Clinical significance of preoperative C-reactive

protein and squamous cell carcinoma antigen

levels in patients with penile squamous cell
carcinoma
Zai-Shang Li*,†,‡, Kai Yao*,†,‡, Yong-Hong Li*,†,‡, Jie-Ping Chen*,†,‡, Chuang-Zhong
Deng*,†,‡, Qi Zhao§, Peng Chen¶, Bin Wang**, Qi-Wu Mi††, Zhuo-Wei Liu*,†,‡, Zi-Ke
Qin*,†,‡, Hui Han*,†,‡ and Fang-Jian Zhou*,†,‡
*Department of Urology, Sun Yat-sen University Cancer Center, †State Key Laboratory of Oncology in Southern China ,
‡
Collaborative Innovation Center of Cancer Medicine , §School of Life Science, Sun Yat-sen University, Guangzhou ,
¶
Department of Urology, Affiliated Tumor Hospital of Xinjiang Medical University, Urumchi , **Department of Urology,
Cancer Center of Guangzhou Medical University, Guangzhou , and ††Department of Urology, Dong Guan People’s
Hospital, Guang Dong, China
Z.-S. L. and K. Y. contributed equally to this work.

Objective extension (chi-squared trend test, P < 0.001), pelvic LNM

To evaluate the relevance of C-reactive protein (CRP) and (chi-squared trend test, P = 0.024), pathological tumour
squamous cell carcinoma antigen (SCC-Ag) levels in relation status (chi-squared trend test, P = 0.002), pathological
to clinicopathological factors and prognosis in penile cancer. nodal status (chi-squared trend test, P < 0.001), and disease-
specific survival (DSS; log-rank test, P < 0.001). Moreover, the
Patients and Methods influence of CRP and SCC-Ag levels on DSS (P = 0.033,
A total of 124 Chinese patients with penile squamous cell hazard ratio 3.390, 95% confidence interval 1.104–10.411)
carcinoma (SCC), treated between November 2007 and remained after adjusting for smoking history, phimosis,
October 2014, were analysed retrospectively. Receiver- tumour status, tumour cell differentiation and nodal status.
operating characteristic curves were used to identify the Conclusions
combination of markers with the best sensitivity and
specificity for prognosis prediction. Statistical data analysis The present study shows that the combined measurement of
was performed using a non-parametric method, and survival preoperative CRP and SCC-Ag levels may serve as an
analysis was performed using the log-rank test and Cox independent biomarker for LNM, advanced tumour stage and
proportional hazard model. DSS in patients with penile SCC.

Results Keywords
Levels of CRP ≥4.5 mg/L and SCC-Ag ≥1.4 ng/mL were both penile neoplasm, staging system, lymph node metastasis,
significantly associated with lymph node metastasis (LNM) lymph node excision, prognosis
laterality (chi-squared trend test, P = 0.041), extranodal

curative in cases with minimal metastases [1–3,5]; however, a

Introduction significant number of patients with enlarged lymph nodes do
More than 95% of penile malignancies are classified as not present with metastatic spread; consequently, up to 80% of
squamous cell carcinoma (SCC) [1,2]. As this genitourinary patients are overtreated [9,10], leading to high morbidity rates
cancer is typically characterized by stepwise regional lymph [11,12]. Preoperative diagnosis and decreased intervention
node spread prior to the formation of distant metastases [3–5], without the loss of positive results is therefore of paramount
the lymph node metastasis (LNM) stage is the most important importance. Because classical molecular markers are not
predictor of survival in penile cancer [1–3,6–8]. Inguinal clinically useful for SCC of the penis, a tumour marker related
lymphadenectomy is currently the most useful and commonly to disease burden and activity would be helpful for the
performed surgery for penile cancer staging, and it can be optimum management of this disease.

© 2015 The Authors

BJU International © 2015 BJU International | doi:10.1111/bju.13379 BJU Int 2015
Published by John Wiley & Sons Ltd. www.bjui.org wileyonlinelibrary.com
Li et al.

