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Chapter 16
it is now well established that an increased risk is
associated with familial conditions such as Peutz–
Jeghers syndrome and germ-line mutations in
BRCA1/BRCA2 (hereditary breast–ovarian cancer
syndrome),
and melanoma syndrome),
cancer syndrome),
syndrome),
40
CDKN2A (familial atypical mole
40
41
mismatch repair genes (Hereditary Non
40
PALB2 (familial breast
ATM (familial breast cancer
Polyposis Colorectal Cancer or Lynch syndrome)
and PRSS1 and SPINK1 of hereditary pancreatitis.
Guidelines for family members at risk of hereditary
pancreatic cancer are being developed, albeit based
on expert opinion.
42
Precursor lesions
Pancreatic carcinogenesis comprises histologically
distinct precursor lesions. Preneoplastic lesions are
usually asymptomatic and are small in size (usually
5 mm), making them radiographically occult and
<
hence they are more commonly discovered at the
time of resection. They appear to follow a multistep progression to invasive carcinoma, analogous
to that in colorectal cancer.
lesions include pancreatic intraepithelial neoplasia
(PanIN), intraductal papillary mucinous neoplasm
(IPMN) and mucinous cystic neoplasm (MCN).
The commonest of these is Pan-IN, observed in
approximately 82% of neoplastic pancreases.
They are traditionally subclassified into PanIN-1,
PanIN-2 and PanIN-3, depending upon the degree
43
These precursor
44
45
45
of cytological and architectural atypia.
However,
following the recent Baltimore Consensus Meeting
for Neoplastic Pancreatic Precursor Lesions, a
revised two-tiered classification system has been
suggested such that all precursor lesions are either
low-grade (PanIN-1, Pan-IN-2) or high-grade
(PanIN-3, carcinoma in situ) dysplastic lesions.
These lesions, first observed adjacent to resected
adenocarcinoma, exhibit similar genetic alterations
to the frankly invasive samples. In particular, the
frequency of p16 and K-ras mutations increases
with the severity of PanIN and this observation led
to the development of a pancreatic tumourigenesis
model involving a stepwise progression from PanIN
to invasive carcinoma,
diverse molecular changes (
47
in turn characterised by
Fig. 16.1). Evidence
suggests that pancreatic adenocarcinoma harbours
approximately 63 genetic alterations, of which the
majority are point mutations, including genes such
as K-ras, p16/CDKN2A, TP53 and SMAD4.
commonest observed mutation is K-ras, seen in
>90% of pancreatic adenocarcinoma and also in
about 45% of low-grade PanIN lesions.
49,50
involved in various downstream signalling pathways,
and mutations result in constitutive activation.
P16/CDKN2A (cyclin-dependent kinase inhibitor
2A gene) is a tumour suppressor gene that is inactivated
in up to 90% of pancreatic adenocarcinoma.
It functions to regulate the cell cycle. TP53 and
SMAD4 are also tumour suppressor genes that are
inactivated in 75% and 55% of pancreatic cancer,
respectively.
53,54
Typically, these mutations are seen in
46
48
The
K-ras is
51
52
Figure16.1 • Diagrammatic representation of the multi-step progression to invasive carcinoma from low-grade to
high-grade neoplasm.
Images courtesy of Dr Paul Crotty.
272
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Pancreatic adenocarcinoma
late-stage precursor lesions, especially in high-grade
55
PanIN.
Waddell et al.56 performed whole-genome
analysis of 100 pancreatic adenocarcinomas and
implicated several other genes, including KDM6A,
PREX2, ERBB2, MET etc. Similarly, whole-genome
sequencing of 456 pancreatic ductal adenocarcinomas
has recently identified 32 significantly mutated
genes, which aggregated into 10 distinct molecular
pathways.
57
Furthermore, work by the same group
defined four independent pancreatic cancer subtypes
(squamous, pancreatic progenitor, immunogenic and
aberrantly differentiated endocrine exocrine), each
of which is characterised by different transcriptional
networks, histopathological features as well as
survival. These data provide valuable insight into the
mechanisms underlining pancreatic carcinogenesis
and provide novel opportunities to target these
molecular pathways. Unfortunately discussion about
each of these genes and their associated transcription
pathways is beyond the scope of this chapter.
