ARTICLE IN PRESS

Urologic Oncology: Seminars and Original Investigations 000 (2021) 1−7

Clinical-Testis cancer
Penile-sparing surgery for patients with superficial or initially invasive
squamous cell carcinoma of the penis: long-term oncological outcomes
Stefano Luzzago, M.D.a,b,*, Alessandro Serino, M.D.a,b, Gaetano Aurilio, M.D., Ph.Dc,
Francesco A. Mistretta, M.D.a, Mattia Luca Piccinelli, M.D.a,b, Vito Lorusso, M.D.a,b,
Michele Morelli, M.D.a,b, Roberto Bianchi, M.D.a, Michele Catellani, M.D.a,
Gabriele Cozzi, M.D.a, Ettore Di Trapani, M.D.a, Antonio Cioffi, M.D.a, Elena Verri, M.D.c,
Matteo Ferro, M.D., Ph.Da, Maria Cossu Rocca, M.D.c, Deliu-Victor Matei, M.D., Ph.Da,
Franco Nole, M.D.c, Ottavio de Cobelli, M.D., Ph.D.a,d, Gennaro Musi, M.D.a,d
a
Department of Urology, IEO European Institute of Oncology, IRCCS, Milan, Italy
b
Universit
a degli Studi di Milano, Milan, Italy
c
Department of Medical Oncology, Division of Urogenital and Head and Neck Tumours, IEO European Institute of Oncology, IRCCS, Milan, Italy
d
Universit
a degli Studi di Milano, Department of Oncology and Hematology-Oncology, Milan, Italy
Received 17 January 2021; received in revised form 5 June 2021; accepted 24 June 2021

Abstract
Purpose: To report long-term oncological outcomes after penile-sparing surgery (PSS) for superficial (Ta-Tis) or initially invasive (T1)
penile cancer patients.
Methods: We retrospectively analysed 85 patients with Ta/Tis/T1cN0cM0 penile cancer (1996-2018). All patients underwent PSS: cir-
cumcision, excision or laser ablation. First, Kaplan-Meier plots and multivariable Cox regression models tested tumor recurrence rates (any
local/regional/metastatic). Second, Kaplan-Meier plots depicted progression-free survival (
T2 or N1-3 or M1 disease).
Results: Median (IQR) follow-up time was 64 (48−95) months. Overall, 48 (56%) patients experienced tumor recurrence. Median (IQR)
time to tumor recurrence was 34 (7−52) months. Higher recurrence rates were observed for Tis (65%) and T1 (64%), compared to Ta
(40%), but these differences were not significant on multivariable Cox regression analyses (HR:2.0 with 95% CI [0.9−5.1] and HR:2.2 with
95% CI [0.9−5.9], respectively). Moreover, higher recurrence rates were observed for G2-3 tumors (74%), compared to G1 (57%), but these
differences were not significant on multivariable Cox regression analyses (HR:1.6; 95% CI [0.8-3.2]). During follow-up, 15 (17.5%) vs. 18
(21.2%) vs. 10 (11.5%) patients underwent 1 vs. 2 vs.
3 PSS. Moreover, 26 (30.6%) and 4 (4.7%) men were treated with glansectomy and
partial/total penile amputation due to local progression, tumor size or patient preference. Additionally, 24 (28%) men underwent invasive
nodal staging. Last, 22 (25.9%) patients experienced disease progression. Median (IQR) time to disease progression was 51 (31−82)
months.
Conclusion: Patients treated with PSS for newly diagnosed superficial or initially invasive squamous cell carcinoma of the penis should
be informed about the non-negligible risk of tumor recurrence and disease progression over time. In consequence, strict follow-up protocols
are needed. Ó 2021 Elsevier Inc. All rights reserved.