C-reactive protein (CRP) is an indicator of acute and chronic score of 3. Patients with either elevated CRP (≥4.5 mg/L or
inflammation [13]. An elevated CRP concentration is elevated SCC-Ag ≥1.4 g/ml) levels only received a score of 2,
independently correlated with tumour load and disease and patients with no elevation received a score of 1. The log-
progression, which is also correlated with survival in various rank test was used to generate Kaplan–Meier plots to estimate
cancers [14,15], and two recent studies have shown that CRP disease-specific survival (DSS); however, we did not evaluate
correlates with tumour burden in penile cancer [16,17]. the role of adjuvant therapy by multivariate analysis because
Another potential prognostic marker in penile cancer is SCC such therapies were not routinely administered to all of the
antigen (SCC-Ag), a serum tumour marker used for various enrolled patients. Several risk factors for penile SCC, which
human SCCs [18,19], and an elevated level of SCC-Ag has were identified according to European Association of Urology
been reported to be associated with clinical outcome in guidelines, were included in the regression analysis. Because
patients with penile cancer [19–21]; however, to the best of LNM laterality, extranodal extension (ENE) and pelvic LNMs
our knowledge, the relationship between CRP and SCC-Ag are included in the 7th nodal staging system, only additional
levels and their potential value in combination as a factors were included in the regression analysis. Multivariable
prognostic marker of survival in penile cancer have not been Cox regression models were fitted to test DSS predictors.
previously explored. In the present study, we retrospectively Because of the small sample size and number of relationships
analysed 124 patients with penile SCC to evaluate the examined and because CRP and SCC-Ag levels are not
combined prognostic value of elevated CRP and SCC-Ag accepted as prognostic predictors in penile cancer, all analyses
levels. were considered exploratory, and results were considered as
hypothesis-generating rather than hypothesis-testing;
Patients and Methods therefore, in our model, a positive signal for each marker was
combined into a single category. The likelihood ratio,
We retrospectively reviewed the charts of 124 consecutive
Akaike’s information criterion and C-index value were
patients diagnosed with primary penile SCCs between
investigated to evaluate the accuracy of the models. All
November 2007 and October 2014 at our institution.
statistical analyses were performed with R2.11.1 (http://
Pretreatment CRP and SCC-Ag serum levels were measured
www.r-project.org), and a two-sided P value <0.05 was taken
using fresh blood samples obtained at the time of diagnosis
to indicate statistical significance.
before any medical intervention (before 3–5 days). The
eligibility criteria were histologically confirmed penile SCC
and treatment (lesions and lymph nodes were proven by Results
pathological analysis). The exclusion criteria were as follows: A total of 124 patients were retrospectively reviewed. Of
neoadjuvant chemotherapy; previous surgery or radiotherapy these, 16 (12.9%) whose treatment plan was penile
of the inguinal region; clinical evidence of distant metastasis; preservation underwent local excision with circumcision, 81
and loss to follow-up. Based on guideline recommendations, (65.3%) underwent partial penile amputation, and 37 (29.8%)
treatment protocols were discussed with each patient [1– underwent total penile amputation. A total of 108 patients
3,22,23]. All histopathology reports were based on the 2015 (87.1%) met the eligibility criteria for the study and
American Joint Committee on Cancer TNM system [1]. underwent bilateral inguinal lymph node dissection, and 60 of
those patients (48.4%) had LNM. The median (interquartile
The deadline for follow-up data to be included in this
range) numbers of positive and removed lymph nodes were 2
analysis was March 2015. The follow-up period for each
(1–13) and 27 (5–55), respectively, and 45 patients received
patient began at the time of cancer diagnosis and ended at
adjuvant chemotherapy therapy. According to the receiver-
death or the deadline. All patients underwent follow-up
operating characteristic curve analysis, the potential
examinations every 3 months for the first 2 years after
preoperative levels of CRP and SCC-Ag were 4.5 mg/L and
surgery, every 6 months in the 3rd and 4th years after
1.4 g/mL, respectively. During the follow-up period, 17
surgery, and once yearly thereafter [2].
patients died from penile cancer at a mean (median; range)
of 17 (12; 2–117) months. The clinicopathological
Statistical Analyses characteristics of the patients are presented in Table 1.
The chi-squared test was used for multiple comparisons. The A close association was observed between an increased CRP
optimum CRP and SCC-Ag cut-off values for prognosis level and ENE (P < 0.001), pelvic LNM (P = 0.007),
prediction were calculated using receiver-operating pathological tumour status (P = 0.002), and pathological
characteristic curve analysis with reference to cancer-specific nodal status (P < 0.001; Table 2). DSS was significantly lower
death [24]. Linear correlation between variables was in the positive CRP group compared with the negative CRP
calculated using linear regression analysis. Patients with both group (P < 0.001; Fig. 1A). A multivariate model that
an elevated CRP level and elevated SCC-Ag were given a included smoking history, phimosis, tumour status, tumour

