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Chapter 15
does not need to be dictated by complex pancreatic
intubation tests or by measurement of faecal elastase
but can be based on pragmatic clinical assessment.
48
Medications of unproven benefit
The search for effective treatment in chronic
pancreatitis has resulted in the assessment of a wide
range of therapies of unproven benefit. Antioxidant
therapy was evaluated on the assumption that orally
administered cocktails of vitamin C, selenium and
methionine would be absorbed into the pancreas in
sufficient concentration to quench oxidative stress.
Antioxidant therapy has been evaluated by two
reasonably large and well conducted randomised trials.
An Indian trial reported a reduction in ‘painful days’
but showed a substantial placebo response and treated
a population with striking dietary deprivation.
European ANTICIPATE trial randomised patients
with painful chronic pancreatitis to a 6-month period
of antioxidant therapy or placebo.
51
The principal
findings were of no intervention-related reduction in
pain or improvement in quality of life. Although there
is one further study whose results are awaited, it seems
unlikely that antioxidant therapy is of any benefit in
chronic pancreatitis. Medications of unproven benefit
should be avoided in this population of vulnerable
patients.
50
The
randomised 72 patients and reported the superiority
of surgical resection or drainage over endoscopic duct
stenting/duct clearance at 5years in terms of pain relief
and weight gain, with no difference in the rate of new
onset diabetes.
52
In the second study from Holland,
endoscopic decompression (with prior pancreatic
lithotripsy in 80%) was compared to open surgical duct
drainage in 39 patients.
53
At the end of follow-up (after
24months) complete or partial pain relief was achieved
in 32% assigned to endoscopic intervention and 75%
treated surgically (P
this cohort was reported in 2011, and again suggested a
better outcome at 5years in patients treated surgically.
= 0.007). Longer-term outcome in
54
Although complication rates, length of hospital stay and
changes in pancreatic function were similar between the
groups, endoscopically treated patients required more
procedures than did patients in the surgery group (8 vs
3; P <0.001). The conclusion was that surgical drainage
was more effective than endoscopic intervention. An
important observation from the Dutch study was that
whilst the response rate in terms of pain relief following
endoscopy was inferior to surgery, those that did obtain
relief did so within the first 3 months, suggesting
persistence with endotherapy in the absence of a rapid
response is unlikely to be beneficial.
An important limitation of the Dutch study is that the
findings apply only to patients with large-duct disease
without a pancreatic head mass as the surgical group
were managed by lateral pancreatico-jejunostomy.
55
Key points in medical management of chronic
pancreatitis:
• Treatment decision-making should be in a
multidisciplinary forum.
• Counselling on avoidance of alcohol consumption
and cigarette smoking.
• Treatment of malnutrition, pancreatic exocrine and
endocrine insufficiency.
• Analgesic use following the WHO ladder combined
with co-analgesics such as gabapentin.
Endoscopic management of
chronic pancreatitis
Surgery and endoscopy should be seen as
complementary rather than competitive treatments.
Hence treatment planning is best undertaken on a
multidisciplinary basis.
Endoscopic drainage compared
to surgical drainage of the main
pancreatic duct
There have been two relatively small randomised trials
comparing surgical drainage to endoscopic therapy
for painful chronic pancreatitis. The first, in 2003,
Endoscopic drainage/stenting of
the main pancreatic duct
Endoscopic drainage is best considered in patients
with a dilated main pancreatic duct without a
pancreatic head mass. The principles of endoscopic
drainage are to access the pancreatic duct, typically
by pancreatic duct sphincterotomy, to remove
intraductal stones and to leave either a single
endobiliary stent or multiple stents in situ to
facilitate prolonged drainage.
More recently, fully covered self-expanding metallic
stents have been used within the pancreas.
56–59
56
A variable
proportion of patients will be definitively treated by
endoscopic decompression. Pancreatic ductal stones
are different to common bile duct stones in that
they may represent focal parenchymal calcifications
with intraductal projections. Where large ductal
calculi are evident on CT, extracorporeal shockwave
lithotripsy (ESWL) should be used in combination
with endoscopic attempts at clearance.