Keywords: Circumcision; Excision; Laser ablation; Penile-sparing surgery; Penile cancer

Funding: This research did not receive any specific grant from funding
agencies in the public, commercial, or not-for-profit sectors
*Corresponding author. Tel: +39-333-542-49298; fax: +390294379271
E-mail address: stefanoluzzago@gmail.com (S. Luzzago).
1. Introduction
Penile-sparing surgery (PSS) is the recommended treat-
ment strategy for superficial (Ta-Tis) or initially invasive
(T1) squamous cell carcinoma of the penis, whenever feasi-
ble [1]. Data on long-term oncological outcomes after PSS

https://doi.org/10.1016/j.urolonc.2021.06.020
1078-1439/Ó 2021 Elsevier Inc. All rights reserved.
 ARTICLE IN PRESS
2 S. Luzzago et al. / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−7

were previously reported by many authors [2−11]. Specifi-

cally, PSS was associated with higher rates of local recur-
rence (10%−55%), but similar survival rates, as compared
to partial or radical penile amputation [3,4,12]. However,
most of the previous studies were significantly biased by
the inclusion of a heterogeneous population that spans from
superficial (Ta-Tis) to locally advanced (T3-4) or regional
(N1-3) penile cancer [2−5,12]. Moreover, other reports
included also patients treated with glansectomy or partial
amputation [2,3,5,12]. Last, to the best of our knowledge,
oncological outcomes of newly diagnosed penile cancer
(i.e., first presentation of cancer in patient’s life, after exclu-
sion of tumour recurrences), are largely unknown. In conse-
quence, a more specific focus on the natural history of
superficial (Ta-Tis) or initially invasive (T1) penile lesions
treated with PSS is needed.
We hypothesized higher rates of disease recurrence, as
compared to previously published series, in newly diag-
nosed penile cancer patients after PSS.
To test our hypothesis, we reported long-term follow-up
data of patients with newly diagnosed superficial (Ta-Tis)
or initially invasive (T1) penile cancer, treated with PSS at
a single tertiary referral centre. Specifically, we focused on
two major oncological outcomes: (1) tumour recurrence
and (2) disease progression.

2. Materials and methods

2.1. Study population

This study was conducted according to the ethical guide-

lines of the Declaration of Helsinki. We retrospectively col-
lected patients with squamous cell carcinoma of the penis
treated at our centre between 1996 and 2018 (n=263).
Patients with locally invasive (T2-4; n= 101) and/or
regional disease (N1-3; n=73) were excluded. Moreover,
patients treated with glansectomy, partial/total penile ampu-
tation were not considered (n=117). Last, men with missing
follow-up data or with short-time follow-up (<6 months)
were excluded (n=23). Overall, 85 consecutive patients
with newly diagnosed (i.e., first diagnosis of penile cancer)
Ta/Tis/T1 cN0cM0 penile cancer were available for the
analyses (Fig. 1).
Fig. 1. Consort Diagram with inclusion and exclusion criteria.

2.2. Penile-sparing surgery and variables definition

All patients were treated with PSS under local anaesthe-

sia in outpatient setting. Specifically, PSS consisted of any
of the following: circumcision, local excision or laser abla-
tion. Laser ablation was performed with either CO2 [13] or
Thulium−yttrium−aluminium−garnet (Tm:YAG) lasers
[14], as previously described. No frozen sections were
taken during surgery. Patients with microscopic positive
margins at final pathology (n=12; 14%) underwent local
radicalization within one month after primary PSS. Local
radicalization consisted of another PSS procedure. All
patients underwent pre-operative physical examination of
penile lesions and groins. Moreover, some patients under-
went pre-operative imaging (CT scan of the abdomen and
pelvis and/or bilateral groin US), according to EAU guide-
lines [1]. All patients had non palpable inguinal lymph
nodes and had no evidence of metastatic disease based on
cross-sectional imaging (cN0cM0) at the time of PSS. None
of these patients underwent a diagnostic sentinel lymph
node biopsy or inguinal lymph node dissection at time of
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S. Luzzago et al. / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−7 3