Presentation
Most patients with pancreatic cancer present
with non-specific symptoms such as weight loss,
bloating and anorexia (Box16.2). As a result, the
disease is usually disseminated at diagnosis, and
approximately 80% of patients have unresectable
4
disease.
Tumours in the body and tail of the pancreas usually
present late. Painful jaundice is the commonest
complaint (46%), followed by pain only (34%) or
painless jaundice (13%). Weight loss and anorexia
are seen in 7% of cases. Occasionally, haematemesis
and malaena occur secondary to tumour invasion
into stomach or duodenum. Late-onset diabetes
mellitus or acute pancreatitis may also be the first
sign of an underlying pancreatic neoplasm.
widespread screening of asymptomatic cohorts does
not appear cost-effective given the low incidence
of the disease and the dearth of a cheap, sensitive
and specific biomarker, targeted screening may be
appropriate in high-risk individuals.
to patients at increased risk for familial pancreatic
cancer, experts at the recent International Cancer
of the Pancreas Screening (CAPS) Consortium
Box16.2 • Symptoms/signs suggestive of pancreatic
neoplasm
Early satiety
Obstructive jaundice (± pain)
Unexplained weight loss
Endoscopy-negative epigastric/back pain
Late-onset diabetes
Signs of malabsorption without defined cause
58
While
59
With regards
Summit recommended screening with endoscopic
ultrasound or magnetic resonance imaging for the
following patients: first-degree relatives of patients
with pancreatic cancer from a familial pancreatic
cancer kindred with at least two affected first-degree
relatives, patients with Peutz–Jeghers syndrome and
p16, BRCA2 and HNPCC mutation carriers with
≥1 affected first-degree relative.
60
The classical Courvoisier’s sign (palpable gallbladder
with painless jaundice) occurs in less than 25% of
patients. Jaundice may represent either primary
disease causing biliary obstruction or external
compression of the biliary system by metastatic
nodal disease. Pain is a more common symptom than
physicians typically appreciate, usually secondary to
involvement of visceral afferent nerves or resultant
local pancreatitis. Pain on initial presentation is
suggestive of unresectability. Weight loss is common,
often associated with early satiety, nausea or vomiting.
The latter may be due to gastric outlet obstruction.
Virchow’s node (left supraclavicular node associated with upper gastrointestinal malignancy),
thrombophlebitis migrans (non-specific paraneoplastic
sign named after Trousseau) and Sister Mary Joseph
nodule (umbilical metastatic lesion via the falciform
ligament) are well-recognised features of advanced
disease. Hepatomegaly is seen in 65% of patients and
may reflect hepatic metastases. Blumer’s shelf (rectally
palpable rectovesicle or rectovaginal mass) rarely
occurs and is not usually sought as part of routine
examination.
The most useful aid in making the diagnosis is a
high index of suspicion. Vague epigastric symptoms
and weight loss in the presence of normal endoscopy
and preliminary radiology mandate further detailed
investigation.
Investigation
Serology
Haematological and hepatic biochemical measurements are largely unhelpful in diagnosis. A mild
normochromic anaemia may be present due to occult
blood loss while thrombocytosis is also sometimes
observed. Elevated serum bilirubin and alkaline
phosphatase confirm obstructive jaundice; amylase
and lipase may be elevated in those presenting
with pancreatitis (5%). An elevated prothrombin
time suggests hepatic dysfunction secondary to
liver infiltration by metastases. Hyperglycaemia is
non-specific and is seen in approximately 20% of
patients and could be related to the fact that type
2 diabetes mellitus confers an increased risk of
pancreatic cancer or may be the first presenting sign
of the underlying cancer. Patients with malnutrition
have hypoalbuminaemia and low cholesterol level.
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273
Chapter 16
Markers
As of yet, there remains no effective tumour marker
for pancreatic adenocarcinoma. The most widely
employed serum marker is sialylated Lewis blood
group antigen on MUC-1 (Mucin 1, cell surface
associated) carbohydrate antigen 19-9 (CA 19-9). It
is a cell surface glycoprotein expressed by pancreatic
neoplastic cells, as well as normal pancreatic and
biliary duct cells, gastric, colonic, endometrial
and salivary epithelia.
sensitivity (41–86%) and specificity (33–100%)
for detecting pancreatic cancer
general population do not express the antigen and
hence do not have detectable serum CA 19-9 levels.