57,59
Endoscopic coeliac plexus block
Endoscopic ultrasonography allows for good
visualisation of the coeliac plexus around the
coeliac trifurcation. Injection of local anaesthesia at
262
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Chronic pancreatitis
EUS can be used as a practical means of assessing
for symptom relief.
60
In those patients who achieve
an improvement in pain control after EUS-guided
injection of local anaesthetic, destruction of the
coeliac plexus can be considered by injection of
alcohol.
Some operators are reluctant to consider alcohol
ablation of the coeliac plexus in benign conditions
and in these, surgical ablation of the greater, lesser
and least splanchnic nerves in the thorax by the
thoracoscopic route remains an option in patients
with good temporary relief, although long-term
outcomes tend to be unsatisfactory.
61
Endoscopic treatment of
complications of chronic
pancreatitis
Endoscopic treatment can be considered for the
treatment of distal bile duct stricture,
pseudocyst (
Fig. 15.2) and short-term duodenal
stenting can be considered in patients with
duodenal obstruction due to inflammation. Longterm benign, symptomatic duodenal obstruction
in chronic pancreatitis is more typically treated by
laparoscopic gastro-jejunostomy.
62
pancreatic
a
c
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b
Figure15.2 • Endoscopic drainage of pancreatic
pseudocyst: (a) shows the pseudocyst on endoscopic
ultrasound, (b) shows the endoscopic approach to the
pseudocyst and (c) shows a pigtail stent in situ protruding
into the duodenal lumen.
263
Chapter 15
Key points in the endoscopic management of
chronic pancreatitis:
• Endoscopic treatment complements surgery.
• Endoscopic pancreatic duct stenting can provide
effective pain relief and may provide definitive
treatment in some patients.
• Randomised trial evidence favours surgical duct
decompression over endoscopic stenting for large
duct disease in patients without a pancreatic head
mass.
• Endoscopic stenting can be used for treatment of
the complications of chronic pancreatitis.
Surgical management of
chronic pancreatitis
Indications for surgery
Surgery can be undertaken on an elective basis for
pain control in patients with chronic pancreatitis.
Surgery can also be indicated for management
of the complications of chronic pancreatitis.
Complications that can be effectively managed by
surgery include distal bile duct stricture in younger
patients where long-term biliary stenting is not
optimal; gastric outlet obstruction secondary to
duodenal stricture and occasionally patients with
pseudocysts in the tail of the gland may require
distal pancreatectomy.
Case selection for surgery in
chronic pancreatitis
In terms of elective surgery, there is evidence
of substantial variation in the thresholds for
intervention
to offer surgery should be taken in a multidisciplinary
setting. Pain is the typical symptom which drives
patients to seek surgery and for which operation
is considered. Although there is little evidence to
support the view that patients who continue to
drink alcohol must have a period of abstention
(including avoidance of cigarette smoking), patients
being selected for elective surgery for chronic
pancreatitis should ideally have avoided alcohol
consumption for at least 6months and preferably
longer. The selection of the specific intervention is
determined by the morphology of the gland, age and
comorbidity.
Timing of surgery
There is no clear consensus on the optimal timing of
surgery. Earlier surgical intervention in the disease
63
and thus, where possible, the decision
course of chronic pancreatitis may avoid long-term
sequelae such as habituation to pain and opioids.
However, earlier intervention may also result in
patients having surgery when this could potentially
have been avoided.
Preparation for surgery
Patients with long-standing chronic pancreatitis
being considered for surgery are often on highdose opiates, may be insulin-dependent diabetics
and are likely to have varying degrees of
malnutrition. Cardiopulmonary exercise testing
(CPET) provides a very reliable assessment of
dynamic, functional reserve and modifiable risk
factors. Although it has been evaluated prior to
elective pancreatic cancer surgery it has not been
formally evaluated as an assessment tool before
surgery for chronic pancreatitis.
physiotherapy review before surgery should be
considered and thought given to management of
postoperative pain with either epidural or patientcontrolled analgesia (PCA).