diagnosis. No patients received radiotherapy or chemother- Table 1

apy before or immediately after PSS. Descriptive characteristics of 85 patients with newly diagnosed superficial
Variables recorded included age at surgery, year of diag- (Ta-TisN0M0) or initially invasive (T1N0M0) penile cancer, treated with
penile-sparing surgery between 1996 and 2018.
nosis, tumor site (glans vs. foreskin vs. glans and foreskin),
tumor size (mm), type of surgery (circumcision vs. excision Age (years) Median (IQR) 62 (52-69)
vs. laser ablation), T stage (Ta vs. Tis vs. T1) and tumor
Age categories, n (%) <55 27 (31.8)
grade (Gx vs. G1 vs. G2 vs. G3). 55-65 25 (29.4)
Follow-up examinations were performed every 3 months >65 33 (38.8)
in the first two years and every 6 months in the following Tumor size (mm) Median (IQR) 13 (9.5-23)
three years. Patients were also advised to perform regular Tumor site, n (%) Glans 64 (75.3)
Foreskin 16 (18.8)
self-examination. Follow-up imaging scans were performed
Glans and foreskin 5 (5.9)
according to the European Association of Urology (EAU) Type of surgery, n (%) Circumcision 15 (17.6)
guidelines [1]. Excision 56 (65.9)
Laser ablation 14 (16.5)
T stage, n (%) Ta 15 (17.6)
2.3. Statistical analyses Tis 23 (27.1)
T1 47 (55.3)
Descriptive statistics relied on tests of means and pro- Tumor grade, n (%) Gx 25 (29.4)
portions and, respectively, used the t-test and the chi- G1 33 (38.8)
square. We conducted a two-step analysis. G2 21 (24.7)
G3 6 (7.1)
First, we tested recurrence rates after surgery. Specifi-
cally, tumour recurrence was defined as any local, regional IQR: interquartile range
or systemic presentation after primary PSS. Tumour recur-
rences were managed according to EAU guidelines [1].
PSS was again performed for Ta/Tis/T1 disease, when fea- lesions were located, respectively, in glans vs. foreskin vs.
sible. Conversely, glansectomy or partial/radical amputa- glans and foreskin. In consequence, 65.9% vs. 17.6% vs.
tion were suggested for invasive disease (T2 or more) or 16.5% patients underwent excision vs. circumcision vs.
because of inability to perform PSS due to tumour size, laser ablation, respectively. Specifically, of all laser abla-
lesion location of patient preference. Moreover, invasive tion procedures (n=14), 7 (50%) vs. 7 (50%) were per-
nodal staging by diagnostic sentinel lymph node biopsy formed with CO2 vs. Tm:YAG laser, respectively. T stage
[15] or inguinal lymph node dissection was suggested for stratification revealed the following distribution: 17.6% Ta
recurrent disease >T1G2 [1]. Recurrence-free survival rates vs. 27.1% Tis vs. 55.3% T1. Moreover, 29.4% vs. 38.8%
during follow-up were tested with Kaplan-Meier plots. Sub- vs. 24.7% vs. 7.1% men had Gx vs. G1 vs. G2 vs. G3
sequently, multivariable Cox regression models tested the tumour grade, respectively.
association between tumour or patient characteristics and
tumour recurrence rates over time.
Second, we tested disease progression after PSS. Specifi- 3.2. Tumor recurrence
cally, disease progression was defined as local stage
T2 or
regional (N1-3) or metastatic (M1) disease. Here, Kaplan- Overall, 48 (56%) patients experienced tumour recur-
Meier plots tested progression-free survival rates over time. rence. Moreover, 19 (39.5%) vs. 18 (37.5%) vs. 11 (23%)
All survival analyses considered time from PSS to event. patients had 1 vs. 2 vs.
3 recurrences over time. Median
For patients with positive margins, survival analyses con- (IQR) time to tumor recurrence was 34 (7−52) months
sidered time from local radicalization to event. (Fig. 2A). In Ta vs. Tis vs. T1 tumours, median time to
All statistical tests were two-sided with a level of signifi- recurrence was, respectively, 96 vs. 38 vs. 20 months
cance set at P<0.05. All analyses were performed using the (P=0.1; Fig. 2E). Last, in Gx vs. G1 vs. G2-3 tumours,
R software environment for statistical computing and median time to recurrence was, respectively, 51 vs. 38 vs.
graphics (version 3.4.1; http://www.r-project.org/). 21 months (P=0.1; Fig. 2F).
In multivariable Cox regression models (Table 2), higher
recurrence rates were observed for Tis (Hazard Ratio [HR]
3. Results
with 95% confidence interval [CI]: 2.05 (0.91−5.14);
3.1. Descriptive analyses P=0.1) and T1 stages (HR: 2.21 [95% CI: 0.95−5.91];
P=0.08), compared to Ta. Moreover, higher recurrence
Median (interquartile range: IQR) age at surgery was 62 rates were observed for G2-3 tumours (HR: 1.67 [95% CI:
(52−69) years (Table 1). Specifically, men aged <55 vs. 0.88−3.26]; P=0.1), compared to G1.
55-65 vs. >65 years old comprised 31.8% vs. 29.4% vs. Recurrence-free survival rates in patients with negative
38.8% of our study cohort. Median (IQR) tumour size was margin at first PSS vs. patients that underwent immediate
13 (9.5−23) mm. Overall, 75.3% vs. 18.8% vs. 5.9% radicalization due to microscopic positive margins at
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Fig. 2. Kaplan-Meier plots depicting recurrence-free survival rates in 85 patients with newly diagnosed superficial (Ta-TisN0M0) or initially invasive
(T1N0M0) penile cancer treated with penile-sparing surgery between 1996 and 2018.
A. Overall population
B. T stage
C. Tumor grade

