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Annales d’Endocrinologie 79 (2017) 53–61

Original article

Predictive factors of endocrine and exocrine insufficiency after resection of a

benign tumour of the pancreas
Facteurs prédictifs d’insuffisance pancréatique endocrine et exocrine après résection d’une tumeur
bénigne du pancréas
Hélène Neophytou a,∗ , Marc Wangermez b , Elise Gand c , Michel Carretier a , Jérôme Danion a ,
Jean-Pierre Richer a
a CHU de Poitiers, service de chirurgie viscérale, 2, rue de la Milétrie, 86000 Poitiers, France
b CHU de Poitiers, service d’hépato-gastro-entérologie et assistance nutritive, Poitiers, France
c CHU de Poitiers, pôle DUNE, Poitiers, France

Abstract
Background. – The aim of the present study is to evaluate the risk factors of endocrine and exocrine insufficiency occurring few years after
pancreatic resections in a consecutive series of patients who underwent pancreatoduodenectomy (PD), left pancreatectomy (LP) or enucleation for
benign neoplasms at a referral centre. Methods. – Pancreatic exocrine insufficiency (PEI) was defined by the onset of steatorrhea associated with
weight loss, and endocrine insufficiency was determinate by fasting plasma glucose. Association between pancreatic insufficiency and clinical,
pathological, and perioperative features was studied using univariate and multivariate Cox regression analysis. Results. – A prospective cohort of
92 patients underwent PD (48%), LP (44%) or enucleation (8%) for benign tumours, from 2005 to 2016 in the University Hospital in Poitiers
(France). The median follow-up was 68.6 ± 42.4 months. During the following, 54 patients developed exocrine insufficiency whereas 32 patients
presented endocrine insufficiency. In the Cox model, a BMI > 28 kg/m2 , being a man and presenting a metabolic syndrome were significantly
associated with a higher risk to develop postoperative diabetes. The risks factors for the occurrence of PEI were preoperative chronic pancreatitis,
a BMI < 18.5 kg/m2 , tumours located in the pancreatic head, biological markers of chronic obstruction and fibrotic pancreas. Undergoing LP or
enucleation were protective factors of PEI. Histological categories such as neuroendocrine tumours and cystadenomas were also associated with
a decreased incidence of PEI. Conclusion. – Men with metabolic syndrome and obesity should be closely followed-up for diabetes, and patients
with obstructive tumours, pancreatic fibrosis or chronic pancreatitis require a vigilant follow up on their pancreatic exocrine function.
© 2017 Elsevier Masson SAS. All rights reserved.

Keywords: Benign; Endocrine; Exocrine; Insufficiency; Surgery; Pancreas

Résumé
Introduction. – Le but de cette étude est d’évaluer les facteurs de risques d’insuffisance pancréatique endocrine et exocrine persistantes à long terme
après résection du parenchyme pancréatique dans une série consécutive de patients chez qui ont été pratiqué une duodénopancréatectomie céphalique
(DPC), une splénopancréatectomie gauche (SPG) ou une énucléation dans un centre de référence et pour lesquels l’anatomopathologie objectivait
une tumeur bénigne du pancréas. Méthodes. – L’insuffisance pancréatique exocrine (IPE) était définie par l’apparition de stéatorrhée, d’une
malabsorption associée à une perte de poids significative nécessitant une supplémentation enzymatique. L’insuffisance pancréatique endocrine
était déterminée par une glycémie à jeûn au-delà de 1,26 g/L associée à la nécessité d’un régime pauvre en hydrates de carbone. L’analyse
en régression statistique univariée et multivariée de Cox teste l’association entre insuffisance pancréatique et critères cliniques, biologiques et
anatomopathologiques. Résultats. – Une cohorte prospective de 92 patients suivis de 2005 à 2016 au centre hospitalier universitaire de Poitiers
(France) montre que 48 % des patients ont eu une DPC, 44 % une SPG, 8 % une énucléation dans le cadre de tumeurs bénignes. La médiane
de suivi est de 68,6 mois ± 42,4 mois. Cinquante-quatre patients ont développé une IPE et 32 ont présenté un diabète. Dans le modèle de Cox,
un IMC > 28 kg/m2 , être un homme et présenter un syndrome métabolique était significativement associé à la survenue de diabète. Les facteurs

∗ Corresponding author.
E-mail address: helene.neophytou@gmail.com (H. Neophytou).

https://doi.org/10.1016/j.ando.2017.10.003
0003-4266/© 2017 Elsevier Masson SAS. All rights reserved.
54 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61

de risques favorisant l’apparition d’IPE étaient un IMC < 18,5 kg/m2 avec une albumine < 35 g/L, une pancréatite chronique préopératoire, des
marqueurs biologiques d’obstruction biliaire, une tumeur localisée dans la tête du pancréas, et une fibrose pancréatique. Bénéficier d’une chirurgie
pancréatique par SPG ou d’une énucléation étaient des facteurs protecteurs d’IPE. Les types histologiques tels que les tumeurs neuroendocrines
de bas grade et les cystadénomes étaient également associés à moins d’IPE. Conclusion. – Les patients obèses, masculins, avec un syndrome
métabolique doivent être suivis de manière rapprochée à la recherche d’un diabète, tandis que les patients dénutris, porteurs de tumeurs obstruant
la voie biliaire, avec une fibrose pancréatique ou une pancréatite chronique nécessitent un suivi sur le long terme de survenue d’IPE.
© 2017 Elsevier Masson SAS. Tous droits réservés.