In addition, only 65% of resectable pancreatic
adenocarcinoma demonstrated an elevated CA
19-9, while the marker was increased in 40% of
patients with chronic pancreatitis.
limitations, CA 19-9 is mostly used as a prognostic
marker to assess response to therapy in patients
already diagnosed with pancreatic cancer.
Other potential markers include CA494,66
CEACAM1 (carcinoembryonic antigen-related
cell adhesion molecule 1),
hormone-related protein),
M2-pyruvate kinase)
human chorionic gonadotropin).
work is required before they can be translated into
clinical practice. An in-depth discussion of each of
these promising markers is beyond the scope of this
chapter.
61
CA 19-9 has suboptimal
62
and 4–15% of the
64
Because of these
65
67
PTHrP (parathyroid
68
TuM2-PK (tumour
69
and serum β-HCG (beta-
70
However, further
63
CT remains the commonest cross-sectional
imaging modality. Conventional CT has been
replaced by more sensitive and dynamic CT with
thinner slice/cuts (1–3 mm) with multidetector
and 3D reconstruction. For lesions >2 cm, the
sensitivity is approximately 90%, decreasing to
approximately 60% for smaller lesions.
73
CT not
only allows assessment of the primary pancreatic
lesion, but also its relationship to the remainder
of the pancreas and peripancreatic vasculature,
and determination of resectability (
Figs16.2–16.5).
Direct evidence of a tumour is often seen as a
hypodense mass, with other subtle signs such as
pancreatic atrophy, deformity of the glandular
contour or double duct dilatation (common bile
duct and pancreatic duct;
Fig. 16.6). Metastatic
lesions can be detected as well as portal vein or
superior mesenteric arterial involvement. However,
despite these advances, CT-imaging is limited
at detecting small liver or peritoneal metastatic
deposits of occult disease.
74
Diagnosis
Imaging studies
Transabdominal ultrasound (US) is the initial
investigation in the jaundiced patient. It is superior to
computed tomography (CT) to detect cholelithiasis.
Common bile duct dilatation (>
7 mm, >10 mm in
post-cholecystectomy patients) is an indirect sign,
together with pancreatic duct dilatation (>
2 mm).
The primary pancreatic lesion is often visible
together with hepatic metastases and ascites if
present. For lesions >
95% sensitive; however, sensitivity is considerably
lower for smaller lesions.
of US is machine quality difference and operator
experience, making it user-dependent.
3 cm, US is approximately
71
The major drawback
72
Colour
Doppler US has been suggested to assess vascular
involvement (portal or superior mesenteric vein/
artery) by the tumour.
While US remains a useful imaging modality for the
initial work-up of the jaundiced patient, additional
imaging modalities are required to examine the
pancreas and assess resectability status.
274
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Figure16.2 • Necrotic mass in the head of the pancreas
(arrow).
Figure16.3 • Locally advanced borderline resectable
tumour (solid arrow) with deformity of the superior
mesenteric vein (dashed arrow).
V
T
Figure16.4 • Locally advanced unresectable tumour (T)
with involvement of the superior mesenteric vein (V) and
artery (A).
M
M
Figure16.5 • Multiple hepatic metastases (M) from
pancreatic neoplasm (N).
A
M
N
Pancreatic adenocarcinoma
Magnetic resonance imaging (MRI) is mainly used
as an adjunct to CT for planning treatment options.
The combination of T1/T2-weighted imaging and
magnetic resonance cholangiopancreatography
(MRCP) is useful to visualise the primary tumour
and its relationship to the biliary and pancreatic
ducts, as well as peripancreatic vasculature. Kim
75
etal.
to identify up to 79% of pancreatic tumours that
appeared isodense on multiphasic CT.
accumulation of [
(FDG) by tumour cells, and has the advantage
of combining metabolic activity with imaging
characteristics while imaging the whole body.
PET-CT scanners are able to detect small (up to
7 mm) pancreatic neoplasms and diagnose metastatic
disease in about 40%.76 PET is increasingly becoming
a common method of assessing tumour response to
treatment and may be prognostic. However, FDGPET is not accurate in pancreatic disease due to
its reliance on normal glucose homeostasis. The
combination of PET-CT carries a sensivity of 92%,
and is superior to either modality alone.