surgery are plotted in Supplementary Figure 1. Here, we did 3.4. Disease progression
not observe different outcomes in these two patients sub-
groups, with time to event that was calculated from the first Overall, 22 (25.9%) patients experienced disease progres-
PSS for patients with negative margins vs. from radicaliza- sion. Specifically, 10 (45.5%) vs. 2 (9%) vs. 10 (45.5%) men
tion in patients with positive margins. harboured Stage II vs. III vs. IV penile cancer according to
the 8Th edition of the AJCC TNM staging system [16].
Median (IQR) time to disease progression was 51 (31-82)
3.3. Findings at follow-up months (Fig. 3A). No meaningful associations with disease
progression rates over time were seen in subgroup analyses
Median (IQR) follow-up time was 64 (48−95) months. that considered T stage and tumor grade (Figs. 3B-C).
During follow-up, 15 (17.5%) vs. 18 (21.2%) vs. 10 During follow-up, 4 (4.7%) and 4 (4.7%) patients experi-
(11.5%) patients underwent 1 vs. 2 vs.
3 PSS treatments enced cancer-specific and other-cause mortality, respec-
due to tumor recurrence. Moreover, 26 (30.6%) and 4 tively.
(4.7%) men were treated with glansectomy and partial/total
penile amputation during follow-up. 4. Discussion
Last, 24 (28%) men underwent invasive nodal staging.
Specifically, 21 (24.7%) and 15 (17.6%) patients under- Robust data on long-term oncological outcomes after
went, respectively, diagnostic sentinel lymph node biopsy PSS for superficial (Ta-Tis) or initially invasive (T1) penile
and inguinal lymph node dissection. cancer are needed. EAU guidelines recommendations for
follow-up [1] are currently based on previous retrospective
Table 2
series that also included locally-advanced and/or regional
Multivariable Cox regression models predicting tumor recurrence rates
over time (any local, regional or metastatic presentation) after penile-spar- tumors [2−5,12], or patients treated with aggressive local
ing surgery in 85 newly diagnosed superficial (Ta-TisN0M0) or initially surgery, such as glansectomy or partial amputation
invasive (T1N0M0) penile cancer patients treated between 1996 and 2018. [2,3,5,12]. We presented long-term follow-up data of a
homogeneous population (Ta-Tis-T1cN0cM0) treated with
HR (95% CI) P-value
PSS (circumcision, local excision or laser ablation) at a sin-
Age at surgery 0.98 (0.96-1.00) 0.2 gle tertiary referral centre. Specifically, we focused on
Tumor site Glans Ref. patients with newly diagnosed penile cancer, after exclud-
Foreskin 1.14 (0.57-2.28) 0.7
ing those treated for tumor recurrences. Our results showed
Glans and foreskin 1.35 (0.40-4.50) 0.6
T stage Ta Ref. several important findings.
Tis 2.17 (0.92-5.39) 0.1 First, we observed non-negligible rates of tumor recur-
T1 2.23 (0.96-5.95) 0.07 rence after PSS. Specifically, 56% of the overall population
Tumor grade G1 Ref. experienced tumor recurrence after a median follow-up
G2-3 1.65 (0.89-3.22) 0.1
time of 34 (7−52) months. Moreover, 34% of them had
2
Gx 0.94 (0.43-2.04) 0.8
recurrences. Last, although we lacked sufficient power (low
HR: Hazard Ratio; CI: confidence interval number of patients) to observe statistically significant
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S. Luzzago et al. / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−7
Fig. 3. Kaplan-Meier plots depicting progression-free survival rates in 85 patients with newly diagnosed superficial (Ta-TisN0M0) or initially invasive
(T1N0M0) penile cancer treated with penile-sparing surgery between 1996 and 2018.
A. Overall population
B. T stage
C. Tumor grade
associations, multivariable Cox regression models showed
higher recurrence rates with increasing T stage (Tis HR:
2.0; T1 HR: 2.2) and tumor grade (G2-3 HR: 1.6). Our find-