Mots clés : Bénin ; Endocrine ; Exocrine ; Insuffisance ; Pancréas ; Chirurgie

1. Abbreviations describe a lower incidence of diabetes and exocrine insuffi-

ciency after segmental resections in a limited number of patients
[28]. The pancreatic function is affected by several factors, and
ALP alkaline phosphatase according to actual literature, the type of surgery is the most
BMI body mass index important [22,29,30]. Others parameters can contribute to the
CI confidence interval development of long-term endocrine and exocrine insufficiency,
GGT gamma-glutamyl transferase such as recognized risks factors for diabetes [31,32], preexis-
HR hazard ratio ting chronic pancreatitis [26] and chronic obstruction leading to
IPMN intraductal papillary mucinous neoplasm fibrosis [18,33].
ISGSP International Study Group of Pancreatic Surgery The aim of the present study is to assess the risk factors for
LP left pancreatectomy long-term endocrine and exocrine insufficiency after pancreatic
PD pancreatoduodenectomy resections (PD, LP and enucleation) for benign tumours in a
PEI pancreatic exocrine insufficiency referral centre.
SD standard deviation

2. Introduction 3. Methods

In recent times, the indications for pancreatic resection of
benign tumours have increased [1,2]. Pancreatoduodenectomy
(PD) and left pancreatectomy (LP) have become standard safe
operations for these diseases: operative morbidity and mortality
(3% for PD and 1% for LP) have decreased to an acceptable
level in high-volume centers of pancreatic surgery [3,4]. Due to
the improvement of surgical technique, as well as a better selec-
tion of patients and perioperative care, pancreatic resection can
be performed safely with a morbidity rate of 27–46% for LP
and around 40% for PD [5–7]. Because long-term survival after
these pancreatic resections has improved, postoperative out-
comes such as pancreatic insufficiency have become important
to study [8–10]. In fact, this complication can lead to malnutri-
tion, maldigestion, nutritional deficiencies and affects the quality
of life [10–15].
Parenchymal-preserving resections such as enucleation aim
at reducing pancreatic insufficiency: depending on the size and
site of the neoplasm, they can be the procedure of choice [16,17].
Many studies analyse these two events in the short postopera-
tive term, but very few report the long-term outcomes pancreatic
resections for benign tumours given that the mean follow-up
published are 30 days [18], 24 months [19] and 48 months [10].
Indeed, pancreatic exocrine insufficiency (PEI) affects 56–78%
patients undergoing PD, and 27.5%–63% following LP accord-
ing to recent published data [10,18]. Shortly after PD, 8–23%
of patients develop pancreatogenic diabetes, which increases to
40–50% during follow-up [20–22]. Six months after LP, the new
onset of diabetes is 12% for benign lesion [23–27]. Authors
In the University Hospital in Poitiers (France), patients under-
going pancreatic resection for benign tumours from 2005 to 2016
were enrolled in the study.
The choice of the surgical procedure between PD, LP and
enucleation was based on its location and size. Especially, enu-
cleation was performed for small tumours located farther than
20 mm from Wirsung’s duct.
Demographic, histopathologic, biochemical [34], opera-
tive, perioperative, and follow-up data were collected. The
metabolic syndrome was defined by the association of 3
criterias among 4 based on National Cholesterol Education
Program Adult Treatment of USA: measure of waist more
than 102 cm for men and 88 cm for women, dyslipidemia
(HDL-cholesterol < 1.04 mmol/L for men and < 1.29 mmol/L
for women or hypertriglycerydemia > 1.5 g/L), hypertension.
Peroperatively after the Whipple procedure, a pancreatico-
gastrostomy or a pancreaticojejunostomy was performed. The
pancreatic stump was either stapled or hand-sewn after LP. The
duration of surgery was recorded.
Postoperative complications were found in the medical record
and classed as cardiopulmonary diseases, gastroparesis, abdom-
inal sepsis, digestive or abdominal haemorrhage and pancreatic
fistula. According to the broad definition of IGSPS, pancreatic
fistula were diagnosed with the following criteria: output via an
operatively placed drain (or a subsequently placed, percutaneous
drain) of any measurable volume of drain fluid on or after post-
operative day 3, with an amylase content greater than 3 times
the upper normal serum value [38].
 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61
The follow-up evaluating the pancreatic function were per-
formed forty days after the procedure, every six months and
annually thereafter. Weight, maldigestion, denutrition and steat-
orrhea, oral supplements of vitamin deficiencies were noted in
the medical record for PEI. Fasting plasma glucose was meant to
be performed six weeks, six months after the surgery and once
a year. It was also prescribed if clinical signs occurred such as
thirst, polyuria, hyperphagia and weight loss. The definition of
PEI was a new onset of steatorrhea at least three times a day,
three days a week, with weight loss or malabsorption signs,
excluding others causes or a pharmacological requirement of
pancreatic enzymes that persisted beyond discharge after initial
surgery [9,10,20,35].
Each patient answered a standardised survey to define the new
onset of steatorrhea and the severity. The questions focused on
number of stools per day, smell and colour, and amount of faecal