64
Dietitian and
Selection of surgical procedure
For practical purposes, patients with chronic
pancreatitis being prepared for surgery can be
categorised into those with and without a pancreatic
head mass and also those with and without main
pancreatic duct dilatation. A guide to the selection
of procedures is seen in Table15.2.
Surgery for chronic pancreatitis in patients
with a pancreatic head mass
In this setting there is often a concern about
underlying malignancy. Preoperative assessment
should include EUS with fine-needle aspiration.
Intraoperatively, frozen section may be considered
but Trucut-type biopsy of the pancreatic head
may yield false-negative results. Differentiation
of adenocarcinoma arising in the typical fibrous
stroma of pancreatic cancer from the fibrous
inflammatory infiltrate of chronic pancreatitis can
be very difficult on frozen section and therefore
it is preferable to have an operative strategy in
place prior to commencing surgery rather than be
exclusively reliant on frozen section histology.
A high index of suspicion may persist in patients
with a hypodense mass in the head of the gland in the
setting of chronic pancreatitis and in this scenario,
resection in the form of pancreatico-duodenectomy
should be considered. Appropriate counselling is
required to explain that major resection may be
undertaken, with all its attendant risks, for a final
diagnosis of benign disease.
264
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Chronic pancreatitis
Table15.2 • Matching the type of endoscopic or surgical procedure to the disease variant in chronic pancreatitis
Indications Treatment options
Isolated pancreatic pseudocyst Endoscopic pseudocyst-jejunostomy.
Pain + dilated duct without a pancreatic mass Partington–Rochelle modification of lateral pancreatico-jejunostomy
Pain + dilated duct with a pancreatic mass Frey pancreatico-jejunostomy
Beger ‘duodenum-preserving pancreatic head resection’
Pancreatico-duodenectomy
Pain + pancreatic head mass + suspicion of malignancy Pancreatico-duodenectomy
Pain + small duct disease (main duct <3 mm) ‘V-shaped’ resection + pancreatico-jejunostomy
Disconnected duct syndrome Endoscopic stent
Distal pancreatectomy
In those patients with a pancreatic head mass
but where there is a low risk of cancer, the main
surgical treatment options are between duodenumpreserving pancreatic head resection (DPPHR) and
pancreatico-duodenectomy. Beger etal. introduced
the duodenum-preserving resection of the
pancreatic head as an organ-sparing procedure
Fig. 15.3). The operation is a subtotal resection
(
65,66
of the pancreatic head after transection of the
pancreas above the portal vein. The pancreas is
drained by pancreatico-jejunostomy. A systematic
review and meta-analysis of four randomised trials
comparing DPPHR to pancreatico-duodenectomy
for pain relief in chronic pancreatitis reported
that both procedures are equally effective in terms
of postoperative pain relief, overall morbidity
and incidence of postoperative endocrine
insufficiency.
67
DPPHR is associated with better
preservation of quality of life and lower long-term
malnutrition.
Figure15.3 • Beger procedure – the duodenum-
preserving pancreatic head resection. The pancreas
is divided at its neck over the portal vein. The
pancreatic head has been cored out and the bile duct
is exposed within the head. Note that the duodenum
has been preserved. Reconstruction is by a Roux
pancreatico-jejunostomy.
Surgery for chronic pancreatitis in patients
with a dilated main pancreatic duct
without pancreatic head mass
Puestow and Gillesby described decompression
of the main pancreatic duct with resection of the
pancreatic tail, splenectomy and longitudinal
lateral pancreatico-jejunostomy.
68
In a classic paper,
Partington and Rochelle of the Cleveland Clinic
reported a modification of this operation, preserving
the spleen to avoid postsplenectomy complications
and also avoiding distal pancreatectomy in order
to preserve islet function.
69
Their modification of
the operation of lateral pancreatico-jejunostomy
with drainage of the opened pancreatic duct into
a retrocolic Roux loop is frequently incorrectly
termed a ‘Puestow’ procedure and is an effective
and relatively simple surgical treatment for largeduct chronic pancreatitis without a pancreatic mass.