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2 BJU International © 2015 BJU International
 Preoperative CRP and SCC antigen levels and penile cancer

Table 1 Clinicopathological characteristics and univariate log-rank test of levels did not correlate with pelvic LNM. Our results showed
prognostic covariates in 124 patients.
that SCC-Ag positivity was a valuable prognostic factor for
Variable 3-year DSS P penile cancer (P < 0.001, Fig. 1B). Similarly to the CRP level,
(95% CI) in a Cox multivariate model that included the SCC-Ag level
Age at surgery (years), 50 (25–86) 0.275
and other risk factors, no factor retained statistical
median (range) significance as a prognostic indicator for penile cancer
≥50 n (%) 63 (50.8) 78.9 (66.9–90.9) (Table 3, model 2).
<50 n (%) 61 (49.2) 86.6 (75.4–97.8)
BMI (kg/m²), median 22.7 (13.6–36.7) 0.148 The CRP level was found to be negatively correlated with the
(range)
≥22.7 n (%) 62 (50.0) 84.6 (70.1–97.1)
SCC-Ag level (r2 = 0.193, P < 0.01). To examine our
<22.7 n (%) 62 (50.0) 80.6 (70.2–91.0) hypotheses (see Statistical Analyses), CRP and SCC-Ag levels
Smoking history, n (%) were combined as a single variable, and the patients were
Yes 74 (59.7) 80.2 (69.4–91.0) 0.277
No 50 (40.3) 86.4 (74.1–98.7)
divided into three groups for prognosis analysis using this
Phimosis, n (%) variable (no marker positive, one marker positive, and two
Yes 92 (74.2) 83.4 (74.8–92.0) 0.900 markers positive). A close association was observed between
No 32 (25.8) 80.1 (59.3–100.0)
LNM laterality, n (%)
the coexistence of a positive status for CRP and SCC-Ag and
Unilateral 35 (28.2) 83.2 (67.2–73.8) <0.001 LNM laterality (P = 0.041), ENE (P < 0.001), pelvic LNM (P
Bilateral 25 (20.2) 35.6 (2.7–68.5) = 0.024), pathological tumour status (P = 0.002), and
ENE, n (%)
Yes 30 (24.2) 40.8 (12.2–69.4) <0.001
pathological nodal status (P < 0.001; Table 4). When survival
No 94 (75.8) 94.1 (89.0–99.2) rates were compared, DSS in the positive CRP and SCC-Ag
Pelvic LNM, n (%) group was significantly reduced compared with the other two
Yes 16 (12.9) 73.1 (50.4–95.8) 0.076
No 108 (87.1) 84.2 (75.6–92.8)
groups (P < 0.001; Fig. 1C). In a multivariate analysis, the
Tumour stage, n (%) combination of positivity for CRP and SCC-Ag had a
≤T1 42 (33.9) 97.6 (92.9–100.0) 0.012 significant influence on DSS, with a high hazard ratio (hazard
T2 68 (54.8) 78.4 (66.8–90.0)
≥T3 14 (11.3) 51.1 (7.4–94.8)
ratio 3.39, 95% CI 1.104–10.411; P = 0.033) after adjusting
Tumour grade, n (%) for possible confounding variables (Table 3; model 3).
G1 79 (62.9) 89.6 (81.0–98.2) 0.008
G2 35 (28.2) 74.5 (56.1–92.9)
G3 10 (8.1) 58.3 (26.7–89.9)
Node status, n (%)
Discussion
