Obesity strongly predicts clinically undetected multiple lymph node metastases in intermediate- and high-risk prostate cancer patients who underwent robot assisted radical prostatectomy and extended lymph node dissection

Abstract

Objective
To evaluate the association between obesity and risk of multiple lymph node metastases in prostate cancer (PCa) patients with clinically localized EAU intermediate and high-risk classes staged by extended pelvic lymph-node dissection (ePLND) during robot assisted radical prostatectomy (RARP).Materials and methods373 consecutive PCa intermediate or high-risk patients were treated by RARP and ePLND. According to pathology results, extension of LNI was classified as absent (pN0 status) or present (pN1 status); pN1 was further categorized as one or more than one (multiple LNI) lymph node metastases. A logistic regression model (univariate and multivariate analysis) was used to evaluate the association between significant categorized clinical factors and the risk of multiple lymph nodes metastases.ResultsOverall, after surgery lymph node metastases were detected in 51 patients (13.7%) of whom 22 (5.9%) with more than one metastatic lymph node and 29 (7.8%) with only one positive node. Comparing patients with one positive node to those without, EAU high-risk class only predicted risk of single LNI (OR = 2.872; p = 0.008).The risk of multiple lymph node metastases, when compared to cases without LNI, was independently predicted by BMI ≥ 30 (OR = 6.950; p = 0.002) together with BPC ≥ 50% (OR = 3.910; p = 0.004) and EAU high-risk class (OR = 6.187; p < 0.0001). Among metastatic patients, BMI ≥ 30 was the only factor associated with the risk of multiple LNI (OR = 5.250; p = 0.041).Conclusions
In patients with clinically localized EAU intermediate and high-risk classes PCa who underwent RARP and ePLND, obesity was a risk factor of multiple LNI.

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International Urology and Nephrology
https://doi.org/10.1007/s11255-020-02554-3
UROLOGY - ORIGINAL PAPER
Obesity strongly predicts clinically undetected multiple lymph node
metastases inintermediate‑ andhigh‑risk prostate cancer patients
who underwent robot assisted radical prostatectomy andextended
lymph node dissection
AlessandroTafuri1,2,3· NeliaAmigoni1· RiccardoRizzetto1· MarcoSebben1· AliasgerShakir3· AlessandraGozzo1·
KatiaOdorizzi1· MarioDeMichele1· SebastianGallina1· AlbertoBianchi1· PaolaOrnaghi1· MatteoBrunelli4·
VincenzoDeMarco1· VittoreVerratti5· FilippoMigliorini1· MariaAngelaCerruto1· WalterArtibani1·
AlessandroAntonelli1· AntonioBenitoPorcaro1
Received: 6 April 2020 / Accepted: 22 June 2020
© Springer Nature B.V. 2020
Abstract
Objective To evaluate the association between obesity and risk of multiple lymph node metastases in prostate cancer (PCa)
patients with clinically localized EAU intermediate and high-risk classes staged by extended pelvic lymph-node dissection
(ePLND) during robot assisted radical prostatectomy (RARP).
Materials and methods 373 consecutive PCa intermediate or high-risk patients were treated by RARP and ePLND. Accord-
ing to pathology results, extension of LNI was classified as absent (pN0 status) or present (pN1 status); pN1 was further
categorized as one or more than one (multiple LNI) lymph node metastases. A logistic regression model (univariate and
multivariate analysis) was used to evaluate the association between significant categorized clinical factors and the risk of
multiple lymph nodes metastases.
Results Overall, after surgery lymph node metastases were detected in 51 patients (13.7%) of whom 22 (5.9%) with more
than one metastatic lymph node and 29 (7.8%) with only one positive node. Comparing patients with one positive node to
those without, EAU high-risk class only predicted risk of single LNI (OR = 2.872; p = 0.008).
The risk of multiple lymph node metastases, when compared to cases without LNI, was independently predicted by BMI ≥ 30
(OR = 6.950; p = 0.002) together with BPC ≥ 50% (OR = 3.910; p = 0.004) and EAU high-risk class (OR = 6.187; p < 0.0001).
Among metastatic patients, BMI ≥ 30 was the only factor associated with the risk of multiple LNI (OR = 5.250; p = 0.041).
Conclusions In patients with clinically localized EAU intermediate and high-risk classes PCa who underwent RARP and
ePLND, obesity was a risk factor of multiple LNI.
