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15 Surgical Treatment ofPancreatic Islet Cell Tumors
217
The anatomic location and local extent of the tumor are best dened with multiphasic, contrast-enhanced cross-sectional imaging of the abdomen, including either CT
or MRI.Intravenous contrast timing is essential when there is a question of vascular
involvement and critical to assess the liver with arterial and portal venous phase
imaging. Functional imaging with somatostatin receptor-based methods (e.g.,
68Ga-DOTATATE PET/CT or MRI) is useful to resolve diagnostic uncertainty on
cross-sectional imaging studies, to identify nodal involvement in normal or borderline enlarged nodes, to localize occult tumors, and to identify metastatic disease and
serves as a useful adjunct to standard cross-sectional imaging in the preoperative
workup. It has particular utility in MEN-1in identifying multifocal disease and
extrapancreatic tumors [32, 33] (Fig.15.1).
Endoscopic ultrasound (EUS) with or without biopsy may be used in cases where
the information gained would alter the management of the patient. Cross-sectional
imaging with CT or MRI is usually sufcient to determine resectability with respect
to vascular structures. EUS and biopsy may aid in determining the extent of resection in the presence of multiple masses on cross-sectional imaging or to conrm the
diagnosis in equivocal cases. As regional lymph nodes will be resected at the time
of surgery, there is likely no benet to sampling nodes prior to resection. EUS may
be useful as an adjunct to cross-sectional imaging in MEN-1 for identifying multifocal disease [34].
c
Fig. 15.1 DOTATATE PET CT scan for a 28-year-old man with MEN-1 with multiple pancreatic
neuroendocrine tumors. The patient had multifocal PNET with involved peripancreatic lymph
nodes (a and b), and underwent pancreaticoduodenectomy for a dominant 3cm mass in the uncinate process (best seen in c), with nal pathology demonstrating a well- differentiated, grade 2
neuroendocrine tumor with 5/26 lymph nodes positive
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J. Kearney et al.
Operative Approaches
Curative Intent
Resection of functional PNETs serves the dual purposes of diminishing risks associated with malignancy and denitively treating morbid endocrine syndromes. For
localized disease, the goal of surgery is removing the tumor with an R0 resection,
i.e., negative margins with no residual microscopic disease [8]. For patients with
MEN-1, the surgical techniques and principles are the same, but the risk/benet
analysis of surgery is different and is considered separately in section “MEN-1”
above. For most neuroendocrine tumors, an additional margin of normal soft tissue
is not required as the tumors are focal or discrete entities without the extensive inltration seen in other malignancies such as pancreatic adenocarcinoma. The extent of
resection is then determined by the lesion’s malignant potential and, moreover, by
the anatomic location. The extent of resection is considered below.
The data is mixed for the value of regional lymphadenectomy. The prognostic
signicance of lymph node metastases is unclear, although most surgeons would
remove suspicious nodes or nodes with biopsy-conrmed disease. Further, as the
risk of nodal metastases increases with the size of the primary lesion, lymphadenectomy is recommended for tumors over 1.5cm in size, although smaller tumors also
have signicant rates of nodal metastases [35]. Studies have demonstrated conicting conclusions such as the presence of metastatic disease within lymph nodes is not
associated with overall survival [36–38], is associated with diminished disease free
survival [35, 39, 40], is associated with survival in T1-T2 disease with no benet
seen with lymphadenectomy [41], or is associated with diminished overall survival
[35, 42]. Overall, formal lymphadenectomy should be considered in the case of
suspicion for nodal disease, in the setting of primary tumors larger than 1.5cm or
with other high-risk features, and in the setting of formal pancreatic resections. This
may ultimately diminish later complications from tumor burden, although evidence
supporting an impact on survival is lacking.
Pancreatic Resections
Pancreaticoduodenectomy
More commonly referred to as the Whipple procedure, this is the standard of care
for tumors in the head and uncinate process of the pancreas, which are to the right
of the superior mesenteric vein (SMV)/portal vein (PV) conuence as it courses
posterior to the pancreas. The approach (open, laparoscopic, or robotic) is determined on a case-by-case basis and by the surgeon’s preference and experience. The
surgery includes en bloc resection of the pancreatic head and uncinate process,
15 Surgical Treatment ofPancreatic Islet Cell Tumors
219
distal stomach and pylorus (classic pancreaticoduodenectomy), duodenum, proximal jejunum, distal common bile duct, and gallbladder. Reconstruction involves the
creation of several anastomoses, including gastrojejunostomy, hepaticojejunostomy, and pancreaticojejunostomy. This surgery requires patency of the celiac trunk
with antegrade ow through the hepatic artery since the gastroduodenal artery
(GDA), which may provide collateral ow retrograde from the superior mesenteric
artery (SMA) through the plexus of pancreaticoduodenal vessels, is ligated. Masses
in the pancreatic head and uncinate process must be conrmed not to involve the
celiac trunk or common hepatic artery or aberrant arterial variants, potentially precluding resection. Pancreaticoduodenectomy is a morbid procedure with a relatively
high rate of perioperative complications, including most commonly pancreatic stula, delayed gastric emptying, wound infection, hemorrhage, pancreatic endocrine
or exocrine insufciency, and pneumonia. Perioperative mortality is low in experienced centers, with rates less than 3% [43].