ings are consistent with some previous analyses, in which
recurrence rates up to 55% with different PSS techniques
were reported [3,9,11,17−19]. Several possible explana-
tions could justify these observed findings. First, the vast
majority of the study population harboured T1 stage and, in
consequence, was more prone to disease recurrence over
time [19]. Second, we included only patients treated with
conservative PSS, after excluding those treated with glan-
sectomy, partial amputation and other aggressive local
treatments. Moreover, we excluded all men treated with
neoadjuvant or adjuvant therapies, such as radiotherapy or
chemotherapy, that were frequently administered in other
series [2,13,20]. Third, as previously addressed in a limited
number of reports [21], we specifically focused on newly
diagnosed penile cancer patients, after excluding those who
underwent PSS for disease recurrence. In consequence, we
clearly reported long-term oncological outcomes of Ta-Tis-
T1 lesions after PSS. Our findings are supported by the
non-negligible follow-up time of the study population
(median [IQR]: 64 [48−95] months) and by the use of mul-
tivariable Cox regression models that were fully adjusted
for all available tumor and patient characteristics. There-
fore, our findings might be used to modulate the follow-up
schemes after PSS proposed by the EAU guidelines [1].
Specifically, follow-up visits for patients at higher risk of
disease recurrence, such as those with Tis-T1 and/or G2-G3
tumors, could be intensified. Conversely, less intense fol-
low-up recommendations could be proposed for patients
with Ta and/or low-grade cancers. However, it should be
stated that our suggestions are based on a retrospective and
single centre series of penile cancer patients treated with
PSS. In consequence, results of other multicentre and,
5
ideally, prospective studies are needed before recommend-
ing EAU guidelines modifications [1].
Second, although we reported significant rates of disease
recurrence over time, the vast majority of patients was still
manageable with PSS. However, 35% of them were subse-
quently treated with more aggressive surgery, such as glan-
sectomy or partial amputation. Furthermore, 28% of
patients also needed invasive nodal staging during follow-
up. Our results confirmed the possibility of achieving onco-
logical disease control, after local recurrence, with repeated
PSS treatments [8,13,17,18].
Third, 25.9% of patients experienced disease progression
after a median (IQR) follow-up time of 51 (31−82) months.
These non-negligible progression rates over time are
consistent with some previous analyses [2−5,12] and are
probably a product of the definition used for the mentioned
outcome (i.e. local stage
T2 and/or regional (N1-3) and/or
metastatic (M1) disease). Moreover, these findings could be
related to the long-term follow-up time of the study popula-
tion (median [IQR]: 64 [48−95] months). However, due to
the low number of events in the current series, we were
unable to show any statistically significant association
between patient or tumor characteristics and progression-
free survival rates over time. Moreover, the low number of
events also precluded fitting multivariable Cox regression
models testing predictors of disease progression.
Our findings warrant particular attention. First, we
believe that PSS should be only proposed to highly selected
Ta-Tis-T1 patients that are absolutely compliant with strict
follow-up. Second, we believe that PSS should be only pro-
posed after detailed patient counselling and after consider-
ation of patient comorbidities, age, sexual function etc..
This said, other series with a higher number of patients