The operation has been undertaken laparoscopically
although this is not a standard method.
70
An
important practical consideration is to exclude
main-duct IPMN before undertaking duct drainage.
Frey and Amikura reported a combined longitudinal
pancreatico-jejunostomy of the body and tail of the
pancreas (Partington–Rochelle procedure) with a
limited duodenum-preserving resection or ‘coring’
of the pancreatic head.
71
In contrast to the Beger
procedure, the pancreas is not divided over the
superior mesenteric/portal vein (
Fig. 15.4). The
head of the pancreas is cored out in this procedure.
Drainage of the cavity of the pancreatic head and the
opened main duct of the body and tail is performed
with a longitudinal pancreatico-jejunostomy using
a Roux-en-Y loop.
delay the progressive loss of pancreatic function.
71
Main-duct decompression may
72
Indications for total pancreatectomy for
chronic pancreatitis
In current practice, total pancreatectomy is not a
widely used option in chronic pancreatitis. Total
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265
Chapter 15
Figure15.4 • The Frey procedure. Note the important
similarities and differences from the Beger procedure.
Frey describes a lateral pancreatico-jejunostomy, opening
the main pancreatic duct out into the tail of the gland
but making no attempt to undertake splenectomy. The
head is then cored out. The key difference from the Beger
operation is that the pancreas is not divided at its neck.
In this illustration, the common bile duct is opened above
the pancreas and a sound or dilator passed through into
the duodenum. This is not usually necessary but can be
done to ensure that there is no accidental injury to the
intrapancreatic portion of the distal bile duct.
pancreatectomy with islet autotransplantation
(TPIAT) does, however, have strong proponents.
73,74
In practical terms, this procedure can only be offered
if there are facilities for islet isolation from the
resected pancreas. Although tempting to consider
TPIAT as a salvage procedure after failed drainage or
subtotal resection, prior surgical treatments reduce
the possibility of achieving a successful islet yield. The
Mayo Clinic experience suggests that a tissue volume
of 0.25 mL/kg be sought during islet manufacture
and that intraportal infusion should be halted, at
least temporarily, if the perfusion pressure exceeds
25 cm H2O.75 This procedure must be reserved for
settings of established chronic pancreatitis with a low
risk of cancer. In practice, the procedure is therefore
optimal in younger patients with genetic chronic
pancreatitis. It would be fair to say that as yet TPIAT
for chronic pancreatitis is not a universally accepted
procedure and further evidence is required before
more widespread adoption can be recommended.
Surgical management of small-duct
chronic pancreatitis
The V-shaped resection operation was developed
for use in small-duct chronic pancreatitis. Izbicki
suggests a longitudinal V-shaped excision of the
ventral aspect of the pancreas combined with a
longitudinal pancreatico-jejunostomy
If this condition is accompanied by an enlarged
pancreatic head, pancreatic head resection should be
performed.
76
(Fig. 15.5).
Figure15.5 • V-shaped excision. The V-shaped
excision is a variant of lateral pancreatico-jejunostomy
undertaken for small-duct chronic pancreatitis. The
main duct is opened out to the tail but a V-shaped
core of tissue deep to the duct and from both above
and below the duct is also excised. The term ‘V’ refers
to the excision of a ‘V-shaped’ area of tissue which
incorporates the main pancreatic duct. This core of tissue
is removed from the head of the gland out to the tail
taking care not to inadvertently damage the portal vein
behind the gland. Reconstruction is by retrocolic Roux
pancreatico-jejunostomy.
Key points in the surgical management of
chronic pancreatitis:
• Large-duct disease without a mass can be
effectively treated by pancreatic duct drainage
combined with ‘coring’ of the pancreatic head. The
head and decompressed duct are then drained into
a Roux loop by lateral pancreatico-jejunostomy.
• Where there is a mass, consider pancreaticoduodenectomy if there is a high index of suspicion
of an underlying cancer.
