










































Key Words Competing Interests Article Information

Penile cancer, cancer staging, circumcision None declared. Received on September 22, 2021 
Accepted on December 30, 2021 
This article has been peer reviewed.

Soc Int Urol J. 2022;3(2):102–107

DOI: 10.48083/OIKH5959

102 SIUJ  •  Volume 3, Number 2  •  March 2022 SIUJ.ORG

This is an open access article under the terms of a license that permits non-commercial use, provided the original work is properly cited.  
© 2022 The Authors. Société Internationale d'Urologie Journal, published by the Société Internationale d'Urologie, Canada.

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The Relationship of Circumcision  
With Clinical Tumor Staging of  
Penile Cancer

Marco Bandini,1 Philippe E. Spiess,2 Yao Zhu,3 Antonio A. Ornellas,4 Benjamin A. Ayres,5  
Oliver W. Hakenberg,6 Friederike Haidl,7 Filippo Pederzoli,1 Giuseppe Basile,1 Alberto Briganti,1  
Francesco Montorsi,1 Juan Chipollini,2 Mounsif Azizi,2 Gert De Meerleer,8 Oscar R. Brouwer,9  
Maarten Albersen,8 Andrea Necchi,10 Peter A. S. Johnstone2

1 San Raffaele Hospital and Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy 2 Moffitt Cancer Center and Research Institute, Tampa, 
United States 3 Fudan University Shanghai Cancer Center, Shanghai, China 4 Hospital Mário Kröeff and Brazilian Cancer Institute, Rio de Janeiro, Brazil 5 St George’s 
University Hospitals, NHS Foundation Trust, London, United Kingdom 6 University Hospital Rostock, Rostock, Germany 7 Universitätsklinikum Köln, Köln, Germany 
8 University Hospitals Leuven, Leuven, Belgium 9 The Netherlands Cancer Institute, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands  
10 Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy

Abstract

In this report, we look at the relationship between prior circumcision and presenting stage of penile cancer. We 
performed an analysis of an international, multicenter database of 1254 penile cancer patients diagnosed from 1980 
to 2019 in the United States, Europe, Brazil, and China, and analyzed the relationship between circumcision and 
presenting T and N stage. A total of 710 patients met the inclusion criteria and were statistically analyzed. We found 
that uncircumcised men with locally advanced tumors (T3–T4) had significantly higher risk of lymph node metastasis 
compared with circumcised men.

The genital microbiome is the only shared human microbiome[1]. Since circumcised men harbor different bacterial 
communities than uncircumcised men[2], we hypothesized that circumcised men may present with a different penile 
squamous cell carcinoma (PSCC) disease burden than uncircumcised men. Were this the case, it could manifest as 
a difference in either the T or N stage of the subsequent disease. To our knowledge, no prior study has discussed the 
relationship of prior circumcision with the presenting tumor stage. In order to do so, we performed a retrospective 
cohort study.

Large clinical datasets of patients with PSCC are uncommon given the rarity of the disease[3]. We have collaborated 
on an international, multicenter retrospective database of 1254 penile cancer patients diagnosed from 1980 to 2019 
in the United States, Europe, Brazil, and China. Previous publications from our group have discussed correlates 
of chemotherapy and lymph node dissection use by participating institutions[4–6], and association between 
human papillomavirus (HPV) infection and radiosensitivity[7]. For this report, we analyzed the relation between 
circumcision and presenting T and N stage. Patients treated with circumcision during the surgery of the primary 
lesion or those without data on time of circumcision were excluded.

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For this analysis, 710 patients met the inclusion criteria 
(Figure 1). Patient characteristics are summarized in 
Table 1. Descriptive statistics included frequencies and 
proportions for categorical variables. Medians and 
interquartile ranges (IQR) were reported for continuous 
variables. The statistical significance of differences in 
medians and proportions between circumcised and 
uncircumcised men with penile cancer was tested with 
the Kruskal-Wallis and chi-square tests, respectively.

Ana lyses were organized in several steps. First, 
we explored predictors of inguina l ly mph node 
metastases (ILNM) among several variables including 
circumcision, histology (squamous cell versus non-
squamous cell), T stage (T< 2 versus T2 versus T3–T4), 
age at penile cancer diagnosis, use of perioperative 
chemotherapy, surgical procedure to the primary (total 
penectomy versus partial penectomy versus no surgery/
local surgical procedures). The choice of the predictors 
for this multivariable model has been made based on 
clinical relevance. Second, to assess whether the higher 
risk of ILNM in locally advanced tumors (T3–T4) was 
different by circumcision status, we tested an interaction 
with T stage and circumcision. Third, we depicted the 
probability of inguinal lymph node metastases for 
circumcised and uncircumcised men with penile cancer 
across T sub-stages.

