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Chapter 6 / Pancreatic Neuroendocrine Neoplasms 71
has been advocated as an alternative and potentially less invasive
means of tumor extirpation. In this technique, dissection
p
roceeds
along the peritumoral plane, and only the tumor is removed. Because
of the limited extent of resection (as compared with partial or total
pancreatectomy), enucleation carries a higher risk of positive resection
margins and does not permit pathologic assessment of peripancreatic
lymph nodes. Therefore, although enucleation has been shown to be
associated with lower operative morbidity, this potential advantage
must be counterbalanced by the risk of oncologically incomplete tumor
clearance. Surgical margins and nodal metastases have been shown to
be prognostically significant variables for patients with resected pan-
creatic neuroendocrine neoplasms; therefore, enucleation is typically
reserved for patients with tumors that are very likely to be benign (e.g.,
insulinomas) or for patients who may not tolerate radical resection. In
this context, retrospective studies have not consistently identified mea-
surable survival differences between patients treated with enucleation
versus radical resection.
Gastrinoma Arising in a Setting of MEN1
One circumstance that deserves special attention is that of gastrinoma
arising in the setting of MEN1. ese patients harbor a genetic predis-
position toward the development of multifocal gastrinoma, as mani-
fested by their very high rates of local and distant disease recurrence
following surgical intervention. In fact, the goal of surgical intervention
in these patients is often directed more at control of refractory peptic
ulcer disease–related symptoms than at cure. Indeed, whether and how
to undertake operative therapy for patients with gastrinoma and MEN1
remains an area of controversy and debate. Preoperatively, every eort
is expended to dene the extent of disease within the pancreas and peri-
pancreatic tissues using cross-sectional CT and/or MRI modalities as
well as EUS, as utilization of multiple techniques maximizes the sensitiv-
ity of multifocal tumor detection. However, because of nite limits in the
sensitivity of even these preoperative maneuvers, additional maneuvers
are undertaken at the time of operative exploration in order to maximally
dene the extent of disease. In addition to performing intraoperative US
of the pancreas and peripancreatic tissues, many surgeons advocate
performing a duodenotomy to more fully evaluate for small tumors pos-
sibly residing within the duodenal wall. Digital palpation and transillu-
mination of the entire duodenal wall have been suggested as eective
adjuncts to enhance the detection of small tumor foci. Operative resec-
tion should then be tailored toward the distribution of disease that is
present, and often necessitates a distal pancreatectomy with resection of
any duodenal wall tumors that may be present. On occasion, a total pan-
createctomy may be necessary. Because of the high likelihood of nodal
metastases, a regional peripancreatic lymphadenectomy should also be
undertaken.
Metastatic Disease
Like other gastroenteropancreatic malignancies, neuroendocrine neo-
plasms have a tendency to metastasize to the liver. Treatment directed
at hepatic neuroendocrine metastases has been advocated as a means of
mitigating tumor burden–mediated symptoms and, possibly, as a way to
prolong survival.
In well-selected cases, surgical resection of hepatic neuroendo-
crine metastases has been associated with favorable control of symp-
toms and with durable survival outcomes. However, these analyses have
Section I / Pancreas72
been limited to noncontrolled, retrospective studies, some of which
have suboptimally compared patients undergoing surgical resection to
patients who were not candidates for operative intervention. Analyses
that have included large patient numbers and durable follow-up sug-
gest that the likelihood of eventual disease recurrence following surgical
metastasectomy is very high. Given the relative rarity and the relatively
indolent disease course of even metastatic neuroendocrine neoplasms,
the extent to which hepatic metastasectomy may prolong survival
remains unclear.
Hepatic neuroendocrine metastases are commonly multifocal and
are often not amenable to complete operative resection. In many cases,
operative resection is combined with intraoperative microwave or radio-
frequency ablation in an eort to preserve hepatic parenchyma. Some
investigators have suggested that even subtotal cytoreduction can oer
palliation of symptoms and prolongation of survival for patients with
extensive hepatic neuroendocrine metastases. For many patients with
extensive multifocal disease, liver-directed therapy relies on transarterial
chemoembolization or radioembolization. ese techniques take advantage
of the fact that hepatic metastases derive the majority of their blood sup-
ply from the hepatic arterial circulation (as opposed to the portal venous
circulation). Selective administration of chemotherapy (most commonly
doxorubicin and cisplatin) or radioactive microspheres is followed by arte-
rial embolization. Transarterial embolization therapy has been shown
to be capable of controlling symptoms and inducing tumoral regression,
but prospective randomized demonstration of survival benet is not yet
available.