• The Beger procedure (duodenum-preserving
pancreatic head resection or DPPHR) is an effective
alternative treatment for chronic pancreatitis with a
mass but a low index of suspicion of cancer.
• Total pancreatectomy with islet autotransplantation
may be considered in young patients where there
is a low risk of cancer. The procedure is not as yet
widely accepted.
• Surgical bypass provides definitive treatment for
biliary and/or duodenal strictures complicating
chronic pancreatitis.
Complications of longstanding
chronic pancreatitis
Complications include distal bile duct stricture with
jaundice,
to duodenal stricture, pseudoaneurysm of one of the
major peripancreatic visceral arteries,
resulting in pseudocyst,
77,78
gastric outlet obstruction secondary
79
80
pancreatic ascites or fistula.
duct disruption
81
266
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Chronic pancreatitis
Biliary stricture
Long-term pancreatic and peripancreatic fibrosis can
lead to distal bile duct stricture. Patients may present
with jaundice or pain, or following investigation of
abnormal liver function tests.
77,78
Initial management
will usually involve exclusion of neoplasia by
combinations of cross-sectional imaging, EUS/FNA,
and internal biliary drainage at ERCP whilst longterm options are evaluated. Jaundice secondary to
extrahepatic biliary obstruction may be managed
by multiple stents or a self-expanding metal stent.
However, biliary bypass should be considered in patients
who are stent dependent with minimal comorbidity,
but have a persistent, symptomatic stricture.
Roux-en-Y hepatico-jejunostomy is the preferred
intervention of choice. Choledochoduodenostomy
and cholecystoduodenostomy carry high rates of
failure and are regarded as obsolete for the treatment
of benign biliary stricture.
Duodenal stenosis
Duodenal obstruction from fibrosis can be managed
by short-term placement of a removable duodenal
stent but gastro-jejunostomy, ideally undertaken
laparoscopically, is the preferred treatment.
Pancreatic ascites
This is a rare complication. It is defined as a massive
accumulation of pancreatic fluid in the peritoneal
81
cavity.
The amylase level in the ascitic fluid is
typically elevated threefold above plasma levels
although plasma amylase levels are also usually
raised. Pancreatic fluid secondary to duct disruption
may also track along tissue planes through
the diaphragmatic hiatus to the mediastinum,
occasionally reaching the pleura or bronchus.
Initial management is usually by percutaneous
drainage and nutritional support followed by ERCP
to localise the site of leakage with insertion of a
transpapillary pancreatic duct stent. Surgery is rarely
required. Additional treatment with somatostatin
or octreotide together with diuretics and repeated
paracentesis may be beneficial for some patients.
Pseudocyst complicating chronic
pancreatitis
The revised Atlanta Classification of acute
pancreatitis retains the term pseudocyst when
describing a persistent fluid collection lasting more
than 4weeks from an episode of acute pancreatitis
but the definition also carries the cautionary
advice that such a collection should contain little
or no necrosis.
30
In practical terms, all persistent
fluid collections following acute pancreatitis
contain some necrosis and should not be termed
pseudocysts – a term that should be reserved for an
amylase-rich fluid collection lined by granulation
tissue more typically seen in association with
chronic pancreatitis. These are invariably associated
with main pancreatic duct disruption, fibrosis and
stricturing of the main pancreatic duct. Features
that point to a pseudocyst complicating chronic
pancreatitis include parenchymal calcification on
CT, pancreatic duct irregularity with segmental
dilatation and absence of acute post-inflammatory
changes in the peripancreatic fat. Pseudocysts
complicating chronic pancreatitis are not liable
to resolve spontaneously and usually require
intervention. Endoscopic drainage is the preferred
modality. Transpapillary stenting may be effective
if any duct stricture can be negotiated. Endoscopic
ultrasound-guided transgastric drainage will
often result in medium-term resolution and stents
are often left in situ to prevent closure of the
endoscopic cystgastrostomy. Disruption of the
main pancreatic duct in its mid-body – typically a
consequence of severe acute pancreatitis but also
seen in chronic disease – produces the ‘disconnected
duct syndrome’ where the distal gland continues
to secrete into the cavity around the middle of
the gland.