Keywords Obesity· Body mass index· Prostate cancer· Robot assisted radical prostatectomy· Lymph node-invasion
* Antonio Benito Porcaro
drporcaro@yahoo.com
1 Department ofUrology, University ofVerona, Azienda
Ospedaliera Universitaria Integrata Verona, Ospedale Civile
Maggiore, Polo Chirurgico Confortini, Piazzale Stefani 1,
37126Verona, Italy
2 Department ofNeuroscience, Imaging andClinical Sciences,
‟G. D’Annunzio″ University, Chieti-Pescara, Italy
3 USC Institute ofUrology andCatherine andJoseph Aresty
Department ofUrology, Keck School ofMedicine, University
ofSouthern California (USC), LosAngeles, CA, USA
4 Department ofPathology, University ofVerona, Azienda
Ospedaliera Universitaria Integrata Verona, Verona, Italy
5 Department ofPsychological, Health andTerritorial
Sciences, University “G. d’Annunzio” ofChieti-Pescara,
Chieti, Italy

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Introduction
Prostate cancer (PCa) is the second most common diagnosed
cancer in men, with an estimated 1.1million cases world-
wide in 2012, accounting for 15% of all cancers [1].
The European Association of Urology (EAU) has estab-
lished guidelines on localized and locally advanced PCa.
According to the risk of biochemical recurrence, they have
stratified the former into low, intermediate and high-risk
classes based on PSA, clinical TNM stage and International
Society of Urologic Pathology (ISUP) groups. The EAU fur-
ther stratified high risk PCa patients into an additional sub-
group with locally advanced disease that includes patients
with clinical extracapsular extension, seminal vesical inva-
sion, invasion of adjacent organs or lymph node invasion
(cT3 or cT4 or cN +) [2].
In the natural history of PCa, lymph node metastasis is a
crucial issue that needs to be recognized to make appropriate
recommendations for risk-adapted treatment [2]. Although
extended pelvic lymph node dissection (ePLND) was not
demonstrated to impact oncological outcomes, it is the
most accurate method to determine nodal disease stage [3],
and scientific societies recommend the use of nomograms
to individually assess patients as candidates for ePLND
during radical prostatectomy (RP) [2, 4]. In this context,
RP, and particularly, robot assisted radical prostatectomy
(RARP), has shown to be a valuable and safe approach and
has become the preferred surgical treatment for PCa in the
United States [5].
Several conditions can influence the natural history of
PCa and among these, obesity has been demonstrated to
have a pivotal role in PCa induction and progression. It can
influence the prostate microenvironment through local and
systemic effects resulting in increases in serum growth fac-
tors and pro-inflammatory cytokine levels as well as an alter-
ation in total testosterone (TT) serum levels [6]. Importantly,
over the past 30years, the prevalence of PCa has mirrored
the spread of obesity and metabolic syndrome [7], and many
studies have identified the direct association between them
and more aggressive PCa biology in terms of grade, stage,
presence of metastasis and PCa-related mortality [8].
The aim of this study is to evaluate associations between
obesity and risk of multiple, clinically undetected, lymph
node metastases in clinically localized intermediate and
high-risk PCa patients who underwent RARP and ePLND.
Materials andmethods
The study gained Institutional Review Board approval. It is
retrospective, but data were collected prospectively. Each
patient provided informed-signed consent for data collection.
Patients were categorized according to EAU PCa risk
classification [2]. Patients classified as low- and locally
advanced disease according to EAU system were excluded.
Only intermediate risk patients showing a probability of
lymph node invasion greater than 5% [2], and high-risk
classes (patients having clinically localized disease with-
out extra-prostatic extension) were entered into the study.
Among included population, none patient had clinically
detected LNI and none patient was under androgen depriva-
tion therapy.
In a period ranging from January 2014 to December 2018,
373 consecutive patients with intermediate or high EAU risk
classes treated by RARP and ePLND were selected.
Age (years), body mass index (BMI; kg/m2), prostate-
specific antigen (PSA; ng/mL), prostate volume (PV, mL)
and biopsy positive cores (BPC; percentage) were consid-
ered for each case.
Tumor, nodal and metastatic status was assessed accord-
ing to TNM system [2]. Pelvic lymph node staging (cN)
was performed by axial imaging modalities. Enlarged pelvic
nodes measuring more than 1 centimeter in diameter were
staged as cN1 disease. The metastatic status was investigated
by both axial imaging and total bone scans.
