence has occurred (survival >90% vs
<40%) [32,36,48]. Comparing ILND, inguinal radiotherapy,
and surveillance in node-negative patients, the best overall
survival was reported for surgery (74% vs 66% and 63%,
respectively) [49].
Surveillance for clinically normal nodes carries the risk of
nodal recurrence because 25% of patients will harbour
micrometastatic disease [48,50]. Management with normal
nodes depends on stage, grade, and the presence or absence
of lymphovascular invasion [26]. Moreover, pTa/pTis and
low-grade tumours are at low risk of lymphatic metastasis,
as is well-differentiated pT1, which otherwise is intermediate risk; pT2 or higher plus all G3 tumours are high risk
[51]. Surveillance should be offered only to patients with
normal inguinal nodes and low-risk tumours. Fine needle
aspiration cytology does not reliably exclude micrometastatic disease.
For patients with intermediate- and high-risk tumours
and impalpable nodes, two invasive diagnostic procedures
are available: modified ILND and dynamic sentinel-node
biopsy (DSNB). Modified ILND defines a limited template
whereby the superficial inguinal lymph nodes from at least
the central and both superior Daseler’s zones are removed
[46] (LE: 3). DSNB is based on the assumption that
lymphatic drainage from penile cancer goes to only one
inguinal lymph node on each side, which may be located in
different positions based on individual anatomy. Technetium Tc 99 nanocolloid is injected around the cancer site,
and a gamma-ray probe detects the sentinel node, which is
possible in 97% of cases [52] (GR: B). Some groups have
reported high sensitivity of 90–94% [52,53] (LE: 2b). In a
pooled meta-analysis of 18 studies, sensitivity was 88% and
was 90% with the additional use of patent blue.
Both methods can miss micrometastatic disease
[32]. The false-negative rate of DSNB can be as high as
12–15% even in experienced centres [48,50], whereas that
of modified ILND is not known. If lymph node metastasis is
found with either method, an ipsilateral radical ILND is
indicated.
With palpable inguinal lymph nodes (cN1/cN2), the
likelihood of metastasis is high. Prophylactic antibiotic
treatment is not indicated. Ultrasound-guided fine needle
aspiration cytology can be an option. Additional staging for
pelvic nodes is useful. 18F-FDG-PET/CT can identify metastases in lymph node–positive patients [54]. Dynamic
sentinel node biopsy is unreliable in patients with enlarged
nodes and should not be used (LE: 3).
In node-positive patients, radical ILND is indicated. Radical
ILND has significant morbidity related to lymph drainage and
wound healing. Although morbidity can be as high as 50%,
with increased body mass index being a significant risk factor,
recent studies reported a complication rate of about 25%
[55,56] (LE: 2b). Radical ILND can be curative and may be
underused for fear of associated morbidity. Lymph node
density is a prognostic factor for complications [57].
Surgical technique should be meticulous regarding
tissue handling and closure of lymph vessels, which cannot
be closed by electrocautery, so ligation or clips should be
used [58]. Additional measures such as inguinal pressure
dressings or vacuum suction [59] and prophylactic antibiotics can reduce postoperative morbidity. The most
commonly reported complications are wound infections
(1.2–1.4%), skin necrosis (0.6–4.7%), lymphedema (5–13.9%),
and lymphocele formation (2.1–4%) [55,56].
The feasibility of performing laparoscopic and robotassisted ILND has been reported. Whether this provides any
advantage is unclear [60,61].
If two or more positive lymph nodes are found or if one
node with extracapsular extension (pN3) is found, ipsilateral pelvic lymphadenectomy is indicated. Positive pelvic
nodes were found in 23% in cases with more than two
positive inguinal nodes and in 56% if three positive inguinal
nodes were found or if extracapsular involvement was
found [36,57] (LE: 2b).
With positive pelvic nodes, the prognosis is worse
compared with pure inguinal nodal metastasis (5-yr cancerspecific survival of 71.0% vs 33.2%). Pelvic lymphadenectomy may be performed simultaneously or as a secondary
procedure. It is important to avoid unnecessary delay if
surgery is indicated [62].