Systemic Therapy
Until recently, systemic therapy for patients with pancreatic neuroendo-
crine neoplasms was restricted to somatostatin analogs and cytotoxic che-
motherapy. Unfortunately, neither approach oered signicant ecacy.
Somatostatin analogs like octreotide or the long-acting variant lanreotide
are able to inhibit hormonal secretion. In addition, they have been shown
to inhibit proliferation of an insulinoma cell line in vitro. However, they
do not appear to have any direct cytotoxic eect. Consequently, soma-
tostatin analogue therapy has been shown to be eective in ameliorat-
ing hormonal symptoms in 60% to 90% of patients; however, patients
typically develop resistance to this therapy after about 1 year, and actual
induction of tumoral regression is rare (5% to 15%). Cytotoxic chemo-
therapy using 5-uorouracil, streptozocin, and doxorubicin has been
shown to have a response rate of 39%. A combination of cisplatin and
etoposide has been shown to be associated with a response rate of 42%
among patients with poorly dierentiated tumors. However, both these
regimens are associated with signicant risks of adverse eects that
often limit their utility.
Very recently, targeted therapies used in the treatment of other
malignancies have been shown to have ecacy against pancreatic
n
euroendocrine neoplasms. Moreover, these agents are associated with
comparatively minimal side eects. Two of these agents, sunitinib and
everolimus, have recently received U.S. FDA approval for use in the treat-
ment of pancreatic neuroendocrine neoplasms. Sunitinib is a tyrosine
kinase inhibitor that targets a number of angiogenic and mitogenic pro-
teins including vascular endothelial growth factor receptor and platelet-
derived growth factor receptors. In a recent phase 3 randomized clinical
trial, treatment with sunitinib promoted signicant prolongation of medi an
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 73
progression-free survival (11.4 months vs. 5.5 months) and signicantly higher
objective response rates (9% vs. 0%) as compared with placebo for patients
with well- dierentiated pancreatic neuroendocrine neoplasms. Everolimus
is an inhibitor of the protein mammalian target of rapamycin. By inhibiting
the cellular proliferation and angiogenic events mediated through mTOR
signaling, everolimus can inhibit the growth and survival of pancreatic neu-
roendocrine neoplasm cell lines in vitro. In a recent multicenter randomized
clinical trial, everolimus induced signicant prolongation of progression-
free survival (11 months vs. 5.4months) and signicantly higher objective
response rates (5% vs. 2%) compared with placebo for patients with well-
dierentiated pancreatic neuroendocrine neoplasms. Importantly, both
sunitinib and everolimus were found to have acceptable side eect proles.
Current investigations are examining newer targeted therapy agents as well
as combination therapies.
OUTCOMES
Retrospective reports of patients undergoing complete resection of pan-
creatic neuroendocrine neoplasms are relatively heterogenous in terms of
their treatment approaches and patient characteristics. However, review
of representative studies with reasonable patient numbers and follow-up
durations suggests that survival outcomes after resection may be gener-
ally favorable, with 5-year survival estimates ranging between 60% and
90% (Table 6.2). Prediction of individual patient outcomes relies on the
identication of prognostically informative clinical variables, and optimal
classication of pancreatic neuroendocrine neoplasms, which remains an
area of persistent controversy. e seventh edition of the American Joint
Commission on Cancer (AJCC) Cancer Staging Manual outlines a staging
system for pancreatic neuroendocrine neoplasms that follows a conven-
tional tumor–node–metastasis (TNM) schema (Table 6.3). However, it has
been evident for some time that tumor grade, as quantied by mitotic activ-
ity, carries signicant prognostic weight for neuroendocrine neoplasms.
e World Health Organization (WHO) rened their classication system
in 2010 to accommodate this variable (Table 6.4). Although histologic
grade does stratify prognostic outcomes, a number of series have shown
that variables such as tumor size, nodal metastases, and resection margin
are prognostically informative variables for patients with resected pancre-
atic neuroendocrine neoplasms. As a result, optimal staging of this disease
is likely to undergo further evaluation and modication in the future.