Experienced surgeons performed operations by the robot
assisted approach. RARP was delivered by the da Vinci
Robot System (Intuitive Surgical, Inc, Sunnyvale, CA, USA)
and was performed through the transperitoneal approach
with antegrade prostatic dissection. The lymph node dis-
section template included bilaterally external iliac (until the
crossing of the ureter and the external iliac artery), Clo-
quet’s, obturator and Marcille’s lymph node packets [9, 10].
Tumours were classified into grade groups according to
the ISUP tumor grade group system [11].
Surgical margins were considered positive when cancer
invaded the inked surface of the specimen. Nodal packets
were grouped according to a standard template and sub-
mitted in separate packages. In each case, the number of
removed lymph nodes and lymph node invasion (LNI) was
assessed. Prostate and nodal specimens were then staged
according to the TNM system.
According to pathology results, LNI was classified as
absent (pN0 status) or present (pN1 status). Patients having
LNI invasion were further classified as having only one or
more than one (multiple LNI) lymph node metastases.
Statistical analysis
Distribution of clinical and pathological factors was evalu-
ated among groups including patients without LNI, one posi-
tive node or more than one positive node.
Among clinical factors associated with the risk of LNI,
we did not consider PSA, ISUP grade group and tumor stage
because all these parameters are included through the EAU

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intermediate and high-risk groups, which were instead con-
sidered in the analysis.
Summary statistics and distributions of factors among
groups were assessed. Data on continuous variables are
reported as medians with interquartile (IQR) ranges. Data
on categorical variables are presented as frequencies and
percentages.
Associations of clinical factors between groups with
different levels of LNI (one positive node versus no LNI,
more than one positive node versus no LNI and more than
one metastatic node versus one LNI) were evaluated by the
Mann–Whitney test for continuous variables and by the Chi
squared test for categorical parameters as well as by Fisher’s
exact test, when appropriate. The logistic regression model
Table 1 Demographics of the patient population with clinically localized prostate cancer (PCA) undergoing extended pelvic lymph node dissec-
tion (ePLND) by the robot assisted approach
IQR interquartile range; EAU European Association of Urology; BMI body mass index; PSA prostate-specific antigen; PV prostate volume; BPC
biopsy positive cores; ISUP International Society of Urologic Pathology tumor grade classification of prostate cancer; cT TNM tumor clinical
stage; pT TNM tumor pathological stage; pN TNM pathological stage of dissected lymph nodes
Factors Population EAU intermediate risk class EAU high risk class p value
Number (%) 373 275 (73.7) 98 (26.3)
Clinical factors
Age (years); median (IQR) 65 (61–70) 65 (60–69) 66.5 (61–71) 0.091
BMI (kg/m2); median (IQR) 25.7 (23.7–27.8) 25.6 (23.5–27.7) 25.8 (23.8–28.6) 0.228
PSA (ng/mL); median (IQR) 7 (5.1–10) 6.5 (5–9) 8.1 (6.1–20.2) < 0.0001
PV (mL); median (IQR) 40 (31–51.5) 40 (30–50) 42 (32.2–56.2) 0.124
BPC (%); median (IQR) 38 (25–57) 36 (22–54) 46 (26.5–67.7) 0.040
ISUP; n (%)
1 35 (9.4) 30 (10.9) 5 (5.1) < 0.0001
2 170 (45.6) 161 (58.5) 9 (9.2)
3 89 (23.9) 84 (30.5) 5 (5.1)
4 64 (17.2) 0 (0) 64 (65.3)
5 15 (4) 0 (0) 15 (15.3)
cT; n (%)
1 225 (60.3) 178 (64.7) 47 (48) 0.004
2 148 (39.7) 97 (35.3) 51 (52)
pathological factors
Dissected nodes (number) 26 (21–33) 26 (21–32) 25.5 (20.7–33.2) 0.001
ISUP; n (%)
1 10 (2.7) 8 (2.9) 2 (2) < 0.0001
2 113 (30.3) 104 (37.8) 9 (9.2)
3 126 (33.8) 110 (40) 16 (16.3)
4 87 (23.3) 45 (16.4) 42 (42.9)
5 37 (9.9) 8 (2.9) 29 (29.6)
pT; n (%)
pT2 260 (69.7) 213 (77.5) 47 (48) < 0.0001
pT3a 46 (12.3) 30 (10.9) 16 (16.3)
pT3b 67 (18) 32 (11.6) 35 (35.7)
Surgical margin; n (%)
Negative 260 (69.7) 202 (73.5) 58 (59.2) 0.008
Positive 113 (30.3) 73 (26.5) 40 (40.8)
pN; n (%)
pN0 322 (86.3) 251 (91.3) 71 (72.4) < 0.0001
pN1 51 (13.7) 24 (8.7) 27 (27.6)
Number of positive nodes; n (%)
Zero 322 (86.3) 251 (91.3) 71 (72.4) < 0.0001
One 29 (7.8) 16 (5.8) 13 (13.3)
More than one 22 (5.9) 8 (2.9) 14 (14.3)

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(univariate and multivariate analysis) evaluated the associa-
tion of significant categorized clinical factors with the risk
of multiple lymph node metastases.