N0 64 (51.6) 100.0 <0.001 Elevated CRP levels before surgery can serve as a diagnostic
N1 8 (6.5) 75.0 (45.0–100.0)
N2 15 (12.1) 93.3 (80.8–100.0)
marker and a marker of poor prognosis in penile cancer
N3 37 (29.8) 49.7 (27.6–71.8) [16,17]. Similarly, several studies have shown that SCC-Ag
CRP, n (%) level, which might also serve as a sensitive marker of disease
Negative: <4.5 mg/L 70 (56.5) 96.9 (92.8–100.0) <0.001
Positive: ≥4.5 mg/L 54 (43.5) 67.8 (53.5–82.1)
progression, is correlated with tumour burden in penile
SCC-Ag, n (%) cancer [19–21]. In the present study, we first show the
Negative: <1.4 g/mL 57 (46.0) 97.8 (93.5–100.0) <0.001 relationship between preoperative serum CRP and SCC-Ag
Positive: ≥1.4 g/mL 67 (54.0) 69.8 (55.9–83.7)
CRP and SCC-Ag*, n (%)
levels in penile SCC.
Score 1 45 (36.3) 100.0 <0.001
Score 2 37 (29.8) 90.6 (80.4–100.0)
C-reactive protein is an acute-phase reactant that responds to
Score 3 42 (33.9) 60.2 (42.4–78.0) the tumour microenvironment, causing tumour cell death and
local tissue damage [25], and high levels of this protein have
BMI, body mass index; CRP, C-reactive protein; DSS, disease-specific survival; ENE,
extranodal extension; LNM, lymph node metastases; SCC-Ag, squamous cell been linked to cancer risk and/or progression in various
carcinoma antigen. *CRP( ), SCC-Ag( ) = score 1; CRP(+), SCC-Ag( )/CRP( ), malignancies [13–15]. In the present study, elevated CRP
SCC-Ag(+) = score 2; CRP(+), SCC-Ag(+) =score 3.
levels were associated with progressive tumour characteristics,
including ENE (P < 0.001), pelvic LNM (P = 0.007),
pathological tumour status (P = 0.002), and pathological
cell differentiation, nodal status and CRP found no statistical
nodal status (P < 0.001; Table 2), consistent with several
significance for any of these factors as prognostic indicators
previous studies [16,17]. Because these pathological
for penile cancer (Table 3 ; model 1).
characteristics are of utmost prognostic importance in penile
An elevated level of SCC-Ag was also positively correlated carcinoma [1–3,22,23], an elevated CRP level may be
with ENE (P < 0.001), pathological tumour status (P = 0.001) predictive of more aggressive and progressive disease [16,17].
and pathological nodal status (P < 0.001); however, despite Furthermore, univariate analysis showed a significant
the fact that the positive SCC-Ag group had a higher correlation between the CRP level and DSS (P < 0.001,
incidence of pelvic LNM compared with the negative SCC-Ag Fig. 1A). Interestingly, when the level of CRP was included in
group (9.6 vs 3.2%; P = 0.071 [Table 2]), presurgical SCC-Ag a multivariate model with previously identified risk factors,