output and the date of the onset. Those data were correlated with
our medical record. We studied variation in body weight before
and after the procedure. A clinical steatorrhea was defined by
more than three stools per day, faecal output of > 200 g/d for
at least three consecutive days, nauseating smell, pale or yel-
low stools, and the appearance of stools as pasty or greasy. A
severe steatorrhea was defined by at least three of these criteria
[35]. Faecal elastase was estimated in every patient that pre-
sented others causes of malabsorption (gastrectomy, small bowel
syndrome). To assess pancreatic endocrine insufficiency, fasting
blood glucose level (normal range < 110 mg/dL) was measured
without administration of an oral hypoglycemic agent or insulin.
A diagnosis of diabetes mellitus was made based on criteria
set by 1985 World health Organization study group on diabetes
mellitus [31,32]. Development of pancreatic endocrine insuffi-
ciency was also defined by the need of new pharmacological
intervention, such as a dietary control, insulin or oral hypogly-
caemic medications that persisted beyond discharge after initial
surgery.
The subjects developing pancreatic insufficiency that per-
sisted at least six months after their operation and before January
2016 were included in the analysis as a new onset of pancreatic
insufficiency. The delay of the development of pancreatic insuf-
ficiency was calculated from the first postoperative day to the
date of new onset of pancreatic insufficiency. Data on patients
with pre-resection endocrine and exocrine insufficiency (such
as need for escalation or continuation of medication) were not
included in the statistical analysis even though they had to update
their pharmacological treatments after the procedure because
they were not enough to perform a relevant subgroup analysis.
Patients who did not benefit of physical examination, fasting
blood glucose level and answering the survey, were lost from
follow-up and excluded from the study.
Statistics: statistical analysis was performed in December
2016 allowing a follow-up of at least 26 months. Quantita-
tive data were expressed as median ± standard deviation (SD)
and comparisons were conducted using Anova test. Qualitative
variables are given as number (percentage) of patients and com-
parisons were performed with Chi2 or Fisher exact tests. Risk
prediction model established by Cox proportional hazard model
was used to analyse the effect on study outcome. Hazard ratio
55
and its 95% confidence interval were presented. All hypotheses
were tested at the 5% level of significance. We aim at include at
least 40 patients for postoperative PEI and 30 patients for post-
operative diabetes. Statistical analyses were carried out using
the SAS version 9.3 software package (SAS Inc, Cary, NC,
USA). Our primary hypothesis assessed that pancreatic insuffi-
ciency was more frequent after PD than after LP or enucleation.
If the hypothesis was confirmed by the risk prediction model
established by Cox, we performed a multivariate analysis includ-
ing clinical features (chronic pancreatitis with albumin < 35 g/L,
preoperative weight loss), biochemical markers of cholestatic
jaundice, histology, location of the tumour, duration of surgery,
pancreatic fibrosis noted during the operation confirmed by his-
tology and postoperative gastroparesis.
4. Results
4.1. Population
From 2005 to 2016, 92 patients underwent pancreatic
resection for benign neoplasms. The incidence was slightly
higher in women (63%; 58 patients) (Fig. 1). Median inter-
val between operation and evaluation was 68.6 months ± 42.4
(range 26 to 126) without any notable difference between group
of patients. Among the 92 patients, 44 (48%) had PD, 41 (44%)
underwent LP and finally 7 (8%) had an enucleation. Clinical
and pathological features of the patients were summarized in
Table 1 whereas per and postoperative characteristics were pre-
sented Table 2. The age at surgery was significantly higher in
the PD group and enucleation group than in LP (P = 0.0435)
(Table 1). Weight loss before surgery (P < 0.0001) and metabolic
syndrome (P = 0.0318) was significantly more frequent in the PD
group than in the other two groups (Table 1).
As for pathology, we classed the benign tumours in five
groups: adenoma, cysts, endocrine tumours, IPMNs and oth-
ers (including pancreatic hamartoma, solid pseudo-papillary
tumours). PD group had more adenomas and IPMNs whereas LP
group presented more neuroendocrine tumours and pancreatic
cysts (P < 0.0001).
Operations were shorter in LP and enucleation groups
(P < 0.0001). After the surgery, the incidence of pancreatic fis-
tula was significantly higher after PD than after LP (P = 0.0439).
The PD group had more frequent gastroparesis (P < 0.0001), per-
cutaneous drainage (P = 0.0145) and reoperation (P < 0.0001).
The follow-up duration did not present significant difference
between the three groups (P = 0.7749).
4.2. Diabetes
During the analysis of the new onsets of diabetes, two patients
were excluded for loss of follow-up and 11 excluded for preoper-
ative diabetes among the initial 92 patients. Seventy-nine percent
patients with 32 occurrences (41%) were included. Twenty-two
of 32 (69%) of those occurrences happened after six postopera-
tive weeks and later. Thirty-two percent of patients undergoing
PD developed this disease; this incidence was not statistically
different from the LP group (39%) or the enucleation group
56 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61