The software used to run the analysis was IBM-SPSS ver-
sion 20 (All tests were two-sided with p < 0.05 considered
to indicate statistical significance.
Results
The distribution of factors in the patient population and
EAU risk groups is summarized in Table1.
Overall, 275 out of 373 patients were intermediate
EAU risk class (73.7%) and 98 (26.3%) belonged to the
high-risk group. BPC, which was higher in the high EAU
risk class, was a factor differentiating the two groups
(p = 0.04).
Considering pathological factors, the high-risk class
showed features of more aggressive cancer when compared
to the intermediate risk group, as expected. In particular,
patients belonging to the high-risk class showed higher rates
of high-grade cancers, invasion of seminal vesicles and posi-
tive surgical margins, as shown in the Table1.
In the patient population, the median number of dissected
nodes was 26 and did not significantly differ between groups.
The incidence of LNI was significantly higher in the high-
risk (27.6%) compared to the intermediate risk group (8.7%,
p < 0.0001). The distribution of multiple metastases was sig-
nificantly higher in the high-risk class (14.3%) compared to
the intermediate EAU risk group (2.9%, p < 0.0001).
Table2 illustrates the distribution of factors among LNI
groups in the patient population: group A, no LNI; group B,
one LNI; group C, more than one LNI).
Overall, lymph node metastases were detected in the sur-
gical specimen in 51 patients (13.7%) of whom 29 (7.8%
group C) with only 1 positive node, and 22 (5.9%, group C)
with more than 1 metastatic lymph node.
Considering clinical factors, tumor stage, ISUP grade
group and EAU high-risk class showed significant positive
associations with patients having one metastatic node when
compared to negative cases. Patients presenting with more
than one metastatic node showed significant positive asso-
ciations with BMI, PSA, BPC and EAU high-risk class when
compared to subjects without LNI.
As illustrated in Table2, in the surgical specimen,
patients with multiple lymph node invasion harbored more
aggressive cancers for grade and stage when compared to
cases without LNI (see Table2). When looking at cases with
LNI, BMI was the only factor that was positively associ-
ated with multiple lymph node metastases compared with
patients with only one lymph node metastasis (p = 0.022).
Considering clinical factors associated with the risk of
LNI, we evaluated EAU risk classes, BMI and BPC.
Continuous variables were categorized; as such, BMI
was classified according to the recommended WHO catego-
ries (< 25, ≥ 25 and < 30, ≥ 30 kg/m2, considering “obese”
patients with a BMI ≥ 30) [7] and BPC to 50% (< 50%
and ≥ 50%), as recommended by PCa guidelines [2, 4].
Results are depicted in Table3.
Comparing patients with one positive node to those with-
out LNI in univariate analysis, EAU high-risk class was the
only factor that predicted the risk of single LNI (OR = 2.872;
95% CI 1.320–6.252; p = 0.008). The risk of multiple lymph
node metastases, when compared to cases without LNI,
was independently predicted by BMI ≥ 30 (OR = 6.950;
95% CI 2.057–23.478; p = 0.002) as well as BPC ≥ 50%.
(OR = 3.919; 95% CI 1.549–9.867) and EAU high-risk class
(OR = 6.187; 95% CI 2.496–15.335 p = < 0.0001). Among
metastatic patients, BMI ≥ 30 was the only factor that associ-
ated with the risk of occult multiple LNI (OR = 5.250; 95 CI
1.069–25.789; p = 0,041).