FIGURE 1.

Inclusion/exclusion criteria and study population

710 patients enrolled  
in this study cohort

1254 patients  
with penile cancer

475 patients without 
circumcision data

779 circumcised and 
uncircumcised patients  

with penile cancer

2 patients without 
available pT and  
pN stage data

777 patients with available 
pT and pN stage data

20 patients without  
type of surgery of the 

primary data

757 patients received 
surgery of the primary

47 patients without 
available follow-up  

data

TABLE 1. 

Epidemiological, geographical, and disease-specific characteristics of 710 penile cancer patients treated 
within 9 tertiary referral institutions 

Variable
Overall

 (n = 710)
Circumcised 

(n = 550)
Not circumcised 

(n = 160)
P-value

Median age at diagnosis (range) 59 (50–69) 59 (50.2–68.8) 58 (48.8–69) 0.98

Median ILMN (range) 13.3 (4.3–25) 13.3 (4.8–25) 12.5 (0–26.8) 0.89

Geographical areas (%)

Europe
Brazil
United Kingdom
United States

388 (54.6)
173 (24.4)
77 (10.8)
72 (10.1)

304 (55.3)
145 (26.4)

66 (12)
35 (6.4)

84 (52.5)
28 (17.5)
11 (6.9)
37 (23.1)

< 0.001

HPV infection (%)
Yes
No
NA

371 (52.3)
38 (5.4)

301 (42.4)

284 (51.6)
26 (4.7)

240 (43.6)

87 (54.4)
12 (7.5)

61 (38.1)
0.21

Smoking habit (%)
Current or former
Never
NA

246 (34.6)
166 (23.4)
298 (42)

204 (37.1)
121 (22)

225 (40.9)

42 (26.2)
45 (28.1)
73 (45.6)

0.04

CHT: chemotherapy; ILNM: inguinal lymph node metastasis; LND: lymph node dissection; RT: radiotherapy; SCC: squamous cell carcinoma

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TABLE 1. 

Epidemiological, geographical, and disease-specific characteristics of 710 penile cancer patients treated 
within 9 tertiary referral institutions 

Variable
Overall

 (n = 710)
Circumcised 

(n = 550)
Not circumcised 

(n = 160)
P-value

Histology (%)
SCC
Non-SCC

622 (87.6)

88 (12.4)
477 (86.7)
73 (13.3)

145 (90.6)
15 (9.4)

0.21

pT stage (%)
pT<2
pT2
pT3-4

277 (39)
279 (39.3)
154 (21.7)

190 (34.5)
235 (42.7)
125 (22.7)

87 (54.4)
44 (27.5)
29 (18.1)

< 0.001

pN stage (%)
Nx-N0
N1-N2
N3

230 (32.4)
193 (27.2)
287 (40.4)

182 (33.1)
151 (27.5)
217 (39.5)

48 (30)
42 (26.2)
70 (43.8)

0.60

Inguinal LND (%)
Bilateral
Unilateral
Not performed

479 (67.5)
143 (20.1)
88 (12.4)

364 (66.2)
107 (19.5)
79 (14.4)

115 (71.9)
36 (22.5)

9 (5.6)
0.01

Node metastasis side (%)

Negative ILNM
Bilateral ILNM
Unilateral ILNM
ILND not performed
NA

112 (15.8)
174 (24.5)
158 (22.3)

21 (3)
245 (34.5)

78 (14.2)
133 (24.2)
120 (21.8)
19 (3.5)

200 (36.4)

34 (21.2)
41 (25.6)
120 (21.8)

2 (1.2)
45 (28.1)

0.1

Type of surgery of the 
primary penile lesion (%)

Total penectomy
No surgery/ local 
procedures
Partial penectomy

162 (22.8)

97 (13.7)

451 (63.5)

141 (25.6)

40 (7.3)

369 (67.1)

21 (13.1)

57 (35.6)

82 (51.2)

< 0.001

Perioperative CHT (%)
No CHT
CHT
NA

328 (46.2)
258 (36.3)
124 (17.5)

249 (45.3)
193 (35.1)
108 (19.6)

79 (49.4)
65 (40.6)
16 (10)

0.02

Perioperative RT (%)
No RT
RT
NA

509 (71.7)
82 (11.5)
119 (16.8)

388 (70.5)
57 (10.4)
105 (19.1)

121 (75.6)
25 (15.6)
14 (8.8)

< 0.01

Pelvic LND (%)
No
Yes
NA

366 (51.5)
264 (37.2)
80 (11.3)

271 (49.3)
207 (37.6)
72 (13.1)

95 (59.4)
57 (35.6)

8 (5)
0.01

CHT: chemotherapy; ILNM: inguinal lymph node metastasis; LND: lymph node dissection; RT: radiotherapy; SCC: squamous cell carcinoma

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TABLE 2a.