(ERCP) is reserved mainly to assess obstructive
intraductal lesions and to relieve biliary obstruction
in selected cases. MRCP has replaced ERCP as a
diagnostic modality of choice.
to stage pancreatic adenocarcinoma. In addition
to being more sensitive than CT in detecting small
neoplastic lesions, it also provides tissue diagnoses
through fine-needle aspiration (FNA) with higher
sensitivity and specificity compared to CT-guided
FNA, and without the need of administration of
a contrast agent.
conditions mimicking cancer, such as sclerosing
pancreatitis or atypical choledocholithiasis. However,
EUS is costly, invasive and operator-dependent.
suggested that MR imaging might be able
Positron emission tomography (PET) shows
18
F]2-fluoro-2-deoxy-D-glucose
77
Endoscopic retrograde cholangiopancreatography
Endoscopic ultrasound (EUS) is increasingly used
78
It may also help clarify benign
B
NP
Figure16.6 • Biliary duct (B) and pancreatic duct (P)
obstruction by pancreatic neoplasm (N) denoting the
double duct sign.
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Cytology/histology
Multidetector cross-sectional CT is the radiological
modality of choice in the staging and diagnosis of
pancreatic cancer. In selected cases, histological
confirmation of malignancy may not be established
prior to surgery. However, in patients selected for
neoadjuvant therapy, histological confirmation is
essential via FNA by EUS/ERCP or percutaneously
by CT-guidance.
Advanced staging techniques
Laparoscopy
Despite advances in non-invasive imaging, laparoscopic staging and ultrasound have a role in selected
275
Chapter 16
cases. Laparoscopy can be performed immediately
before conversion to laparotomy or as an interval
staging measure. The routine use of diagnostic
laparoscopy remains controversial and institutiondependent. However, laparoscopic ultrasonography
can potentially identify radiographically occult
metastatic disease and hence obviate the need
for non-curative laparotomies. It enables direct
visualisation of intra-abdominal organs and can
detect metastatic deposits <
hepatic structures, thereby offering more accurate
disease staging
Staging laparoscopy (with a 30-degree lens) in
patients diagnosed with pancreatic cancer should be
used selectively. Hepatic and/or peritoneal deposits,
if present, should be sampled. Laparoscopic
ultrasound is reserved for patients with suspected
vascular invasion and may help detect intrahepatic or
lymph node metastases, and hence influence
resectability status.
Figure16.7 • Staging laparoscopy demonstrating
peritoneal metastases (P).
Figure16.8 • Staging laparoscopy demonstrating a liver
metastasis.
79
(Figs16.7 and 16.8).
3 mm on peritoneal and
P
P
P
A recent meta-analysis concluded that diagnostic
laparoscopy with biopsy of suspected lesions prior
to definitive laparotomy avoided non-curative
laparotomies in 21% of cases, all of which were
deemed resectable by CT imaging.
80
Detractors of laparoscopy argue that a significant
proportion of patients require (open) surgical bypass
and therefore laparoscopic staging should only
be used if bypass would not be contemplated at
open surgery.
81
Evidence from single-centre studies
suggests that the need for subsequent operative
palliation for established gastric outlet obstruction
is less than 5%.
82
Moreover, less invasive options
are now available for managing malignant gastric
outlet obstruction such as endoscopic stenting
and laparoscopic gastroenterostomy. A small (24
patients) randomised study comparing open versus
laparoscopic gastroenterostomy concluded that
the laparoscopic approach was associated with
significantly less intraoperative blood loss, shorter
time to oral solid food intake and less delayed
gastric emptying.
83
Gurusamy et al. performed a
meta-analysis to address the need for prophylactic
gastrojejunostomy in patients with unresectable
periampullary cancers (pancreatic cancer made up
92.1% of cases) and reported that prophylactic
gastrojejunostomy was associated with a statistically
significant lower risk of gastric outlet obstruction
compared to controls.
84
However, there was no
difference in quality of life between the two groups.
The authors went on to recommend routine
prophylactic gastroenterostomy in patients with
unresectable disease (with or without hepaticojejunostomy). However, it is important to mention
that both trials included in this meta-analysis
were associated with a high risk of bias and that
all patients underwent exploratory laparotomy.
Therefore, the results are not applicable to patients
with unresectable disease diagnosed during staging
laparoscopy.