83
Disconnected duct syndrome can be
managed by endoscopic drainage but is one of the
rare indications for distal pancreatectomy in chronic
pancreatitis.
83
False aneurysm of visceral vessels
Rarely, patients with chronic pancreatitis can
present with gastrointestinal haemorrhage due to
false aneurysms of the visceral vessels (
Fig.15.6).
84
The splenic artery and gastroduodenal artery are the
most frequently affected and optimal intervention is
angiographic embolisation.
79
Extrahepatic portal hypertension
Chronic peripancreatic inflammation and swelling
involving the head of the gland can lead to portal
vein occlusion resulting in the development of a
collateral circulation and cavernous transformation
Fig. 15.7).
(
stage finding in chronic pancreatitis. Although
there is some evidence favouring anticoagulation
in acute portal vein thrombosis, the evidence in
chronic occlusion is less clear and the risks of
anticoagulation are considerable. Occlusion of the
85
Often this is an asymptomatic late-
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267
Chapter 15
Figure15.6 • False aneurysm in chronic pancreatitis.
Selective mesenteric angiography with cannulation of the
superior mesenteric artery (SMA) showing a 2-cm false
aneurysm arising from the first jejunal branch.
splenic vein can lead to sinistral (or left-sided) portal
hypertension with a variceal collateral circulation
running through the wall of the stomach.
86
should be noted that transjugular portosystemic
stent shunt (TIPSS) is not effective in extrahepatic
Figure15.7 • Portal vein occlusion in chronic
pancreatitis. Coronal view of a venous phase contrast CT
showing a smooth post-inflammatory stenosis of the main
portal vein at the level of the spleno-portal confluence
(white arrow). There is post-stenotic dilatation of the portal
vein. Parenchymal calcification is also seen.
It
Pancreatic cancer complicating
chronic pancreatitis
portal hypertension due to portal vein thrombosis,
as the procedure creates a shunt between the
intrahepatic portal circulation and the systemic
circulation. Gastrointestinal bleeding is rare, and the
significance of superior mesenteric vein/portal vein
thrombosis, with formation of venous collaterals, is
the restriction of subsequent surgical options and
approaches.
There is an increased lifetime risk of cancer arising
in long-standing chronic pancreatitis and this
should be borne in mind in older patients. The
relative risk is 13.3 for developing pancreatic cancer
in those with chronic pancreatitis, with a 10–20year lag between the incidences of pancreatitis and
pancreatic malignancy.
87
Key points
• Long-term alcohol overuse and cigarette smoking are the commonest aetiological factors for chronic
pancreatitis.
• Abdominal pain is the most frequent presenting symptom.
• Baseline assessment must include, in addition to clinical history and physical examination, cross-
sectional imaging (usually by CT), assessment of nutritional status, exocrine insufficiency and
diabetes mellitus.
• Medical management is typically the first step, with analgesia following the WHO analgesic ladder.
• Endoscopic treatment is widely utilised as a second step in patients with chronic pancreatitis. Many
patients may be effectively managed without surgery.
• Surgical duct decompression by lateral pancreatico-jejunostomy (the Partington–Rochelle procedure)
has been shown to be superior to endoscopic treatment for patients with large duct chronic
pancreatitis without a pancreatic head mass.
• In patients with a pancreatic head mass, coexistent pancreatic cancer must be excluded.
268
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Chronic pancreatitis
• If cancer cannot reliably be excluded, resectional surgery such as pancreatico-duodenectomy is
appropriate.
• In patients with a pancreatic head mass and a low risk of cancer, surgical treatment can either utilise
the Frey procedure or the Beger duodenum-preserving pancreatic head resection.
• In longstanding chronic pancreatitis, there is an increased risk of diabetes mellitus, malnutrition and
pancreatic cancer.
Full references available at http://expertconsult.
inkling.com
Key references
16. Conwell DL, Lee LS, Yadav D, et al. American
Pancreatic Association practice guidelines in
chronic pancreatitis: evidence-based report on
diagnostic guidelines. Pancreas 2014;43:1143–62.