Authors Year
Number of
Patients
Median
Follow-up
(Months)
5-Year
Survival
Kazankian, et al. 2006 70 50 89%
Schurr, et al. 2007 45 55 64%
Ferrone, et al. 2007 183 44 87%
Bilimoria, et al. 2008 3,855 51 59%
Hill, et al. 2009 1,815 26 ~ 70%
Ballian, et al. 2009 43 68 91%
Summary of Recent Retrospective Analyses of
Patients Undergoing Surgical Resection of Pancreatic
Neuroendocrine Neoplasms
TABLE
6.2
Section I / Pancreas74
Primary tumor (T) Stage T N M
Tx Primary tumor cannot be assessed 0 Tis N0 M0
T0 No evidence of primary tumor IA Tl N0 M0
Tis Carcinoma in situ IB T2 N0 M0
T1 Tumor limited to pancreas, ≤ 2 cm in greatest dimension IIA T3 N0 M0
T2 Tumor limited to pancreas, > 2 cm in greatest dimension IIB Tl Nl M0
T3 Tumor extends beyond pancreas but without involvement of the celiac axis or
thesuperior mesenteric artery
T2 Nl M0
T4 Tumor involves the celiac axis or the superior mesenteric artery (unresectable
primarytumor)
T3 Nl M0
III T4 any N M0
Regional lymph nodes (N)
IV any T any N Ml
Nx Regional lymph nodes cannot be assessed
N0 No regional lymph node metastases
N1 Regional lymph node metastases
Distant metastasis (M)
M0 No distant metastasis
M1 Distant metastasis
AJCC Classication System of Pancreatic Neuroendocrine Neoplasms
TABLE
6.3
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 75
Suggested Readings
Ballian N, Loeer AG, Rajamanickam V, et al. A simplied prognostic scoring
system for resected pancreatic neuroendocrine neoplasms. HPB (Oxford)
2009;11:422–428.
Bilimoria KY, Bentrem DJ, Merkow RP, et al. Application of the pancreatic adenocar-
cinoma staging system to pancreatic neuroendocrine tumors. J Am Coll Surg
2007;205:558–563.
Ferrone CR, Tang LH, Tomlinson J, et al. Determining prognosis in patients with pan-
creatic endocrine neoplasms: can the WHO classication system be simplied?
JClin Oncol 2007;25:5609–5615.
Hill JS, McPhee JT, McDade TP, et al. Pancreatic neuroendocrine tumors: the impact of
surgical resection on survival. Cancer 2009;115:741–751.
Kazanjian KK, Reber HA, Hines OJ. Resection of pancreatic neuroendocrine tumor:
results of 70 cases. Arch Surg 2006;141:765–770.
Martin RC, Kooby DA, Weber SM, et al. Analysis of 6,747 pancreatic neuroendocrine
tumors for a proposed staging system. J Gastrointest Surg 2011;15:175–183.
Norton JA, Fraker DL, Alexander HR, et al. Surgery increases survival in patients with
gastrinoma. Ann Surg 2006;244:410–419.
Raymond E, Dahan L, Raoul JL, et al. Sunitinib malate for the treatment of pancreatic
neuroendocrine tumors. N Engl J Med 2011;364:501–513.
Schurr PG, Strate T, Rese K, et al. Aggressive surgery improves long-term survival in
neuroendocrine pancreatic tumors. Ann Surg 2007;245:273–281.
Yao JC, Shah MH, Ito I, et al. Everolimus for advanced pancreatic neuroendocrine
tumors. N Engl J Med 2011;364:514–523.
Differentiation Grade Mitotic Figures
Ki-67 Staining
Positivity
Well differentiated Low grade (G1) <2 per 10 HPF
a
<3%
Intermediate
grade (G2)
2 − 20 per 10
HPF
a
3%− 20%
Poorly differentiated High grade (G3) >20 per 10 HPF
a
>20%
a
high-power elds
WHO Classication of Pancreatic Neuroendocrine
Neoplasms
TABLE
6.4
76
PREOPERATIVE CONSIDERATIONS
Pancreatic resection, in particular, pancreaticoduodenectomy, is a tech-
nical and perioperative tour de force in abdominal surgery and should be
performed only in carefully selected patients. As with any major abdominal
procedure, preoperative evaluation for pancreatic surgery should include
a detailed history and physical examination (including functional status),
laboratory studies, and optimization of medical comorbidities. Tumor
markers (serum carbohydrate antigen [Ca19-9], carcinoembryonic antigen
[CEA]) have prognostic value, and CA19-9 is being used to identify those
patients at very high risk for harboring subclinical, radiographically occult,
distant metastases. High-resolution abdominal computed tomography
(CT) imaging is the mainstay of clinical staging. Contrast-enhanced multi-
detector pancreas protocol CT provides important information regarding
tumor–vessel relationships. In particular, direct assessment of the relation-
ship to the major vascular structures (superior mesenteric artery [SMA],
superior mesenteric vein [SMV], SMV–portal vein conuence [SMV–PV],
celiac axis, and common hepatic artery [CHA]) is readily determined in a
reproducible manner. In addition, arterial and venous anomalies that aect
the technical aspects of the operation should be noted and potential sites
of metastatic disease identied. Resectability status must be established on
the basis of high-quality imaging prior to treatment as it forms the basis for
which stage-specic therapy is delivered both as part of a clinical trial and
as o-protocol therapy. Resectability criteria utilized by the Medical College
of Wisconsin pancreatic cancer team are found in Table 7.1.