In multivariate analysis, BMI ≥ 30 (OR 6.372; 95% CI
1.734–23.519, p = 0.005), BPC ≥ 50% (OR 6.372, 95% CI
1.41–7.948, p = 0.026), and EAU high-risk class (OR 5.854;
95% CI, 2.258–15.157, p < 0.0001) were predictors of mul-
tiple LNI, when compared with patients without LNI, as
detailed in Table3.
Furthermore, we evaluate the associations of clinical
factors with the risk of multiple lymph node metastases in
patients presenting with clinically localized PCa includ-
ing EAU intermediate and high-risk classes. Results with
adjusted odds ratios are detailed in Table4. The risk of
detecting multiple lymph node metastases, when com-
pared to cases without LNI, was independently predicted
by obesity (BMI ≥ 30, adjusted OR = 5.118; 95% CI
1.746–15.001) as well as BPC ≥ 50% (OR = 3.087; 95% CI
1.174–8.119) and EAU high-risk class (OR = 5.966; 95%
CI 2.310–15.409).
Obese patients, who comprised 11.2% of the population,
had a five-fold risk of harboring multiple lymph node metas-
tases compared to subjects who were not obese.
In our cohort, 30% of patients (n = 112) had complica-
tions. Among these, 88% (n = 99) had Clavien-Dindo grade
1–2 complications, 6% (n = 7) had grade 3a, 4% (n = 5) had
grade 3b and one patient had 4a complication. Overall, four
patients had lymphoceles treated with percutaneous drain-
age (grade 3a).
Discussion
Clinical under staging of pelvic lymph nodes is a critical
issue that is far to be solved by actual imaging modalities. In
the last few years, novel imaging tools have been introduced
in clinical practice to perform accurate pre-operative PCa
staging. Among these, 68Ga -prostate-specific membrane

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antigen (PSMA) positron-emission tomography (PET)/CT
is increasingly used with promising results [12]. In a recent
study including 103 high-risk LNI PCa patients, 68Ga
-PET-PSMA was performed in 97 patients prior to RP and
ePLND and showed high specificity (90.9%) and moder-
ate sensitivity (42.3%) [13]. Although this, when clinically
Table 2 Factors associated with occult lymph node invasion (LNI) in clinically localized prostate cancer (PCA) including intermediate and high
EAU risk classes that have been staged by robot assisted extended pelvic lymph node dissection (ePLND)
IQR interquartile range; EAU European Association of Urology; BMI body mass index; PV prostate volume; ISUP International Society of Uro-
logic Pathology tumor grade system; PSA prostate-specific antigen; PV prostate volume; BPC biopsy positive cores; EAU European Association
of Urology risk-group classification
Factors No LNI (group A) LNI with one
positive node
(group B)
LNI with more than
one positive node
(group C)
B vs A (p value) C vs A (p value) C vs B (p value)
Number (%) 322 (86.3) 29 (7.8) 22 (5.9)
Clinical factors
Age (years); median
(IQR)
65 (60–70) 67 (62–72) 64.5 (60–69.2) 0.153 0.814 0.238
BMI (kg/m2); median
(IQR)
25.7 (23.7–27.8) 24.9 (23.8–26.8) 28.1 (25.1–31) 0.661 0.009 0.022
PSA (ng/mL); median
(IQR)
6.9 (5.1–9.6) 7.2 (5.3–11.2) 12.9 (5.1–22.5) 0.355 0.009 0.104
PV (mL); median
(IQR)
40 (30–50) 50 (31.5–64.4) 42 (38–55.2) 0.086 0.132 0.588
BPC (%); median
(IQR)
35.5 (21–53) 50 (27–73) 57 (41.7–74.7) 0.057 < 0.0001 0.159
ISUP; n (%)
1 29 (99) 3 (10.3) 3 (13.6) 0.005 < 0.0001 0.513
2 157 (48.8) 9 (31) 4 (18.2)
3 81 (25.2) 6 (20.7) 2 (9.1)
4 48 (14.9) 7 (24.1) 9 (40.9)
5 7 (2.2) 4 (13.8) 4 (18.2)
Tumor clinical stage (cT); n (%)
cT1 201 (62.4) 12 (41.4) 12 (54.5) 0.026 0.462 0.351
cT2 121 (37.6) 17 (58.6) 10 (45.5)
EAU risk class; n (%)
Intermediate 251 (78) 16 (55.2) 8 (36.4) 0.006 < 0.0001 0.183
High 71 (22) 13 (44.8) 14 (63.6)
Pathological factors
Dissected nodes
(number); median