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Li et al.

Table 2 Associations between preoperative CRP and SCC-Ag levels and clinicopathological characteristics (n = 124).

Variable CRP SCC-Ag

Negative, n (%) Positive, n (%) P Negative, n (%) Positive, n (%) P

Age at surgery (years)

≥50 32 (25.8) 31 (25.0) 0.197 25 (20.2) 38 (30.6) 0.154
<50 38 (30.6) 23 (18.5) 32 (25.8) 29 (23.4)
BMI (kg/m²)
≥22.7 39 (31.5) 23 (18.5) 0.147 32 (25.8) 30 (24.2) 0.207
<22.7 31 (25.0) 31 (25.0) 25 (20.2) 37 (29.8)
Smoking history
Yes 40 (32.3) 34 (27.4) 0.512 35 (28.2) 39 (31.5) 0.718
No 30 (24.2) 20 (16.1) 22 (17.7) 28 (22.6)
Phimosis
Yes 52 (41.9) 40 (32.3) 0.979 41 (33.1) 51 (41.1) 0.595
No 18 (14.5) 14 (11.3) 16 (12.9) 16 (12.9)
LNM laterality
Unilateral 17 (13.7) 18 (14.5) 0.054 10 (8.1) 25 (20.2) 0.256
Bilateral 6 (4.8) 19 (15.3) 4 (3.2) 21 (16.9)
ENE
Yes 7 (5.6) 23 (18.5) <0.001 5 (4.0) 25 (20.2) <0.001
No 63 (50.8) 31 (25.0) 52 (41.9) 42 (33.9)
Pelvic LNM
Yes 4 (3.2) 12 (9.6) 0.007 4 (3.2) 12 (9.6) 0.071
No 66 (53.2) 42 (33.9) 53 (42.7) 55 (44.4)
Tumour stage
≤T1 32 (25.8) 10 (8.1) 0.002 29 (23.4) 13 (10.4) 0.001
T2 34 (27.4) 34 (27.4) 24 (19.4) 44 (35.5)
≥T3 4 (3.2) 10 (8.1) 4 (3.2) 10 (8.1)
Tumour grade
G1 48 (38.7) 31 (25.0) 0.358 40 (32.3) 39 (31.5) 0.262
G2 18 (14.5) 17 (13.7) 12 (9.7) 23 (18.5)
G3 4 (3.2) 6 (4.8) 5 (4.0) 5 (4.0)
Node status
N0 47 (37.9) 17 (13.7) <0.001 44 (35.5) 20 (16.1) <0.001
N1 4 (3.2) 4 (3.2) 1 (0.8) 7 (5.6)
N2 9 (7.3) 6 (4.8) 5 (4.0) 10 (8.1)
N3 10 (8.1) 27 (21.8) 7 (5.6) 30 (24.2)
CRP
Negative – – – 45 (36.3) 25 (20.2) 0.112
Positive – – 12 (9.7) 42 (33.9)

BMI, body mass index; CRP, C-reactive protein; ENE, extranodal extension; LNM, lymph node metastases; SCC-Ag, squamous cell carcinoma antigen.

none of those risk factors retained significance as an therapy and tumour prognosis. Univariate analysis in the
independent prognostic indicator for penile SCC (Table 3; present study also confirmed positive relationships between
model 1). This finding may be attributable to the following elevated SCC-Ag and ENE (P < 0.001), pathological tumour
factors: (i) the small sample size; (ii) the strong association status (P = 0.001), pathological nodal status (P < 0.001;
between CRP level and metastasis; and (iii) the fact that Table 2) and DSS (P < 0.001, Fig. 1B). SCC-Ag may promote
nodal disease was the only significant predictor of cancer- tumorigenesis by inhibiting apoptosis, promoting tumour cell
related death in the multivariate analyses [17]. We also survival, and increasing cell migration [30], and SCC-Ag may
acknowledge that the small sample size restricted the number accordingly play a role in tumour invasion and metastasis.
of variables in the multivariate analysis and the power of Unfortunately, SCC-Ag level did not retain significance as an
model comparison. The optimum cut-off for these predictors independent prognostic indicator of penile cancer in our
needs further evaluation in a large multicentre study. multivariate analysis (Table 3; model 2). This result may be
Accordingly, all of the analyses reported in the present paper attributed to the fact that the level of SCC-Ag does not have
may be considered exploratory rather than hypothesis-testing. sufficient sensitivity for the detection of tumours with a small
tumour burden and has minimal prognostic significance with
Squamous cell carcinoma antigen is a tumour-associated
regard to survival after surgery [19].
protein that was first identified in the cervix [26]. As an
increasing number of studies have since shown the clinical To the best of our knowledge, the present study is the first to
significance of SCC-Ag in human cancers [18,19,27–29], show the relationship between CRP and SCC-Ag levels and
serum SCC-Ag level is useful for evaluating response to penile SCC. Larger internal and external validation is

© 2015 The Authors

4 BJU International © 2015 BJU International
 Preoperative CRP and SCC antigen levels and penile cancer

Fig. 1 Kaplan–Meier estimates for disease-specific survival stratified by (A)

necessary to confirm the prognostic value of elevations in
C-reactive protein (CRP) level, (B) squamous cell carcinoma antigen
these levels. Furthermore, combined CRP and SCC-Ag level
(SCC-Ag) level and (C) CRP and SCC-Ag level.
measurement was more significantly correlated with clinical
A 100 status than either level alone. Indeed, positivity for increases
in both CRP and SCC-Ag levels had a profoundly significant
association with LNM laterality (P = 0.041), ENE (P < 0.001),
Disease Specific Survival (%)