In patients with pN2/pN3 disease, adjuvant chemotherapy is recommended (GR: C). This is based on one
retrospective study in which survival with adjuvant
chemotherapy was much better than without in a historical
control group (84% vs 39%).
In bulky and fixed inguinal lymph nodes, metastatic
disease is beyond doubt, and histologic verification by
biopsy is not generally required. With reasonable doubt, an
excisional or core needle biopsy may be done. These
patients have poor prognosis, and primary surgery is not
generally recommended because it is unlikely to be curative
(GR: B) Neoadjuvant chemotherapy followed by radical
ILND in responders is recommended [63,64]. For such
patients, long-term survival of 37% has been reported [63].
3.4.4.
Management of lymph node recurrence
Patients with regional recurrence after surveillance should be
treated as patients with primary cN1/cN2 disease. Patients
with regional recurrence following negative invasive staging
have disordered lymphatic anatomy and are at high risk of
irregular metastatic progression. Patients with inguinal
nodal recurrence after therapeutic radical ILND have poor
prognosis, with 5-yr survival of 16% [65]. There is no evidence
for the best management, but neoadjuvant chemotherapy
and radical lymph node surgery are advised.
3.4.4.1. The role of radiotherapy for the treatment of lymph node
disease. Due to a lack of positive evidence, radiotherapy for
inguinal nodal disease in penile cancer is not generally
recommended. Neither neoadjuvant nor adjuvant radiotherapy has been reported to improve oncologic outcome in
node-positive patients [66]. A prospective trial comparing
inguinal radiotherapy with radical ILND reported superior
results for surgery [49], and in one retrospective series,
adjuvant chemotherapy was superior to adjuvant radiotherapy in node-positive patients. A Surveillance
EUROPEAN UROLOGY 67 (2015) 142–150
Epidemiology and End Results database analysis of
2458 patients treated by either surgery alone or surgery
combined with radiotherapy found no positive effect of
adjuvant radiotherapy on cancer-specific survival [67]. Adjuvant inguinal radiotherapy may be a palliative option for
surgically unresectable disease.
3.4.4.2. Chemotherapy. In nodal disease, adjuvant chemotherapy improves survival [63]. A triple-drug regimen containing cisplatin is recommended when the goal is curative
treatment (LE: 2b). Vincristine, bleomycin, and methotrexate (VBM regimen) is also effective [63], and similar results
were achieved with cisplatin and 5-FU, with lower toxicity
(LE: 2b). A taxane-based regimen (cisplatin and 5-FU plus
paclitaxel or docetaxel) resulted in 52% disease-free
survival, and similar results were obtained with a paclitaxel–
cisplatin regimen [68]. No data support adjuvant chemotherapy in stage pN1; this approach should be restricted to clinical
trials.
For neoadjuvant treatment in bulky inguinal lymph
nodes (cN3), a triple combination including cisplatin and a
taxane is advisable (LE: 2a; GR: B). Median overall survival
of 17 mo has been reported [69] (LE: 2a).
In advanced cases, the presence of visceral metastases
and an Eastern Cooperative Oncology Group performance
status 1 are independent prognostic factors. Cisplatinbased chemotherapy gives better outcomes than non–
cisplatin-based regimens [70] (LE: 3), and taxanes seem to
have enhanced the efficacy of the regimens used
[32,64,68,69,71–74]. There is only one report of secondline therapy with paclitaxel monotherapy, showing a 30%
response rate but no survival [74] (LE: 2a; GR: B).
Because epidermal growth factor receptor (EGFR) is
almost invariably expressed in penile SCC [75,76], antiEGFR targeted monotherapy with panitumumab and
cetuximab has been used with modest success [77,78]
(LE: 4). The same applies to tyrosine kinase inhibitors [76].
3.5.
Follow-up
Recurrence mostly occurs within 2 yr of primary treatment.