Fig. 1. Flow chart of patients undergoing pancreaticoduodenectomy (PD), left pancreatectomy (LP) and enucleation for benign pancreatic neoplasm, included in the
prospective cohort.

Table 1
Clinical and pathological features of patients undergoing pancreaticoduodenectomy (PD), left pancreatectomy (LP) and enucleation for benign pancreatic neoplasm.
All PD LP Enucleation P value
n = 92 n = 44 n = 41 n=7

Population characteristics
Age at surgery (years) 58.5 ± 14 61.5 ± 12.7 54.5 ± 15.4 63.3 ± 6.8 0.0435
Sex: man n (%) 34 (37%) 21 (48%) 11 (27%) 2 (29%) 0.1329
Preoperative diabetes n (%) 11 (12%) 4 (9%) 7 (16%) 0 (0%) 0.4630
Preoperative PEI n (%) 3 (3%) 1 (2%) 2 (5%) 0 (0%) 0.6911
Weight loss n (%) 28 (30%) 22 (50%) 5 (12%) 1 (14%) < 0.0001
Current body mass index (kg/m2 ) 26.4 ± 5.0 26.4 ± 5.2 26.4 ± 5.3 26.5 ± 2.2 0.9995
Preoperative BMI < 18.5 kg/m2 2 (2%) 0 (0%) 2 (5%) 0 (0%) 0.3353
Preoperative BMI > 28 kg/m2 n (%) 30 (33%) 12 (27%) 17 (41%) 1 (14%) 0.1906
Active smokers n (%) 14 (15%) 6 (14%) 8 (20%) 0 (0%) 0.3631
Non-Caucasian living in France n (%) 10 (11%) 6 (14%) 4 (10%) 0 (0%) 0.7814
Cardiovascular history n (%) 26 (28%) 14 (32%) 10 (24%) 2 (29%) 0.7490
Dyslipidaemia n (%) 19 (21%) 11 (25%) 7 (17%) 1 (14%) 0.6062
Metabolic syndrome n (%) 27 (29%) 10 (23%) 17 (41%) 0 (0%) 0.0318
Chronic pancreatitis n (%) 24 (26%) 13 (30%) 11 (27%) 0 (0%) 0.2920
Chronic alcohol consumption n (%) 12 (13%) 7 (16%) 4 (10%) 1 (14%) 0.6981
Acute pancreatitis n (%) 28 (30%) 16 (36%) 11 (27%) 1 (14%) 0.4736
Biochemical data
Albumin < 35 g/L n (%) 23 (25%) 19 (44%) 4 (10%) 0 (0%) 0.0004
High conjugated bilirubin n (%) 3 (3%) 3 (7%) 0 (0%) 0 (0%) 0.4038
Pathology
Size (centimetre) 3.2 ± 2.3 3.2 ± 1.9 3.4 ± 2.8 1.3 ± 0.6 0.1316
Histology < 0.0001
Adenoma 15 (16%) 15 (34%) 0 (0%) 0 (0%)
Endocrine tumour 16 (17%) 2 (5%) 9 (22%) 5 (71%)
Cyst 25 (27%) 7 (16%) 17 (41%) 1 (14%)
IPMN 17 (19%) 9 (20%) 8 (20%) 0 (0%)
Other 19 (21%) 11 (25%) 7 (17%) 1 (14%)

PEI: pancreatic exocrine insufficiency; IPMN: intraductal papillary mucinous neoplasm; BMI: body mass index.
 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61 57

Table 2
Per- and postoperative characteristics of patients undergoing pancreaticoduodenectomy (PD), left pancreatectomy (LP) and enucleation for benign pancreatic
neoplasm.
All PD LP Enucleation P value
n = 92 n = 44 n = 41 n=7