General laparoscopy is performed with an
angled (usually 30˚) lens looking for small-volume
peritoneal and liver metastases. The liver is examined
systematically and usually all but segment 7 can be
viewed. Biopsy of hepatic or peritoneal deposits for
frozen-section histology is taken, and the procedure
is terminated if positive. If metastases are not seen,
the hepatico-duodenal ligament is inspected for
nodal disease. The lesser sac is opened by incising
the gastrocolic omentum to inspect for tumour, and
biopsies of the primary may be undertaken. This is
achievable in 80% of cases. In certain institutions,
the duodenum is mobilised but this is unnecessary
in the majority of cases. With more effective
neoadjuvant regimens, it is important to use
laparoscopic strategies to define patients who may
be suitable for downstaging, similar to advanced
rectal lesions.
276
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a b
Figure16.9 • (a) Laparoscopic ultrasonography, and (b) liver metastasis (white arrow).
Pancreatic adenocarcinoma
Laparoscopic ultrasound (LUS) has been
advocated as an additional aid to detect intrahepatic
metastases, lymph node or vascular involvement
to determine resectability (
Fig.16.9). However, the
added value is <10% and therefore LUS should be
reserved only for cases in which there is concern of
vascular invasion.
85
The role of peritoneal cytology taken during
laparoscopic staging is less well defined, although
it may improve staging accuracy. Recently, Oh etal.
found that 14% of patients who would otherwise
be classified as having potentially resectable disease
had positive peritoneal cytology during routine
staging laparoscopy and were subsequently upstaged
to stage IV disease.
86
Moreover, most patients
(86%) with positive cytology experienced disease
progression after chemotherapy/chemoradiotherapy
and their 5-year survival was zero.
Pathology
Ductal adenocarcinomas account for >85% of all
pancreatic neoplasms. Other types of malignant
tumours include the following:
• adenosquamous carcinoma
• mucinous non-cystic (colloid) carcinoma
• mucinous cystic neoplasms
• intraductal papillary mucinous neoplasm with
an associated invasive carcinoma
• solid pseudopapillary neoplasm
• acinar cell carcinoma
• pancreatoblastoma
• serous cystadenocarcinoma
• undifferentiated (anaplastic) carcinoma
• signet-ring cell carcinoma
• giant cell carcinoma.
Treatment
Treatment strategies should be discussed at
a multidisciplinary level, with emphasis on
established guidelines. The American Joint
Committee on Cancer TNM staging is outlined in
Table16.1.
Figure16.10 outlines the authors’ current treatment
algorithm for patients with pancreatic cancer.
Resection
Surgical treatment remains the only potential cure
for pancreatic cancer, yet patient selection remains
paramount.
In patients with obstructive jaundice and surgically
resectable disease, the use of preoperative biliary
drainage is a topic of ongoing debate. Proponents of
decompression argue that jaundiced patients undergoing surgery are at increased risk of perioperative
sepsis, pancreatic fistula and wound infections
while detractors argue that routine biliary drainage
is itself associated with an increased risk of
procedure-specific complications such as cholangitis,
pancreatitis and stent-related perforations.
88
87
A recent
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277
Chapter 16
Table16.1 • American Joint Committee on Cancer TNM staging, 2013
Primary tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour limited to the pancreas, ≤
2 cm in greatest dimension
T2 Tumour limited to the pancreas, >2 cm in greatest dimension
T3 Tumour extends beyond the pancreas but without involvement of the coeliac axis or the
superior mesenteric artery
T4 Tumour involves the coeliac axis or the superior mesenteric artery (unresectable primary
tumour)
Regional lymph nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Regional lymph node metastasis
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
Stage T N M
0 Tis N0 M0
IA T1 N0 M0
IB T2 N0 M0
IIA T3 N0 M0
IIB T1 N1 M0
T2 N1 M0
T3 N1 M0
III T4 Any N M0
IV Any T Any N M1
Courtesy of AJCC Cancer Staging Manual, Eighth Edition
meta-analysis reported that patients who underwent
Pancreatico-duodenectomy
internal preoperative biliary drainage sustained
statistically fewer major adverse events compared to
those who had surgery only.
89
The authors’ practice is
not to decompress the bile duct preoperatively unless
symptoms and signs of cholangitis or secondary signs
of hyperbilirubinaemia are present. If a neoadjuvant
approach is being considered, biliary stenting is
required prior to commencing chemo/radiotherapy.