PMID: 25333398.
This paper provides a concise but comprehensive
overview of the diagnostic standards for chronic
pancreatitis.
23. AghdassiAA, Weiss FU, MayerleJ, et al. Genetic
susceptibility factors for alcohol-induced chronic
pancreatitis. Pancreatology 2015;15(Suppl):S23–31.
PMID: 26149858.
This paper provides a good overview of the genetic
susceptibility factors for alcohol-induced chronic
pancreatitis.
33. Nordback I, Pelli H, Lappalainen-Lehto R,
et al. The recurrence of acute alcohol-associated
pancreatitis can be reduced: a randomized controlled trial. Gastroenterology 2009;136:848–55.
PMID: 19162029.
This important randomised trial shows the effect
of counselling in avoidance of repeat admission in
alcohol-related pancreatitis.
53. CahenDL, GoumaDJ, NioY, etal. Endoscopic versus
surgical drainage of the pancreatic duct in chronic
pancreatitis. New Engl J Med 2007;356:676–84.
PMID: 17301298.
This important randomised trial compares surgery to
endoscopic therapy in patients with large-duct chronic
pancreatitis.
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269
16
16
Pancreatic adenocarcinoma
Shaheel M. Sahebally
Kevin C. Conlon
Introduction
Whilst adenocarcinoma of the pancreas accounts for
only 3% of new cancer cases annually, it represents
the fourth leading cause for cancer-related mortality
for both men and women.
the disease, coupled with its ambiguous presentation
and lack of a diagnostic biomarker, frequently result
in delayed diagnosis.
cure for pancreatic cancer, yet only 10–15% of
newly diagnosed patients have surgically resectable
disease at presentation.
undergo a curative R0 resection, most will still
recur within 2years, leading to disappointing 5-year
survival rates of 20–25%.
The majority (~95%) of pancreatic tumours are
adenocarcinomas, originating from the exocrine
part of the pancreas. Nearly all of these are ductal
adenocarcinomas, which is the focus of this chapter.
1
The aggressive nature of
2,3
Surgery remains the only
4
For those patients who
5,6
Epidemiology
It is estimated that there will be 53 070 new cases of
pancreatic cancer diagnosed in the United States alone
in 2016, with an estimated 41 780 cases expected to
die from the disease.1 Pancreatic cancer is the eleventh
commonest cancer in males and eighth commonest
cancer in females.
and ethnicity, and is highest is Northern Europe and
North America,
observed in tropical countries.
of pancreatic adenocarcinoma is approximately 9
per 100 000 population.10 Keane et al.11 explored
incidence trends in pancreatic adenocarcinoma in
7
Its incidence varies with age, sex
8
being 3-4 times higher than rates
9
The UK incidence
a large UK primary care cohort between 2000 and
2010 and noted increases in annual incidence by an
average of 3% per year (95% CI 1–4%) but found no
association between incidence and social deprivation.
The peak incidence for the disease occurs between
the seventh and eighth decades of life, and is rare
under the age of 30.
12
Risk factors (see Box16.1)
Smoking
Tobacco smoking remains the most consistent
modifiable risk factor associated with the
development of pancreatic cancer.
analysis of 82 studies
pancreatic cancer in current and former smokers
to be 1.74 (95% CI 1.61–1.87) and 1.2 (95% CI
1.11–1.29), respectively. It is postulated that a dosedependent relationship occurs, necessitating longterm exposure.
for a minimum of 10 years following cessation.
The exact mechanism through which cigarette
smoking affects pancreatic carcinogenesis is still
unknown, but it is hypothesised that N-nitroso
compounds in tobacco are carried haematogenously
to the pancreas where they have been shown to
induce pancreatic cancer in animal models.