Peroperative characteristics
Duration (minutes) 320.9 ± 89.5 355.9 ± 66.5 252.9 ± 37.3 228.6 ± 118.4 < 0.0001
Laparoscopy 4 (4%) 0 (0%) 2 (5%) 2 (29%) 0.0072
Postoperative characteristics
Hospital stay (days) 19.9 ± 31.2 26.6 ± 42.3 12.4 ± 8.7 21.9 ± 26.7 0.1098
Complication < 30 days after surgery 58 (63%) 25 (57%) 29 (71%) 4 (57%) 0.3627
Postoperative outcomes
Cardiopulmonary 7 (8%) 6 (14%) 1 (2%) 0 (0%) 0.1853
Pancreatic fistula 27 (29%) 18 (41%) 7 (17%) 2 (29%) 0.0439
0.1160
Pancreatic fistula grade A 18 (20%) 12 (27%) 6 (15%) 0 (0%)
Pancreatic fistula grade B & C 9 (10%) 6 (14%) 1 (2%) 2 (29%)
Sepsis 21 (23%) 16 (36%) 2 (5%) 3 (43%) 0.0011
Digestive haemorrhage 8 (9%) 6 (14%) 2 (5%) 0 (0%) 0.3446
Gastroparesis 38 (41%) 38 (86%) 0 (0%) 0 (0%) < 0.0001
Interventional radiologic treatment 6 (7%) 4 (9%) 0 (0%) 2 (29%) 0.0120
Embolization 2 (2%) 2 (5%) 0 (0%) 0 (0%) 0.5690
Percutaneous drain 3 (3%) 1 (2%) 0 (0%) 2 (29%) 0.0145
Reoperation 11 (12%) 6 (14%) 4 (10%) 1 (13%) < 0.0001
Readmission 8 (9%) 6 (14%) 1 (2%) 1 (14%) 0.1265
Follow-up
Months 68.6 ± 42.4 71.5 ± 44.5 65.1 ± 39.7 71.2 ± 48.9 0.7749
Postoperative pancreatic insufficiency
Endocrine 32 (41%) 14 (32%) 16 (39%) 2 (29%) 0.3499
Exocrine 54 (61%) 39 (72%) 14 (26%) 1 (2%) < 0.0001

ISGSP: International Study Group of Pancreatic Surgery define grade A, B and C.

Table 3
Univariate analysis the main risk factors among clinical features for development of exocrine and endocrine insufficiency.
Diabetes n = 79 PEI n = 88

HR 95% CI P value HR 95% CI P value

Clinical features
Age at surgery (years) 1.02 0.99–1.04 0.2448 1.00 0.98–1.02 0.8091
Age > 45 years 1.76 0.62–5.02 0.2913 1.18 0.61–2.29 0.6326
Non-Caucasian living in France 1.07 0.31–3.31 0.9904 1.25 0.57–2.78 0.5775
Preoperative BMI > 28 kg/m2 2.21 1.09–4.50 0.0288 0.74 0.42–1.35 0.3243
Familial history of diabetes 3.98 0.94–16.86 0.0608 1.53 0.69–3.40 0.2930
Smoking status (reference: non-smoker) 0.1357 0.3599
Past smokers 1.87 0.82–4.23 1.60 0.84–3.04
Active smokers 2.22 0.90–5.46 1.07 0.49–2.31
Hypertension 1.48 0.70–3.16 0.3074 1.05 0.59–1.86 0.8777
Dyslipidaemia 2.01 0.94–4.29 0.0701 0.91 0.47–1.76 0.7703
Chronic pancreatitis 1.07 0.48–2.39 0.8658 2.60 1.95–4.90 0.0016
Preoperative diabetes – – – 1.91 0.85–4.26 0.1155
Alcohol (reference: none) 0.1934 0.4235
Occasional consumption 0.84 0.11–6.25 2.71 0.64–11.46
History of alcohol 3.21 0.43–24.22 0.69 0.01–4.99
Chronic alcoholism 2.52 0.99–6.41 1.47 0.69–3.14
Acute pancreatitis 1.18 0.55–2.49 0.6741 1.58 0.90–2.78 0.1116
Sex: man 1.43 1.22–1.87 0.0191 0.68 0.40–1.18 0.1718
Metabolic syndrome 4.52 2.17–9.41 < 0.0001 0.87 0.48–1.57 0.6350
Albumin < 35 g/L 1.31 0.58–2.93 0.5173 3.05 1.05–6.10 < 0.0001
BMI < 18.5 kg/m2 1.74 0.23–12.92 0.5905 0.84 0.12–6.07 0.8610
Jaundice 1.15 0.40–3.27 0.8003 2.85 1.41–5.74 0.0034
Preoperative weight loss 0.76 0.34–1.71 0.5131 2.78 1.81–4.30 0.0026