PANCREATICODUODENECTOMY
Pancreaticoduodenectomy involves resection of the pancreatic head, duo-
denum, gallbladder, and bile duct with or without removal of the gastric
antrum. Our recommended technique includes a brief staging laparoscopy
to exclude liver and peritoneal metastases followed by a midline upper
abdominal incision.
e surgical resection is divided into the following steps:
1. Isolation of the infrapancreatic SMV and separation of the colon and
its mesentery from the duodenum and pancreatic head: e lesser sac
is entered by mobilizing the greater omentum up o of the transverse
colon. e loose attachments of the posterior gastric wall to the ante-
rior surface of the pancreas are divided. e hepatic exure of the colon
is freed from its retroperitoneal attachments, exposing the pancreatic
head and duodenum. e visceral peritoneum along the inferior border
of the pancreas is incised starting from the left of the middle colic ves-
sels toward the patient’s right and inferiorly to expose the junction of
Technical Aspects of
Pancreatic Surgery
Charles H. C. Pilgrim, Douglas B.
Evans, and Kathleen K. Christians
7
Chapter 7 / Technical Aspects of Pancreatic Surgery 77
Tumor–Artery Relationship Tumor–Vein Relationship Extrapancreatic Disease
Resectable No radiographic evidence of
arterialabutment (celiac, SMA,
orhepatic artery)
Tumor-induced narrowing <50% of SMV, PV,
orSMV–PV
Nil
Borderline Tumor abutment (<180 degrees) of
theSMA or celiac artery
Tumor abutment or short-segment
encasement (>180 degrees) of
thehepatic artery
Tumor-induced narrowing of>50% of SMV, PV,
orSMV–PV conuence
Short-segment occlusion of SMV, PV, SMV–PV
withsuitable PV (above), and SMV (below)
toallow for safe vascular reconstruction
CT scan ndings suspicious,
but not diagnostic of
metastatic disease (e.g., small
indeterminate liver lesions that
are too small to characterize)
Locally advanced Tumor encasement (>180 degrees)
oftheSMA or celiac artery
Occlusion of SMV, PV, or SMV–PV without
suitablevessels above and below the tumor
toallow for reconstruction (no distal or
proximaltarget for vascular reconstruction)
No evidence of peritoneal, hepatic,
or extra-abdominal metastases
Metastatic N/A N/A Evidence of peritoneal or distant
metastases
SMA, superior mesenteric artery; SMV, superior mesenteric vein; PV, portal vein; SMV–PV, superior mesenteric–portal vein conuence
Medical College of Wisconsin CT-based Clinical Staging of Pancreatic Cancer
TABLE
7.1
Section I / Pancreas78
the middle colic vein and SMV. e retroperitoneal attachments of the
small bowel and right colon mesentery are taken down to a much greater
extent in patients with uncinate tumors extending into the small bowel
mesentery. When necessary, the small bowel mesentery can be mobi-
lized by incising the visceral peritoneum all the way up to the ligament
of Treitz (Cattell-Braasch maneuver).
2. e Kocher maneuver is begun at the third part of the duodenum by
identifying the inferior vena cava. All tissue medial to the right gonadal
vein and anterior to the inferior vena cava is elevated along with the
pancreatic head and duodenum. is dissection is continued to the left
lateral edge of the aorta, with exposure of the anterior surface of the left
renal vein. A complete Kocher maneuver is necessary for the subsequent
dissection of the pancreatic head from the SMA (step 6). Particularly
important is the division of the leaf of peritoneum that extends from
the retroperitoneum to the root of mesentery; incision of this portion of
peritoneum is perhaps the most important part of the Kocher maneuver.
3. e portal dissection is commenced by exposing the CHA proximal and
distal to the right gastric artery and the gastroduodenal artery (GDA).
Both the right gastric and the GDA are then ligated and divided. Division
of the GDA allows mobilization of the hepatic (common-proper) artery
o the underlying PV. Cholecystectomy is then performed, and the com-
mon hepatic duct is transected at or above its junction with the cystic
duct. Following transection of the bile duct, bile cultures are sent and
indwelling endobiliary stents are removed. A bulldog clamp is placed on
the transected hepatic duct to prevent bile from soiling the right upper
quadrant until biliary reconstruction is completed. Note, the PV should
always be exposed and the location of the right hepatic artery noted prior
to dividing the common hepatic duct.
e PV should be identied but not extensively mobilized until step
6, at which time the stomach and pancreas have been divided. Care must
be taken to avoid injury to the superior pancreaticoduodenal vein drain-
ing the pancreatic head at the superolateral aspect of the PV, or signicant
bleeding may occur when one does not yet have adequate exposure and
vascular control.