17
found the overall risk of
18
For ex-smokers, the risk persisted
Diet and alcohol
A meta-analysis of observational studies comprising
6643 patients found an overall statistically significant
13,14–16
A meta-
19
17
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Pancreatic adenocarcinoma
Box16.1 • Risk factors for pancreatic cancer
Age (above 60years)
Smoking
Obesity
High fat diet
Alcohol abuse
Pancreatitis
Chronic pancreatitis
Hereditary pancreatitis
Diabetes mellitus
Family history of pancreatic cancer
Genetic predisposition
Peutz–Jeghers syndrome
Li–Fraumeni syndrome
Fanconi syndrome
Familial adenomatous polyposis
Lynch syndrome
Gardner syndrome
Multiple endocrine neoplasia
BRCA1
Von Hippel–Lindau syndrome
association between processed meat consumption and
pancreatic cancer risk, while red meat consumption
significantly increased the risk only in men.
20
It has
been suggested that fruit and vegetable intake may
confer a protective effect against the development of
pancreatic cancer;
21,22
however, a pooled analysis of
14 prospective studies from North America, Europe
and Australia found no overall statistically significant
association.
23
In regards to dairy products (including
calcium and vitamin D) and risk of pancreatic cancer,
a recent pooled meta-analysis showed no statistically
significant overall association.
consumption (i.e. ≥9 drinks/per day) significantly
increased the risk of pancreatic cancer.
24
Finally, heavy alcohol
25
Occupation
pancreatic adenocarcinoma and noted that diabetes
duration of 2 or more years was associated with a
1.5–1.7-fold increased risk of cancer. However, this
risk was inversely proportional to disease duration.
Diabetes mellitus, especially for ≥2 years, is
associated with an increased risk of pancreatic
carcinogenesis. However, the risk is inversely
proportional to the duration of disease.
30
The mechanism linking diabetes mellitus to
pancreatic tumourigenesis may be partly explained
by pronounced reactive oxygen species (ROS)
production secondary to persistent hyperglycaemia,
which in turn enhances the migratory capacity of
tumour cells.
31
Histories of gallstone disease or cholecystectomy
have also been shown to be independent risk factors
for pancreatic carcinogenesis.
Both gallstones and prior cholecystectomy
significantly increase the risk of pancreatic cancer in
Asian as well as white populations. This positive
association was independent of factors such as
smoking, diabetes mellitus, obesity and number of
years post cholecystectomy.
32
32
Chronic pancreatitis is characterised by irreversible
glandular damage and accumulating evidence
points to an increased risk of pancreatic cancer,
although the highest risk is in patients with early
onset pancreatitis, such as hereditary and tropical
pancreatitis.
around 5% of patients with chronic pancreatitis
will develop pancreatic cancer.
linked to pancreatic adenocarcinoma include
cystic fibrosis,
33
However, over a 20-year period, only
33
Other conditions
34
Gardner’s syndrome and multiple
endocrine neoplasia type 1 syndrome (MEN 1).
Occupational exposure to electromagnetic fields,
asbestos, acrylamide and halogenated hydrocarbons
is associated with a higher risk of developing
pancreatic adenocarcinoma. There is evidence of
an amplified risk in people exposed to chlorinated
hydrocarbon solvents (metal degreasing workers and
dry cleaners) and nickel compounds as well as people
working in the paint/varnish and textile industries.
26
Past medical history
Prior meta-analyses have shown an association
between diabetes mellitus and pancreatic adenocarcinoma.
of long-term diabetes mellitus on incidence of
27–29
Song etal.30 examined the influence
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Hereditary pancreatic cancer
Epidemiological evidence
degree relatives with pancreatic cancer have at
least a twofold increased risk of developing the
disease. A meta-analysis of 6568 pancreatic cancer
cases showed a significant increase in pancreatic
cancer risk associated with having an affected
relative, with an overall summary RR of 1.8 (95%
CI 1.48–2.12).
cancer make up 8–10% of all cases of pancreatic
38,39
cancer.
37
Patients with familial pancreatic
Familial pancreatic cancer kindreds have
two or more first-degree relatives diagnosed with
pancreatic adenocarcinoma.
Although novel genes that predispose to familial
pancreatic cancer remain to be fully elucidated,
35,36
suggests that first-
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