HR: hazard ratio; CI: confidence interval; PEI: pancreatic endocrine insufficiency.
For diabetes, we analysed 79 patients with 32 new onset of diabetes. For PEI, we analysed 88 patients with 54 new onset of PEI.
58 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61
(29%) (P = 0.3499). In the Cox model, in univariate analysis,
a BMI > 28 kg/m2 (P = 0.0288), having a metabolic syndrome
(P < 0.0001) and being a man [HR (95% CI): 1.43 (1.22–1.87),
P = 0.0191] were significantly associated with the risk of devel-
oping postoperative diabetes, regardless the type of procedure
(Table 3). Among those 32 patients, 19 (59%) were controlled
by diet alone, 9 (28%) had oral medication and 4 (12.5) had
insulin (P = 0.0031).
The diabetes was not statistically linked to type of surgery
(P = 0.3499): given that the primary hypothesis was not sta-
tistically confirmed, the multivariate analysis could not be
performed (Tables 1 and 3).
4.3. PEI
From the initial 92 patients enrolled, one patient was
excluded for loss of follow-up and 3 excluded for preopera-
tive exocrine insufficiency. Eighty-eight patients were included
with 54 occurrences (61%). Seventy-two percent (39/54) of
those PEI appeared from six weeks and after during the follow-
up. Firstly, practicing LP [HR (95% CI): 0.18 (0.10–0.33)]
or enucleation [HR (95% CI): 0.05 (0.01–0.40)] cause less
postoperative PEI (Tables 4 and 5). In multivariate analy-
sis, among clinical features, chronic pancreatitis [HR (95%
CI): 2.86 (1.35–4.12) P = 0.026], malnutrition represented by
albumin < 35 g/L [HR (95% CI): 3.45 (1.95–6.09) P < 0.0001]
and preoperative weight loss of at least 5% of initial weight
[HR (95% CI): 2.48 (1.41–4.34) P = 0.0016] (Table 6). As
for biochemical data, markers of cholestatic jaundice (ele-
vated gamma-glutamyl transferase and alkaline phosphatase)
were significant risk factors: [HR (95% CI): 4.66 (2.20–9.87),
P < 0.0001] and [HR (95% CI): 2.70 (1.38–5.29), P = 0.0039]. A
tumour located in the head of the pancreas was also a risk factor:
HR (95% CI): 3.52 (1.97–6.29) P < 0.0001. As for pathology, we
observed that compared to adenoma, neuroendocrine tumours
[HR (95% CI): 0.23 (0.08–0.64)] and cysts (serous cystadenoma,
mucinous cystadenoma) [HR (95% CI): 0.42 (0.19–0.93)] were
associated with less PEI, unlike IPMNs (P = 0.0269) (Table 6).
As for intraoperative characteristics, a fibrotic pancreas found
peroperatively appeared to be a risk factor of PEI: HR (95% CI):
1.96 (1.11–3.47 P = 0.0213) (Table 6). We tested all confound-
ing variables in a multivariate analysis for all factors related to
the appearance of PEI: clinical features (chronic pancreatitis
with albumin < 35 g/L, preoperative weight loss), biochemi-
cal markers of cholestatic jaundice, histology, location of the
tumour, duration of surgery, pancreatic fibrosis noted during
the operation confirmed by histology, postoperative gastropare-
sis (Table 6). The multivariate analysis showed three possible
confounding variables related at the same time to PD and PEI:
preoperative weight loss, gastroparesis and duration of surgery.
Finally, the multivariate analysis concluded that the relation-
ship between PD and PEI were not modified by the introduction
of these factors (P < 0.0001, P < 0.0001 and P = 0.0187 respec-
tively adjusted for preoperative weight loss, gastroparesis and
duration of surgery).
As for subgroup analysis, 60% of the patients undergoing PD
had a pancreatojejunostomy. Thirty-two percent of them had a
postoperative diabetes and 96% developed postoperative PEI.
Among the patients with pancreaticogastrostomy, 35% had a
postoperative diabetes and 88% developed postoperative PEI.
Postoperative events were not related to the type of anasto-
mosis (P = 0.8241 and P = 0.2837 for endocrine and exocrine
pancreatic respectively) (Table 5).
Finally, concerning the devices used during LP, we observed
that using stapler had better effect on postoperative exocrine
insufficiency than hand-sewn closing of pancreatic (P < 0.0001)
(Table 5).
5. Discussion
The relevance of this study is the long-term follow-up of
patients with benign tumours that should have far better progno-
sis than malignant tumours. Our data suggest are convinced that
those patients should be followed for longer postoperative period
adequately both in endocrine and exocrine functions, especially
when they present factors that affect the postoperative diabetes
and PEI. In the current literature, exocrine and endocrine insuf-
ficiencies have a striking long-term impact in patients operated
for benign disease with a long life expectancy [10–14].
The pancreatic function is affected by several factors, and
accordingly to literature, the major risk factor was the type of
surgery [20,31,32]. We also analysed the recognized risk factors
for diabetes (age, metabolic syndrome, obesity, cardiovascular
history) [31,32] and those related to pancreatic insufficiency
(smoking, consumption of alcohol, biliary obstruction with
fibrosis, malnutrition, weight loss) [20].
The preoperative pancreatic function depends on the thick-
ness [30] and on the quality of the parenchyma, directly related
to a chronic pancreatitis [10,33], chronic biliary obstruction
[33,36] and finally preoperative diabetes [23]. Peroperative qual-
ity of the pancreatic remnant is evaluated by the surgeon:
degree of fibrosis in the remnant pancreas [37,38], patency of
pancreatic-enteric anastomosis [26,29,39–41]. These factors are
often present concomitantly and it is difficult to establish which
plays the dominant role [10,22].
5.1. Diabetes
The recognized risk factor for diabetes are genetic
background (family history and non-White ethnic groups), phen-
otypes of insulin resistance (obesity, metabolic syndrome) and
history of vascular disease [15,31,42]. We find similar results
in our study and in the published data reporting an incidence of
diabetes ranging from 10% to 24% after PD [10,19,43,11], and
from 8% to 60% after LP [10,19,44,45].
In our study, BMI > 28 kg/m2 , metabolic syndrome and being
a man are risks factors for postoperative diabetes. Diabetes is
controlled by diet alone in most of the case and therefore seem to
be less severe than expected. But generally diabetes occurs when
PEI is already present, and indicates that pancreatic parenchyma
is less effective: a close follow-up is still important even if the
diet alone controls the disease.
Our population presents a selection bias: patient are old (58.5
years ± 14), present a female predominance (ratio 3:1), and a
 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61 59