(IQR)
26 (21–32.2) 28 (22.5–36) 30.5 (22.2–33.5) 0.168 0.353 0.782
ISUP; n (%)
1 10 (13.1) 0 (0.0) 0 (0.0) < 0.0001 < 0.0001 0.520
2 111 (34.5) 2 (6.9) 0 (0.0)
3 117 (36.3) 6 (20.7) 3 (13.6)
4 65 (20.2) 12 (41.4) 10 (45.5)
5 19 (5.9) 9 (31) 9 (40.9)
Tumor stage (pT); n (%)
pT2 247 (76.7) 10 (34.5) 3 (13.6) < 0.0001 < 0.0001 0.160
pT3a 40 (12.4) 4 (13.8) 2 (9.1)
pT3b 35 (10.9) 15 (51.7) 17 (77.3)
Surgical margins; n (%)
Negative 233 (72.4) 14 (48.3) 13 (59.1) 0.007 0.182 0.443
Positive 98 (27.6) 15 (51.7) 9 (40.9)

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localized PCa is diagnosed, scientific societies recommend
performing an ePLND according to a well-defined tem-
plate, to have an appropriate nodal stage, if specific nomo-
grams indicate a high probability of having LNI. Extended
PLND can be performed using the different approaches,
which include open, laparoscopic and robot assisted tech-
niques which are equally recommended by scientific socie-
ties’ guidelines [2, 4]. Specifically, in the last few decades,
RARP has shown to be a valuable and safe approach and
has become the preferred PCa surgical treatment in the
Table 3 Categorized clinical factors associated with the risk of occult lymph node invasion including cases with one or more than onemetastatic
node in patients with clinically localized prostate cancer (PCA) staged by robot assisted extended pelvic lymph node dissection (ePLND)
OR odds ratio; CI confidence interval; BMI body mass index; BPC biopsy positive cores; EAU European Association of Urology
Statistics One positive node versus no LNI More than one postive node versus no
LNI
More than one positive node versus
one positive node
OR (95% CI) p value OR (95% CI) p value OR (95% CI) p value
Univariate analysis
BMI
 < 25 1 1 1
 ≥ 25 BMI < 30 0.598 (0.260–1.374) 0.226 1.794 (0.598–5.376) 0.297 3.000 (0.786–11.445) 0.108
 ≥ 30 1.324 (0.409–4.288) 0.640 6.950 (2.057–23.478) 0.002 5.250 (1.069–25.789) 0.041
BPC
 < 50% 1 1 1
 ≥ 50% 1.955 (0.911–4.194) 0.085 3.910 (1.549–9.867) 0.004 2.000 (0.30–6.352) 0.240
EAU risk class
 > Intermediate 1 1 1
 > high 2.872 (1.320–6.252) 0.008 6.187 (2.496–15.335) < 0.0001 2.154 (0.692–6.707) 0.186
Multivariate analysis
BMI
 < 25 1
 ≥ 25 BMI < 30 1.408 (0.454–4.371) 0.554
 ≥ 30 6.372 (1.734–23.419) 0.005
BPC
 < 50% 1
 ≥ 50% 3.011 (1.141–7.948) 0.026
EAU risk class
> Intermediate 1
 > High 5.854 (2.258–15.175) < 0.0001
Table 4 Categorized clinical
factors associated with the
risk of occult multiple lymph
node metastases of pelvic
nodes staged by robot assisted
extended pelvic lymph node
dissection (ePLND) in clinically
localized prostate cancer (PCA)
witout extra-prostatic extension
and including intermediate and
high EAU risk classes
OR odds ratio; CI confidence interval; BMI body mass index; BPC biopsy positive cores; EAU European
Association of Urology
Overall population Group without LNI Group with
multiple LNI
OR (95% CI)
Number (%) 344 322 (93.6) 22 (6.4)
BMI
 < 30 309 (89.8) 294 (95.1) 15 (4.9) 1
 ≥ 30 35 (11.2) 28 (80) 7 (20) 5.118 (1.746–15.001)
BPC
 < 50% 215 (62.5) 208 (96.7) 7 (3.3) 1
 ≥ 50% 129 (37.5) 114 (88.4) 15 (11.6) 3.087 (1.174–8.119)
EAU risk class
Intermediate 259 (75.3) 251 (96.9) 8 (3.1) 1
High 85 (24.7) 71 (83.6) 14 (16.4) 5.966 (2.310–15.409)

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United States [5]. Level I evidences suggest that the robotic
approach has improved operative time, length of stay, intra-
operative adverse events, pain relief and lymph node yield
as well as a lower rate of short and long-term hospital read-
mission compared to open approach [14, 15]. Additionally,
RARP accelerates postoperative patient’s stress recovery
[16].