4. e terminal branches of the left gastric artery are ligated and divided
along the lesser curvature of the stomach prior to gastric transection. e
stomach is then transected with a linear gastrointestinal (GIA) stapler at
the level of the third or fourth transverse vein on the lesser curvature and
at the conuence of the gastroepiploic veins on the greater curvature to
complete a standard antrectomy (Fig. 7.1). e omentum is then divided
at the level of the greater curvature transection. In the pylorus-preserving
variant, the duodenum is divided just distal to the pylorus.
5. e loose attachments of the ligament of Treitz are taken down with care
to avoid injury to the inferior mesenteric vein (IMV) situated immedi-
ately to the patient’s left running caudal to cranial. e jejunum is then
transected with a linear GIA stapler approximately 8 to 10cm distal to
the ligament of Treitz and its mesentery sequentially ligated and divided
with an energy device such as the LigaSure. is dissection is continued
proximally to involve the fourth and third portions of the duodenum. e
duodenal mesentery is divided to approximately the level of the aorta,
allowing the devascularized segment of duodenum and jejunum to be
reected beneath the mesenteric vessels into the right upper quadrant.
6. is step is oncologically the most important and dicult part of the
operation. Traction sutures are placed on the superior and inferior
borders of the pancreas, and the pancreas is then transected with
Chapter 7 / Technical Aspects of Pancreatic Surgery 79
electrocautery at the level of the PV. ere is usually a small artery that
runs along the inferior border of the pancreas that is secured with the
traction sutures. If there is evidence of tumor adherence to the PV or SMV,
the pancreas is divided more upstream (to the tail) in the preparation for
segmental venous resection. e specimen is separated from the SMV
by ligation and division of the small venous tributaries to the uncinate
process and pancreatic head (Fig. 7.2). Complete removal of the uncinate
process from the SMV is required for full mobilization of theSMV–PV
conuence and subsequent identication of the SMA. Failure to fully
mobilize the SMV–PV conuence risks injury to the SMA and may result
in a positive SMA margin. In addition, without complete mobilization of
the SMV, it is dicult to expose the SMA. e inferior pancreaticoduode-
nal arteries (IPDAs) arising from the SMA must be identied and directly
ligated. Mass ligation of the IPDAs with mesenteric soft tissue is a com-
mon cause of postoperative hemorrhage as the vessels may retract with
the usual changes in blood pressure after extubation.
FIGURE 7.1 Illustration demonstrating completion of step 3 and step 4. The porta hepatis
has been dissected, with ligation of the gastroduodenal and right gastric arteries. The
gallbladder has been removed and the common hepatic duct transected (step 3). The antrum
of the stomach has been divided at the level of the third or fourth transverse vein on the
lesser curvature (step 4).
Section I / Pancreas80
Proper mobilization of the SMV involves identication of its rst
jejunal branch. is branch originates from the right posterolateral aspect
of the SMV (at the level of the uncinate process), travels posterior to the
SMA, and enters the medial (proximal) aspect of the jejunal mesentery.
e jejunal branch may course anterior to the SMA in up to 20% of cases,
a situation that makes this dissection somewhat simpler. If tumor involve-
ment of the SMV (at the level of the jejunal branch) prevents dissection of
the uncinate process from the SMV, the jejunal branch should be divided
proximal to the site of tumor encasement and again at its junction with
the main trunk of the SMV. Once the uncinate is separated from the distal
SMV, medial retraction of the SMV–PV conuence allows exposure of the
SMA. e specimen is then separated from the right lateral wall of the SMA,
which is dissected to its origin at the aorta; the plane of dissection should
be directly on the adventitia of this vessel (Fig. 7.3).
e pancreatic and common hepatic duct transection margins are
submitted for frozen-section evaluation. Positive resection margins dem-
onstrating invasive carcinoma on the biliary or pancreatic duct mandate
FIGURE 7.2 Illustration of step 6. The pancreatic head and uncinate process are being
separated from the SMV–PV conuence. The pancreas has already been transected at
the level of the PV. Small venous tributaries from the PV and SMV are ligated and divided
including delicate branches from the uncinate to the rst jejunal branch of the SMV.