Table 4
Univariate analysis the main risk factors among biological and pathological features for development of exocrine and endocrine insufficiency.
Diabetes n = 79 PEI n = 88

HR 95% CI P value HR 95% CI P value

Biological and pathological features

Elevation of conjugated bilirubin 1.05 0.37–3.00 0.9309 1.72 0.86–3.43 0.1276
Elevation of GGT 1.28 0.47–3.45 0.6321 3.10 2.90–8.00 < 0.0001
Elevation of ALP 1.77 0.66–4.75 0.2548 3.14 1.68–4.09 0.0027
Histology (reference: adenoma) 0.3073 0.0177
Cyst 1.10 0.32–3.76 0.31 0.21–0.90
Endocrine tumours 2.57 0.79–8.35 0.25 0.09–0.57
IPMNs 2.29 0.67–7.84 1.18 1.07–1.51
Other 1.35 0.36–5.05 0.80 0.18–2.90
Location
Ampulloma 1.27 0.49–3.30 0.6255 1.94 0.99–3.78 0.0505
Tumour of the head of pancreas 0.73 0.32–1.70 0.4676 4.01 2.98–7.58 < 0.0001

HR: hazard ratio; CI: confidence interval; PEI: pancreatic endocrine insufficiency; GGT: gamma-glutamyl transferase; ALP: alkaline phosphatase; IPMN: intraductal
papillary mucinous neoplasm.

Table 5
Univariate analysis the main risk factors among per and postoperative characteristics for development of exocrine and endocrine insufficiency.
Diabetes n = 79 PEI n = 88

HR 95% CI P value HR 95% CI P value

Peroperative characteristics
Surgery (reference: PD) 0.3499 < 0.0001
LP 1.52 0.74–3.11 0.18 0.10–0.33
Enucleation 0.65 0.15–2.85 0.05 0.01–0.40
Pancreatic fibrosis 1.75 0.82–3.71 0.1458 2.56 1.68–5.78 0.0130
Subgroup PC
Anastomosis: (reference pancreaticojejunostomy) 0.8241 0.2837
Versus pancreatogastrostomy 1.02 0.40–2.70 0.60 0.22–1.68
Subgroup LP
Pancreatic stump (reference: hand-sewn closing) 0.3279 < 0.0001
Versus stapler device 1.42 0.70–2.88 0.26 0.14–0.51
Postoperative characteristics
Pancreatic fistula 1.05 0.50–2.22 0.9015 1.59 0.91–2.76 0.1032
Pancreatic pseudocyst 1.12 0.43–2.92 0.8108 0.69 0.31–1.52 0.3567
Sepsis for abdominal collection 1.06 0.47–2.35 0.8934 1.78 0.99–3.19 0.0549
Diabetes after surgery – – – 1.15 0.67–1.96 0.6181
Development of anastomotic stenosis 2.19 0.29–16.52 0.4479 3.31 0.79–13.78 0.1007

PEI: pancreatic endocrine insufficiency; HR: hazard ratio; CI: confidence interval; PD: pancreaticoduodenectomy; LP: left pancreatectomy; mL: millilitres.