Anatomical evidence demonstrated that approximately 20
pelvic lymph nodes may be adequate during ePLND [17].
In patients with suspected nodal invasion, the incidence of
LNI with more than one positive node is 46.2% compared to
cases with only one positive node (53.8%) [18]. Retrospec-
tive studies have demonstrated that the number of positive
nodes predicted cancer-specific survival in PCa patients, and
it seems that patients ≤ 2 positive nodes will have better sur-
vival compared to cases with more than two positive lymph
nodes [19–21].
In the present study, we found that in patients with clini-
cally localized intermediate- and high-risk PCa accord-
ing to EAU classification, the incidence of multiple LNI
after RARP and concomitant ePLND was around 43.1% of
pN + cohort. This is an important issue to consider during
patients’ management in daily clinical practice.
Obesity andaggressive prostate cancer
biology
Obesity is becoming a critical health issue because it has
been implicated in the natural history of aggressive PCa.
Indeed, over the last 30years, the prevalence of PCa has
mirrored the increase in obesity and metabolic syndrome [7].
For this reason, several studies have evaluated the relation-
ship between visceral obesity (estimated through BMI) and
PCa outcomes. De Nunzio etal. found that obesity was asso-
ciated with high-grade diseaseat the time of biopsy [22].
Kelly etal. suggested that increasing BMI during adulthood
results in an increased risk of fatalPCa [23]. Jentzmik etal.
reported that obesity, was significantly associated with high-
grade and metastatic PCa. However, low levels of serum
testosterone were not found to be associated with PCa [24].
Freedland etal. found that higher BMI was associated with
biochemical recurrence after radical prostatectomy [25]. In a
recent meta-analysis, Gacci etal. demonstrated that the pres-
ence of metabolic syndrome predicts aggressive PCa and
biochemical recurrence after treatment [26], and diabetes
mellitus has been associated with short PSA doubling time
after radical prostatectomy [27].
Further, we recently have shown that increased BMI pre-
dicts the risk of high-grade complications after RARP and
ePLND [28].
The influence of obesity on PCa would be mainly
explained by environmental determinants of BMI, rather
than genetically elevated BMI. It may be explained by
biological and hormonal changes associated with obesity
which impact the disease oncogenesis and natural history
[2, 29]. Indeed, it is known that visceral obesity can have
local and systemic effects on cancer induction and progres-
sion through dyslipidemia, deregulation of the insulin/IGF-1
axis, and increased serum concentrations of inflammatory
factors and leptin [6].
The association of obesity with aggressive disease may be
explained by hormonal, dietary and life-style factors. Bio-
logical and hormonal changes associated with obesity may
impact the oncogenesis of the disease.
It is known that visceral obesity can have local and sys-
temic effects on cancer induction and progression through
dyslipidemia, deregulation of the insulin/IGF-1 axis, and
increased serum concentrations of inflammatory factors and
leptin. The association of BMI with aggressive prostate can-
cer might be related to low total testosterone levels, due to
the increased aromatization of androgen hormones which
have been demonstrated in obese patients [30]. In theory,
low testosterone levels in the prostate microenvironment
may trigger intracellular and extracellular molecular path-
way disturbances and subsequently cause intracellular stress
and DNA damage [31, 32]. Collectively, these mechanisms
may generate cancer induction and increased PCa aggres-
siveness and progression. As a result, prostate tumors in
obese men may grow and progress faster than non-obese
cases [30, 33].
In the present study, BMI emerged as an independent pre-
dictor of multiple lymph node metastases compared to cases
without; moreover, among metastatic patients, BMI was the
only factor that predicted the risk of multiple LNI compared
to cases having only one metastatic node. Specifically, obese
patients showed a five-fold increased risk of harboring mul-
tiple LNI when compared to non-obese patients.