Univariable and multivariable analysis testing the risk of ILMN according to several predictors

Univariable analysis Multivariable analysis

Covariates OR 5% 95% P-value OR 5% 95% P-value

Previous circumcision 0.72 0.46 1.14 0.2 0.63 0.36 1.10 0.1

Non-SCC histology 5.19 2.10 17.28 0.002 2.82 1.00 10.17 0.07

pT2 stage (ref T < 2) 1.36 0.87 2.14 0.2 1.82 1.06 3.15 0.03

pT3-T4 stage (ref T < 2) 2.22 1.25 4.14 0.009 2.83 1.42 5.86 0.004

Age at diagnosis 1.01 0.99 1.02 0.4 1.01 0.99 1.03 0.2

Perioperative CHT unknown (ref. no perioperative CHT) 13.62 4.11 84.31 < 0.001 7.36 1.92 48.71 0.01

Perioperative CHT (ref. no perioperative CHT) 9.59 5.40 18.42 < 0.001 10.57 5.88 20.54 < 0.001

Total penectomy versus no surgery/local surgical 
procedures

0.90 0.46 1.83 0.9 2.42 0.97 6.20 0.06

Total penectomy versus partial penectomy 0.96 0.58 1.56 0.9 1.28 0.71 2.26 0.4

CHT: chemotherapy; OR: odds ratio; SCC: squamous cell carcinoma

TABLE 2b.

Interaction between circumcision and pT stage for prediction of lymph node invasion adjusted for all the 
other covariates: histology, age, perioperative CHT, surgical procedure on the primary penile lesion

Variable OR 5% 95% P-value

Previous circumcision*T2 stage 0.48 0.14 1.61 0.2

Previous circumcision*T3-T4 stage 0.21 0.04 0.92 0.03

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The Relationship of Circumcision With Clinical Tumor Staging of Penile Cancer

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Uncircumcised patients harbored T< 2 tumors more 
frequently than did circumcised men (54.4% versus 
34.5%; P < 0.001) (Table 1). No statistical difference 
was found regarding N stage between circumcised and 
uncircumcised men. Furthermore, circumcision rates 
differed with smoking and geographic patient variables, 
and with several treatment variables including extent of 
surgery and delivery of chemotherapy and radiother-
apy. Multivariable analyses showed a clear and expected 
association between advanced pT stages and higher risk 
of ILNM, as well as between use of perioperative chemo-
therapy and higher risk of ILNM. Conversely, no asso-
ciation was found between circumcision and the risk 
of ILNM. Nevertheless, we found that circumcision, 
compared with no-circumcision, conferred a lower risk 
of ILNM (Table 2) in patients with locally advanced 
tumors (T3–T4). The risk of ILNM according to T stage 
in circumcised versus uncircumcised penile cancer 
patients is depicted in Figure 2.

Debate continues about the potential role of circum-
cision in subsequent development of PSCC[8,9]. To our 

knowledge, no prior study has discussed the association 
of prior circumcision with tumor stage at presentation. 
Our data reveal correlations between circumcision and 
PSCC staging. First, there is an association of prior 
circumcision with presenting T stage on multivariable 
analysis. Second, there is no association of circumcision 
with presenting N stage. These findings suggest there 
may be a difference in local microbiota in uncircumcised 
compared with circumcised individuals, which might 
contribute to development of PSCC.

Limitations of this analysis include a lack of broad 
generalizability, since data are lacking from Africa, 
India, and most of South America, and we consider our 
coverage of North America and Europe to be subopti-
mal. Lack of data on HPV status on these patients is a 
limitation in terms of understanding its potential etiol-
ogy in penile cancer, most notably in non-circumcised 
men. Specific analysis of large populations with equal 
access to health care would help clarify the potential role 
of the genital microbiome in this process.

FIGURE 2.

Risk of ILNM according to T-stage in circumcised versus uncircumcised penile cancer patients

Uncircumcised

Circumcised60

T<2 T2 T3–4

70

80

90

T stage

Pr
ob

ab
ili

ty
 o

f L
N

 in
va

si
on

ILNM: inguinal lymph node metastasis

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