and events are required for testing predictors of disease pro-
gression rates over time.
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6 S. Luzzago et al. / Urologic Oncology: Seminars and Original Investigations 00 (2021) 1−7
Despite the significant number of disease progressions in
the current analysis, we observed only four disease-specific
deaths over time. In consequence, we believe that other
studies focusing on other major oncological outcomes,
namely metastasis-free and cancer-specific survival, should
be performed excluding patients with superficial (Ta-Tis)
or initially invasive (T1) penile cancer from PSS. Indeed,
four previous analyses showed that 5-year cancer-specific
survival was not jeopardized by the use of PSS instead of
partial/radical penile amputation [3−5,12].
Taken together, we reported long-term oncological
results after PSS in a series that specifically focused on
newly diagnosed (i.e, no previous history) superficial (Ta-
Tis) or initially invasive (T1) penile cancer patients treated
with PSS. We observed significant recurrence rates after
primary treatment. However, the vast majority of tumor
recurrences were still manageable with PSS. Moreover,
patients should be properly counselled about the possibility
of tumor progression over time and, in consequence, of the
necessity to adhere to strict follow-up schemes.
Despite its novelty, our study has limitations. First, the
current data are retrospective and influenced by inherent
selection bias. For instance, only patients with tumors con-
fined to the glans and/or foreskin were available for final
analyses. Moreover, median tumor size (13 mm) was
smaller, as compared to previously published series. Sec-
ond, as previously stated, the low number of patients and
events precluded fitting multivariable Cox models predict-
ing disease progression rates over time. Moreover, multi-
variable Cox analyses predicting disease recurrence rates
over time were, in consequence, underpowered. Addition-
ally, we did not consider other important oncological out-
comes, such as cancer-specific or overall survival. Third,
we were unable to distinguish between true local recur-
rences and metachronous new occurrences, as previously
reported [22]. Fourth, we dichotomized surgical margins as
positive vs. negative. In consequence, information about
millimiters of clear surgical margins were missing [23
−25]. However, Sri et. al previously demonstrated that a
clear margin >1 millimiter has very low risk of local recur-
rence after PSS [22]. Fifth, we lacked of other important
pathological features, such as histological subtype, lympho-
vascular invasion and T1 sub-classification (T1a vs. T1b)
[26−28]. Last, although we tried to select a homogeneous
population of penile cancer patients, we created heterogene-
ity by including several PSS techniques, such as circumci-
sion, excision and laser ablation. Moreover, other PSS such
as Moh’s micrographic surgery [8], glans resurfacing
[17,29,30] or topical chemotherapy agents [31] were not
performed.
5. Conclusion
Patients treated with PSS for newly diagnosed superficial
or initially invasive squamous cell carcinoma of the penis
should be informed about the non-negligible risk of tumor
recurrence and disease progression over time. In conse-
quence, strict follow-up protocols are needed.
Conflicts of interest
None
Acknowledgments
This work was partially supported by the Italian Ministry
of Health with Ricerca Corrente and 5 £ 1000 funds
Stefano Luzzago 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.
Supplementary materials
Supplementary material associated with this article can
be found in the online version at https://doi.org/10.1016/j.
urolonc.2021.06.020.
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