Moreover, 74% of all recurrences occur within 2 yr, as do
66% of local recurrences, 86% of regional recurrences, and
100% of distant recurrences. Overall, 92.2% of all recurrences
occurred within the first 5 yr, and all seen after that were
local recurrences or new primary lesions [32].
Intensive follow-up during the first 2 yr is necessary,
with less intensive follow-up thereafter for a minimum of
5 yr. Follow-up should continue thereafter but may be
omitted in patients who reliably carry out self-examination
[32].
In node-negative patients, follow-up includes physical
examination of the penis and the groins; additional imaging
is of no proven value. After laser ablation or topical
chemotherapy, histology may need to be obtained to
ascertain a disease-free status. After curative treatment
for inguinal nodal metastases, imaging by CT or MRI should
be done at 3-mo intervals during the first 2 yr [79].
3.5.1.
147
Recurrence
Local recurrence is more likely with all types of local organpreserving treatment [32] and occurs during the first 2 yr in
up to 27%. After partial penectomy, the risk of local
recurrence is 4–5% [32]. Patient education for selfexamination is important.
The highest rate of regional recurrence (9%) occurs in
patients under a surveillance strategy, the lowest after
invasive nodal staging with negative nodes (2.3%). Ultrasound and fine needle aspiration cytology in doubtful cases
may improve early detection of regional recurrence
[23,80]. After ILND with positive nodes without adjuvant
treatment, the risk of regional recurrence is 19% [32].
3.6.
Quality of life
In patients with long-term survival, sexual dysfunction,
voiding problems, and cosmetic appearance are treatment
consequences. In studies after laser treatment, one reported
a marked decrease in some sexual practices but general
satisfaction with life overall; another noted no patientreported problems with erectile capability or sexual
function [38]. After glansectomy, 79% of patients did not
report any difference in spontaneous erection, rigidity, or
penetrative capacity [41]. After partial penectomy, 55.6%
reported erectile function that allowed sexual intercourse
but markedly reduced satisfaction [81,82]. After full- or
near-total penile amputation, total phallic reconstruction
can be an option in selected cases.
4.
Conclusions
Approximately 80% of penile cancer patients of all stages
can be cured. Partial penectomy has negative consequences
for self-esteem and sexual function. With increasing
experience in the management of penile cancer, it is
recognized that organ-preserving 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.
Author contributions: Oliver W. Hakenberg had full access to all the data
in the study and takes responsibility for the integrity of the data and the
accuracy of the data analysis.
Study concept and design: Hakenberg, Compérat, Minhas, Necchi, Protzel,
Watkin.
Acquisition of data: Hakenberg, Compérat, Minhas, Necchi, Protzel,
Watkin.
Analysis and interpretation of data: Hakenberg, Compérat, Minhas, Necchi,
Protzel, Watkin.
Drafting of the manuscript: Hakenberg.
Critical revision of the manuscript for important intellectual content:
Hakenberg, Compérat, Minhas, Necchi, Protzel, Watkin.
Statistical analysis: None.
Obtaining funding: None.
Administrative, technical, or material support: None.
Supervision: Hakenberg.
Other (specify): None.
148
EUROPEAN UROLOGY 67 (2015) 142–150
Financial disclosures: Oliver W. Hakenberg certifies that all conflicts of
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interest, including specific financial interests and relationships and
penile squamous cell carcinoma. Genes Chromosomes Cancer
affiliations relevant to the subject matter or materials discussed in the
2001;31:48–53.
manuscript (eg, employment/affiliation, grants or funding, consultan-
[18] Kayes OJ, Loddo M, Patel N, et al. DNA replication licensing factors
cies, honoraria, stock ownership or options, expert testimony, royalties,
and aneuploidy are linked to tumor cell cycle state and clinical
or patents filed, received, or pending), are the following: None.
outcome in penile carcinoma. Clin Cancer Res 2009;15:7335–44.
[19] Poetsch M, Hemmerich M, Kakies C, et al. Alterations in the tumor
Funding/Support and role of the sponsor: None.
suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas. Virchows Arch 2011;458:221–9.
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