80 pelvic LNM (P = 0.024), pathological tumour status (P =

0.002), pathological nodal status (P < 0.001) and poorer DSS
(P < 0.001) compared with positivity for one or neither of
60 those factors (Tables 1 and 4 and Fig. 1C). Interestingly, the
correlation of these two markers in combination with survival
was confirmed by multivariate analysis after adjusting for the
40 CRP(-) same factors (Table 3; model 3), indicating that the
CRP(+) combination of these two markers can serve as an
P<0.001 independent prognostic marker in patients with penile SCC.
20 Various studies have shown that para-carcinoma, carcinoma
and LNM tissues are generally accompanied by inflammation,
which promotes inflammatory cell infiltration and cytokine
production and results in increased CRP and SCC-Ag serum
0 12 24 36 48 60 72 84 96 108 120
levels; thus, accelerated tumour growth is associated with
Time(months)
elevated CRP and SCC-Ag levels [28,29]. Clinically, Huang
B 100
et al. [29] demonstrated that elevated SCC-Ag and CRP levels
are associated with a high metabolic rate as well as
Disease Specific Survival (%)

proliferative activity in oral SCC.

80
Radical surgery is curative in patients with penile SCC with
minimal metastases but represents overtreatment in >80% of
60 cases if applied unselectively to all patients [9]. Nonetheless,
SCC-Ag(-) the value of properly performed inguinal lymphadenectomy
SCC-Ag(+) in the treatment of penile cancer is undisputed. Because
40 P<0.001 classic molecular markers are not clinically useful in SCC of
the penis, in the present study we explored the use of the
combination of CRP and SCC-Ag levels as an independent
20
prognostic marker and a biomarker in penile SCC to stratify
patients for timely individualization of treatment without
overtreatment. Further analysis of the molecular mechanisms
0 12 24 36 48 60 72 84 96 108 120 of the observed interaction between CRP and SCC-Ag in
Time(months) penile SCC may help clarify the results of this study.
C 100
The present study has some limitations. First, the data
collection was retrospectively performed, and the follow-up
Disease Specific Survival (%)

period was relatively short, therefore, further research and

80
longer follow-up periods are required. Second, the diversity of
treatment in the present study, i.e. adjuvant therapy and
60 pelvic lymphadenectomy, may potentially affect other
variables. Pelvic lymphadenectomy was not routinely
performed before 2009 because it was not recommended by
Score1
40 Score2 the guidelines as standard treatment for penile cancer. In
Score3 addition, adjuvant therapies as well as the course of treatment
varied. Unfortunately, some patients who should have been
20 treated with adjuvant therapies declined to receive them. A
large proportion of Chinese patients present with advanced
cancer when they see a doctor, and these individuals are
0 12 24 36 48 60 72 84 96 108 120 typically poor and undereducated and live in outlying regions
Time(months) of major cities. The results of the present study may also be

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Li et al.

Table 3 Multivariate Cox regression model of prognostic covariates in 124 patients with penile squamous cell carcinoma.

Variable Multivariate analysis model 1 Multivariate analysis model 2 Multivariate analysis model 3

HR 95% CI P HR CI (95%) P HR CI (95%) P

Smoking history
No vs Yes 1.165 0.300–4.525 0.825 1.371 0.348–5.401 0.652 0.839 0.249–2.830 0.778
Phimosis
No vs Yes 0.586 0.141–2.434 0.959 0.622 0.173–2.228 0.465 0.967 0.269–3.476 0.959
Tumour stage
≤T1 vs T2 vs ≥T3 0.952 0.293–3.095 0.935 1.297 0.418–4.021 0.652 1.158 0.422–3.174 0.776
Tumour grade
G1 vs G2 vs G3 1.201 0.521–2.769 0668 2.239 0.963–5.209 0.061 1.898 0.914–3.942 0.086
Node status
N0 vs N1 vs N2 vs N3 2.109 0.960–4.632 0.063 1.503 0.583–3.879 0.399 2.370 1.139–4.930 0.021
CRP
Negative vs positive 8.416 0.976–72.583 0.053 — — — — — —
SCC-Ag
Negative vs positive — — — 4.564 0.583–35.755 0.148 — — —
CRP and SCC-Ag
Score 1 vs Score 2 vs Score 3 — — — — — — 3.390 1.104–10.411 0.033

CRP, C-reactive protein; HR, hazard ratio; SCC-Ag, squamous cell carcinoma antigen.