Coagulopathy, if present, is treated with vitamin K,
prior to resection.
Patient selection is key, including cardiovascular
and respiratory evaluation. Curative surgery is
associated with a median survival of 11–23months,
with approximately 10–27% alive at 5 years.
Previously, pancreatic resections were associated
with significant mortality; however, with advances
in perioperative supportive care, mortality rates are
now <5% in high-volume centres.
91
Pancreatico-duodenectomy was first described by
Kausch in 1912, and later popularised by Whipple
in 1935. The classical Whipple procedure (twostage) was an en bloc resection of the pancreatic
head, duodenum, common bile duct, with the distal
stomach and surrounding lymph nodes. Later being
performed as a one-stage operation, it still remains
the surgical therapy for tumours of the pancreatic
head and neck.
The right colon is mobilised, exposing the third
and fourth parts of the duodenum, and an extended
Kocherisation is performed. This allows a tumour in
90
the head of the pancreas to be palpated and exposes
the left renal vein. The aortocaval and portal vein
(PV) nodal packages are dissected and the respective
vessels are skeletonised. Resectability is finally
assessed as extensive involvement of the confluence
278
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Pancreatic adenocarcinoma
Clinical suspicion of pancreatic cancer
Head <2cm
CA 19-9 <150ku/L
Resection
Symptomatic therapy
Figure16.10 • Treatment algorithm for patients with pancreatic cancer.
of the PV/superior mesenteric vein (SMV) may
herald termination of the procedure. It is important
to remember that short segments of the PV can be
resected if necessary, and therefore an involved PV
does not necessarily denote unresectability.
nodes are cleared. Cholecystectomy facilitates
higher ligation of the bile duct, which is transected
just proximal to the insertion of the cystic duct. It
is the authors’ practice to send a biliary aspirate
for routine culture and sensitivity, as postoperative
infective complications tend to involve enteric
organisms.
the hepatico-duodenal ligament is dissected along
its length, taking care to identify and preserve the
common hepatic artery and PV. The gastroduodenal
artery is ligated while care is taken not to damage
an aberrant right hepatic artery.
resected. This is the authors’ favoured approach as
resection includes the nodes along the greater and
lesser curves, reduces stomach-emptying dysfunction
postoperatively, diminishes the density of parietal
cells and theoretically reduces the risk of gastritis.
The stomach is transected at the antrum along with
the attached omentum. The proximal jejunum along
Resectable
Neoadjuvant therapy
Laparotomy
Resectable
Localised disease
Head >2cm
all body/tail
CA 19-9 >150ku/L
Laparoscopy
Unresectable
Adjuvant therapy
MSCT scan, EUS, MRCP
Locally advanced disease
Borderline resectable
Combined modality therapy
CA 19-9
Laparoscopy
Neoadjuvant therapy
Metastatic disease
Chemotherapy
Best supportive care
with its mesentery is transected and the mobilised
duodenum and jejunum is delivered back under the
ligament of Treitz.
The pancreas is transected between four stay
sutures (to facilitate haemostasis in the marginal
arteries) after the uncinate process has been
The relationship of the tumour to the first jejunal
branch of the SMV is often the critical determinant of
resectability. If this is involved by tumour, the
likelihood of being able to reconstruct the SMV is low.
dissected from the superior mesenteric vessels.
Retroperitoneal dissection allows the tumour and
nodal package to be delivered en bloc. If any doubt
exists regarding the adequacy of tumour clearance,
the pancreatic resection margin should be sent for
frozen section histology. Verbeke and Menon had
The remaining porta hepatis is dissected, and
shown that a discrepancy between margin status and
clinical outcome is due to frequent under-reporting
of microscopic margin involvement.
of a standardised pathological examination, with
confusing nomenclature and controversy regarding
92
The common bile duct is mobilised distally and
the definition of microscopic margin involvement,
results in the wide variation of reported R1 rates
(between 18% and 85%).
94
Reconstruction is undertaken with the biliary
anastomosis followed by the pancreatic and
finally the gastric. Pancreatico-jejunostomy and
pancreatico-gastrostomy are the most commonly
employed techniques for pancreatico-enteric
reconstruction. A recent meta-analysis reported
In a conventional Whipple, the distal stomach is
statistically significantly fewer rates of pancreatic
fistula and intra-abdominal fluid collections after
pancreatico-gastrostomy, with no significant
differences in overall morbidity, mortality or length
of hospital stay.