Another study has shown that obesity was a risk factor
of aggressive PCa in clinically localized disease; however,
it differed from our investigation for several features [24].
First, it did not report the number of patients included in
each of the EAU risk classes. Second, the extent of lymph
node dissection as well the number of removed nodes was
not evaluated. Third, the association of obesity with the risk
of multiple lymph node metastases was not assessed.
Additionally, Pfitzernmaier etal. have found that in
620PCa patients BMI was not a predictor of adverse prog-
nosis after radical prostatectomy. Particularly, the frequency
of positive lymph nodes was not different between normal
weight, overweight and obese patients (p = 0.58). In that
study, the authors did not specify the surgical approach, the
number of dissected nodes, as well as the adopted template
[34]. For this reason, it cannot be compared to the current
study.

International Urology and Nephrology
1 3
To the best of our knowledge, this is the first study
showing that, in patients presenting with clinically local-
ized intermediate- high risk-PCa undergoing robot assisted
radical prostatectomy and ePLND, obesity is a risk factor
of upstaging.
Implications ofthestudy inclinical practice
According to our findings, patients with clinically local-
ized EAU intermediate and high-risk classes PCa have an
elevated risk of harboring multiple LNI that are missed by
imaging staging systems. Beyond well-known parameters
defining EAU risk classes (PSA, cT, ISUP grade group),
we have shown that obesity is an additional risk factor
for multiple nodal metastases when patients presenting
with clinically localized PCa are treated with radical pros-
tatectomy and ePLND. Also, when patients are catego-
rized according to WHO categories, obese patients are
more likely to have multiple lymph node metastases when
compared to normal or over-weight patients. As a conse-
quence, obese patients belonging to the intermediate EAU
risk class presenting with a risk of LNI less than 5% need
careful counseling before undergoing surgery because of
the risk of multiple metastases will remain undetected if
appropriate ePLND is not planned at time of surgery.
On the other, radiation oncologists, who may deliver
active treatment to these patients, should also consider
this adjunctive clinical risk factor that will help in mak-
ing clinical decisions if radiation of the pelvis should be
considered with or without androgen blockade.
Additionally, when active surveillance is recommended
for obese patients in the intermediate EAU risk category,
an even more close follow-up protocol should be consid-
ered because of the high risk of aggressive PCa. Further-
more, dietary preventive measures should be undertaken
in obese patients diagnosed with PCa under active sur-
veillance. More generally, appropriate behavioral dietary
habits might prevent obesity thus reducing the risk of
developing aggressive PCa.
Based on these evidences, BMI should be included in
the risk calculators to identify patients with increased risk
of LNI.
According to our findings, higher level studies are
required for investigating BMI risk calculators to identify
patients with increased risk of LNI.
Strengths andlimits ofthestudy
Our study has many strengths. First, it is a single institu-
tional study including a contemporary cohort of Caucasian
Italian males undergoing surgical staging with ePLND by
robot assisted approach. Second, the population is contem-
porary, large and represent specific categories of the EAU
risk group system presenting with clinically localized
PCa without extra-prostatic extension. Third, we excluded
patients who under androgen blockade. Fourth, data were
collected prospectively.
Our study has also limitations. First, although data was
prospectively collected, it was analyzed retrospectively.
Second, prostate volumes and biopsies performed else-
where were not re-evaluated; however, inclusion criteria
allowed a robust analysis. Third, several surgeons per-
formed ePLND by the robot assisted approach; however,
each surgeon was otherwise experienced and skilled in
performing the technique.
Conclusions
In patients with clinically localized EAU intermediate and
high-risk classes PCa who underwent RARP and ePLND
obesity was a risk factor of multiple LNI. These patients
need careful counseling before making management deci-
sions. BMI should be included in the LNI risk calculators.
Funding The authors did not receive financial support.
Compliance with ethical standards
Conflict of interest The authors declare that they have no conflict of
interest.
Ethical approval All procedures performed in studies involving human
participants were in accordance with the ethical standards of the insti-
tutional and/or national research committee and with the 1964 Helsinki
declaration and its later amendments or comparable ethical standards.
Informed consent Informed consent was obtained from all individual
participants included in the study.
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