Table 4 Associations between preoperative C-reactive protein and

squamous cell carcinoma antigen levels and clinicopathological
affected by selection bias, which is inherent to retrospective
variables (n = 124). studies. Dynamic sentinel node biopsy has been suggested as
an alternative for low-risk patients in a few centres; however,
Variable Score 1*, Score 2*, Score 3*, P
n (%) n (%) n (%)
such multidisciplinary teamwork requires ultrasonography,
nuclear imaging, surgical exploration and meticulous
Age at surgery (years) pathological examination, which has limited its widespread
≥50 19 (15.3) 19 (15.3) 25 (20.2) 0.271
<50 26 (21.0) 18 (14.5) 17 (13.7)
use in developing countries such as China. Dynamic sentinel
BMI (kg/m²) node biopsy was therefore not considered in the present
≥22.7 27 (21.8) 17 (13.7) 18 (14.5) 0.748 study, potentially adding bias. Third, the correlation between
<22.7 18 (14.5) 20 (16.1) 24 (19.4)
Smoking history
CRP/SCC-Ag and recurrence rates should be assessed in
Yes 29 (23.4) 17 (13.7) 28 (22.6) 0.124 future research. Given that penile cancer is a relatively rare
No 16 (12.9) 20 (16.1) 14 (11.3) malignancy, the sample size of 124 is a fairly large cohort and
Phimosis
Yes 33 (26.6) 27 (21.8) 32 (25.8) 0.935
well reflects our intent. The limited number of patients and
No 12 (9.7) 10 (8.1) 10 (8.1) other limitations described above, however, also inhibited our
LNM laterality ability to perform multivariate analyses and to select patients
Unilateral 6 (4.8) 15 (12.1) 14 (11.3) 0.041
Bilateral 3 (2.4) 4 (3.2) 18 (14.5)
for inguinal lymph node dissection vs surveillance. For
ENE example, the inclusion of tioncancers as one group leads to
Yes 2 (1.6) 8 (6.5) 20 (16.1) <0.001 an inherent selection bias, and authors should consider
No 43 (34.7) 29 (23.4) 22 (17.7)
Pelvic LNM
subgrouping these patients. All analyses can be considered
Yes 2 (1.6) 4 (3.2) 10 (8.1) 0.024 exploratory rather than hypothesis-testing. Overall, the
No 43 (34.7) 33 (26.6) 32 (25.8) relevance of the markers examined in the present study and
Tumour stage
≤T1 26 (21.0) 9 (7.3) 7 (5.6) <0.001
their ultimate usefulness in patients should be validated
T2 18 (14.5) 22 (17.7) 28 (22.6) externally using larger, independent datasets.
≥T3 1 (0.8) 6 (4.8) 7 (5.6)
Tumour grade In conclusion, the present study showed that the combined
G1 33 (26.6) 22 (17.7) 24 (19.4) 0.183 measurement of both preoperative CRP and SCC-Ag levels
G2 8 (6.5) 14 (11.3) 13 (10.5)
G3 4 (3.2) 1 (0.8) 5 (4.0)
may serve as an independent biomarker for LNM, advanced
Node status tumour stage and DSS in patients with penile SCC. The
N0 37 (29.8) 17 (13.7) 10 (8.1) <0.001 optimum cut-off for these predictors requires further
N1 0 5 (4.0) 3 (2.4)
N2 4 (3.2) 6 (4.8) 5 (4.0)
evaluation in a large multicentre study, and the long-term
N3 4 (3.2) 9 (7.3) 24 (19.4) follow-up also needs external validation.
BMI, body mass index; CRP, C-reactive protein; ENE, extranodal extension; LNM,
lymph node metastases; SCC-Ag, squamous cell carcinoma antigen. *CRP( ), SCC-Ag Conflict of Interest
( ) = score 1; CRP(+), SCC-Ag( )/CRP( ), SCC-Ag(+) = score 2; CRP(+), SCC-Ag
(+) = score 3. None declared.

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 Preoperative CRP and SCC antigen levels and penile cancer

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