95
The nature of the pancreatic reconstruction is
subject to individual variation. The authors favour
a two-layered pancreatico-jejunal anastomosis with
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93
The lack
279
Chapter 16
mucosa-to-mucosa reconstruction. Choledochojejunostomy is performed in a similar end-to-side
manner, leaving the gastrojejunostomy until the
end. Abdominal drains are not routinely placed.
96
Morbidity following resection varies, with the
majority of complications being minor. The most
significant cause of morbidity is development of a
pancreatic fistula, observed in 7–18% of cases.
Octreotide administration in patients with a
soft pancreas and non-dilated ducts did not
significantly lower the rate of pancreatic fistula,
overall morbidity or duration of hospital stay
compared to patients who did not receive the
medication although the trend favoured octreotide.
97,98
97
Most complications can be dealt with either
conservatively or using drains placed by interventional
radiology. A minority (<5%) of cases requires
re-laparotomy.
Pylorus-preserving pancreaticoduodenectomy (PPPDR)
Many centres recommend a PPPDR approach, first
described by Watson in 1942. It is postulated to retain
a functioning pylorus with an intact neurovascular
supply, thereby ensuring good gastrointestinal
function and diminishing nutritive, dumping and
bile reflux sequelae.
Buchler’s group showed no significant differences in
overall survival, postoperative morbidity or mortality
between PPPDR and a classical Whipple; however,
the latter procedure was associated with significantly
less delayed gastric emptying (DGE) whereas
PPPDR resulted in significantly less operating time,
intraoperative blood loss and red cell transfusions.
PPPDR and classical pancreaticoduodenectomy are similar with respect to morbidity,
mortality and survival. However, rates of delayed
gastric emptying are significantly lower with classical
pancreatico-duodenectomy, whilst PPPDR results in
significantly shorter operating time, less blood loss as
well as fewer red cell transfusions.
PPPDR dictates conventional mobilisation to
the point where the stomach requires transection;
the right gastric artery is preserved and the
duodenum is transected at least 2 cm distal to the
pylorus. Reconstruction is usually accomplished by
duodenojejunostomy or gastrojejunostomy.
Subtotal stomach-preserving pancreatico-
duodenectomy (SSPPD) is a relatively novel technique
developed in an attempt to decrease the incidence of
99
A recent meta-analysis from
100
100
101
DGE.
It involves division of the stomach 2–3 cm
proximal to the pyloric ring such that >90% of the
stomach is preserved. In a meta-analysis comparing
SSPPD and PPPDR, comprised of 650 patients,
Huang etal. demonstrated that SSPPD was associated
with a significantly lower rate of DGE but more
intraoperative blood loss.
102
However, there were no
differences in mortality, pancreatic fistula or intraabdominal abscess rates between the two techniques.
Nakamura etal. went one step further and compared
rates of DGE between an antecolic side-to-side gastric
greater curvature-to-jejunal anastomosis and a similar
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anastomosis in all patients undergoing SSPPD.
They
showed that the former technique was associated with
a significantly reduced rate of DGE, but similar overall
morbidity compared to the end-to-side technique.
Extended lymph node and vascular
dissection
It is the authors’ practice to perform extended
dissection including aortocaval nodal clearance in
the majority of cases. At presentation, most tumours
have involvement of lymph nodes beyond the gland
and we believe that clearance of the left gastric and
aortocaval nodes not only increases the specificity
of staging and the resultant predicted prognosis
but also the likelihood of a negative surgical
margin. However, a recent meta-analysis examining
previously published randomised trials failed
to demonstrate improved overall survival with
extended lymphadenectomy compared to standard
dissection.
associated with significantly worse postoperative
morbidity.
pancreatico-duodenectomy increased the number of
excised lymph nodes, it was associated with
increased postoperative morbidity and failed to
translate into improved overall survival, compared to
standard lymph node dissection.