past cardiovascular history (28%) with dyslipidaemia (21%).
This uneven distribution of male and female concerning benign
pancreatic tumours is confirmed by this original study of 230
patients [36]. This bias can probably explain why the results are
not significant for others characteristics: women smoke less, and
have a lower alcohol consumption than men.
Concerning the type of resection, in our series the incidence
of new onset endocrine insufficiency is not significantly different
between patients who underwent PD and LP. It is not in accor-
dance with published data that support an increased incidence of
diabetes after PD [21,22]. Probably due to our small population,
we do not correlate with those other studies.
5.2. PEI
As expected, the type of resection for benign tumours is iden-
tified as an independent factor that influences the development
of exocrine insufficiency in our study, in accordance with actual
literature [10,19].
PD has previously shown to result in exocrine insufficiency
in 30% to 60% of patients, even in the absence of chronic pan-
creatitis [10,18,19,46]. The frequency of exocrine insufficiency
after LP has an average rank incidence from 15 to 42% referring
to the most recent reviews but really depends on whether chronic
pancreatitis is present [10,19,48]. In the presence of chronic pan-
creatitis, most of the studies show more than 60% of PEI after
PD and 27% to 63% after LP [10,46–48].
Indeed, we report that history of chronic pancreatitis,
confirmed by the histopathology, is a significant risk fac-
tor to develop PEI. Also, tumour located in the head of
the pancreas, biochemical markers of cholestatic jaundice
and a peroperative diagnosis of fibrotic pancreas, confirmed
by the pathology, were revealed as significant risk factors
in multivariate analysis. In fact, fibrosis can be the con-
60 H. Neophytou et al. / Annales d’Endocrinologie 79 (2017) 53–61

Table 6
Multivariate analysis the main risk factors among clinical, per and postoperative characteristics for development of exocrine insufficiency, adjusted for preoperative
weight loss, duration of surgery and gastroparesis.
PEI n = 88

HR 95% CI P value adjusted: preoperative weight loss (P < 0.0001),

gastroparesis (P < 0.0001), duration of surgery (P = 0.0187)

Clinical
Chronic pancreatitis 2.86 1.35–4.12 0.0026
Albumin < 35 g/L 3.45 1.95–6.09 < 0.0001
Preoperative weight loss 2.48 1.41–4.34 0.0016
Biochemical characteristics
Elevation of GGT 4.66 2.20–9.87 < 0.0001
Elevation of APL 2.70 1.38–5.29 0.0039
Histology
Histology (reference: adenoma) 0.0269
Cyst 0.42 0.19–0.93
Endocrine tumours 0.23 0.08–0.64
IPMNs 1.33 1.37–1.87
Tumour of the head of pancreas 3.52 1.97–6.29 < 0.0001
Pancreatic fibrosis (confirmed by histology) 1.96 1.11–3.47 0.0213

PEI: pancreatic endocrine insufficiency; HR: hazard ratio; CI: confidence interval; GGT: gamma-glutamyl transferase; ALP: alkaline phosphatase; IPMNs: intraductal
papillary mucinous neoplasms.
In multivariate analysis, the statistical relationship of the characteristics tested are adjusted for preoperative weight loss, duration of surgery and gastroparesis
(P < 0.0001, P < 0.0001 and P = 0.0187).

sequence of chronic pancreatitis, chronic biliary obstruction
and explains why those variables are relevant in our study
[33,39].
Chronic biliary obstruction can lead to malnutrition. Indeed,
we observe that preoperative loss of weight and albumin < 35 g/L
are statistically more frequent in case of postoperative PEI.
Published datas show that pancreatic fibrosis is associated to
the development of IPMNs and adenomas, unlike neuroen-
docrine tumours and cysts [49]. This can explain why they are
significantly correlated to less postoperative PEI even if the mul-
tivariate analysis did not show that the type of pathology was a
confounding variable.
The development of pancreatic insufficiency after PD might
be related to other factors, such as the type of anastomosis in
PD [35] or a higher incidence of adenomas and IPMNs, which
may be associated with chronic obstructive pancreatitis [38].
However, our Cox regression model did not confirm those asso-
ciations.
We observe that stapler device have better outcomes for PEI
than hand-sewn method with significant difference. In actual
literature, authors study the relationship between stapler closure
in LP and pancreatic fistula, not PEI. Due to the poor literature
about this, this result must be confirmed by a dedicated study
[10].
6. Conclusion
As far as postoperative diabetes is concerned, we should be
more careful about follow-up of men with metabolic syndrome
and obesity. Concerning PEI, particular attention must be paid
to patients with obstructive tumours, with pancreatic fibrosis or
chronic pancreatitis.
In conclusion, the presence of such data may allow for more
accurate means of following patients on long-term insufficiency
after the resection of benign pancreatic tumours.
Disclosure of interest
The authors declare that they have no competing interest.
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