The role of extensive vascular resection is very
much an area of ongoing interest as the boundary
of resectability for pancreatic cancer is continuously
being pushed forward in an attempt to improve
curability rates in patients who would otherwise
be deemed unresectable. In a meta-analysis
conducted by Zhou et al. comparing SMV/PV
resection versus no resection in patients undergoing
pancreatico-duodenectomy, there was no difference
in postoperative morbidity or mortality between
the two groups.
survival rate was not significantly different between
104
Moreover, extended dissection was
Whilst extended lymphadenectomy during
104
105
Furthermore, the 5-year overall
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Pancreatic adenocarcinoma
the two groups (12.3% in the vascular resection
versus 17% in the no resection group); translating
into better outcomes compared to strict palliative
therapy. On the other hand, arterial resections
may be indicated in selected cases, despite being
associated with increased perioperative mortality
compared to those without arterial resections.
106
Distal pancreatectomy
Distal pancreatectomy is the procedure of choice
for tumours of the body and tail of the pancreas.
The pancreatic neck is dissected from the portal
vein and the splenic flexure of the colon is taken
down. In the majority of ductal cancers, the
spleen is also resected to achieve an en bloc
clearance. Splenic preservation is generally limited
to patients with benign or borderline neoplasms.
Patients undergoing distal pancreatectomy and
splenic resection are vaccinated prophylactically
preoperatively against encapsulated organisms such
as Haemophilus influenza B, Neisseria meningitidis
and Streptococcus pneumoniae.
Laparoscopic pancreatectomy
Laparoscopic pancreatectomy remains one of the
most challenging minimally invasive abdominal
operations to date. Accumulating evidence shows
that laparoscopic pancreatico-duodenectomy
is safe and feasible.
associated with similar overall survival rates but
significantly lower wound infection and pancreatic
fistula rates, and reduced hospital stay, compared
to the classic open approach.
distal pancreatic resection is currently the
most frequently performed minimally invasive
pancreatic procedure, associated with decreased
blood loss and reduced length of stay as well
as lower rates of wound infections and similar
oncological outcomes.
Kettering Cancer Center group published their
experience of distal pancreatectomy using open,
laparoscopic or robotic approaches.
no significant differences in 90-day morbidity and
mortality or pancreatic fistula rates or oncologic
outcomes between the three groups; however,
the open group was associated with significantly
more intraoperative blood loss. A recent review
by Kocaay et al. concluded that laparoscopic
pancreatic surgery remained a reasonable
treatment modality for low-grade malignant
tumours when performed by skilled surgeons in
high-volume centres.
into its oncological safety and long-term outcomes
is needed before it can be firmly established as
first-line treatment.
107
It has been shown to be
108
Laparoscopic
109,110
The Memorial Sloan-
111
There were
112
However, further research
Total pancreatectomy
Some suggest that pancreatic cancer is a
multicentric disease and therefore advocate total
pancreatectomy. It was initially proposed to avoid
the risk of pancreatico-enteric leaks and to remove
potential undetected synchronous disease in other
parts of the gland. Although total pancreatectomy
can be carried out safely, the survival benefit is
so dismal it questions the indication for the
operation.
Central pancreatectomy
The role of central pancreatectomy (CP) is
rare and limited due to a narrow spectrum
of indications. The procedure is historically
reserved for patients with chronic pancreatitis
and traumatic injuries. More recently, it has been
advocated for use in lesions of the pancreatic
neck. Opponents of this technique argue against
higher rates of pancreatic anastomotic leakage
whilst those in favour say it offers preserved
functional elements (endocrine and exocrine) of
the pancreas.
113
Surgical palliation
Obstructive jaundice
In the majority of cases, biliary obstruction can
be adequately relieved by endoscopic measures.
However, in selected cases, surgical palliation
may be required. Cholecysto-jejunostomy may be
performed in cases where the cystic duct is patent
and the tumour is not within 1 cm of the cystic duct.
Alternatively, choledocho-jejunostomy may be used,
which has equivalent outcomes.
Upper GI tract outflow obstruction
Gastric and duodenal outlet obstruction are said
to occur in up to 20% of cases. Once jaundice has
been addressed, persistent nausea and vomiting
should raise the suspicion of underlying GI
obstruction. If biliary obstruction is being dealt
with at open operation, prophylactic duodenal
bypass should be considered. Laparoscopic
gastrojejunostomy has become the management
of choice when warranted. Whilst endoluminal
stenting is associated with more favourable
short-term results, gastrojejunostomy may be a
better treatment option in those with a predicted
prolonged survival.
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