Distal Pancreatectomy
Distal pancreatectomy or left-sided pancreatectomy is the preferred procedure for
patients with tumors to the left of the SMV/PV conuence in the body or tail of the
pancreas. If the tumor is not apparent on gross examination, intraoperative ultrasound is a useful adjunct to physical examination to assist with localization of the
tumor. The resection begins with dissection and delineation of the splenic artery
after its takeoff from the celiac trunk and splenic vein before the conuence with the
SMV.This is followed by dissection of the distal pancreas with ligation of the pancreas proximal to the tumor. Splenectomy is often performed in cases with bulky
masses or concern for malignancy necessitating regional lymphadenectomy and
must be accompanied by vaccination against encapsulated organisms to reduce the
risk of overwhelming post-splenectomy infections [44, 45].
Total Pancreatectomy
Complete resection of the pancreas is rarely seen in the surgical treatment of pancreatic neuroendocrine tumors and is almost exclusively employed for the management of the multifocal disease in conjunction with a hereditary syndrome [46].
Patients undergoing this operation need counseling on the risks of labile insulindependent diabetes that ensues following this operation. The resection consists of
removing the pancreatic head/body/tail distal common bile duct, duodenum, and
often the spleen. The reconstruction involves mobilization of the proximal jejunum
and two anastomoses: a hepaticojejunostomy and a gastrojejunostomy. There are
variations to this procedure, including duodenal and spleen preserving techniques,
which are beyond the scope of this text.
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J. Kearney et al.
Enucleation
Excision of a mass along its capsule within the pancreatic parenchyma is a common
approach to small nonfunctional tumors in the head of the pancreas, insulinomas,
and multifocal disease in the setting of MEN-1. Larger tumors, tumors with concern
for malignancy or nodal involvement, or tumors within 2–3mm of the pancreatic
duct are not suitable for enucleation. These anatomic features are often determined
preoperatively with cross-sectional imaging but also veried intraoperatively with
ultrasound guidance. If a tumor is not amenable to enucleation, formal anatomic
resections are performed. Enucleation offers the benet of preserved pancreatic
parenchyma at the risk of a higher rate of postoperative pancreatic stulas [47].
Transduodenal Approach
Duodenotomy and local resection was investigated in the early 2000s for the management of small duodenal neuroendocrine tumors with some surgeons successfully resecting these lesions with endoscopic mucosal resections and laparoscopic
transduodenal resections. These approaches fell out of favor due to the prevalence
of lymph node metastases occurring in greater than 50% in patients with duodenal
NETs<2cm. At present, the standard of care for these lesions is a pancreaticoduodenectomy [48].
Nonlocalized Lesions
Exploration without preoperative localization almost exclusively occurs in the setting of Zollinger-Ellison syndrome due to the need for swift control of the gastrin
secreting tumor, which may be small and/or multifocal. In other tumors, patients
can often be medically managed and followed with serial imaging until their primary tumors are visualized on imaging. Experienced surgeons are able to locate a
nonlocalized gastrinoma nearly 100% of the time using palpation, ultrasound, and,
if warranted, duodenotomy [49].
Intraoperative ultrasound is also used to identify masses that are not readily palpated or identied on the surface of the pancreas. This modality helps to identify
and characterize small and/or multiple tumors and evaluate distance to the pancreatic duct in cases being considered for enucleation. This is particularly useful in the
setting of insulinoma, where the use of intraoperative ultrasound in combination
with preoperative modalities raises the probability of successfully identifying and
resecting small, solitary tumors to near 100% [50].
15 Surgical Treatment ofPancreatic Islet Cell Tumors
221
Contraindications andtheManagement ofAdvanced
andInoperable Disease
Surgery forAdvanced Disease
Resection is contraindicated when the anatomic distribution of metastatic disease or
advanced local disease precludes surgery or when a patient is unable to tolerate
surgery due to medical risks. For pancreatic tumor resections in general, intraoperative ultrasound can be employed to assist surgeons in dening key anatomical relationships to vessels throughout the progression of the surgery [51]. Locally advanced
tumors are inoperable if there is direct involvement of the celiac axis, SMA, and/or
common hepatic artery. However, unlike pancreatic adenocarcinoma, PNETs are
more likely to abut vessels without directly invading them, allowing resection even
in cases where masses appear to encroach on critical vessels [52]. Invasion of the
splenic artery and/or vein does not preclude surgery, and splenectomy may be a
necessary addition to pancreatic resection. Tumor involvement of the PV, SMV, or
adjacent organs (e.g., colon and stomach) also does not preclude resection, and
venous resection and reconstruction have comparable outcomes when performed at
an experienced center [53, 54]. Neoadjuvant therapies, including chemotherapy,
peptide receptor radionuclide therapy (PRRT), somatostatin analogues (SSA), and
radiation, have been employed to attempt to downstage tumors and facilitate resection with mixed success [55].
Numerous multimodal therapies may also be used outside the context of neoadjuvant therapy to treat metastatic disease. The choice of therapy necessarily
involves a multidisciplinary discussion involving surgery, medical oncology, gastroenterology, and interventional radiology. The decision on a specic therapy
depends on a number of factors: prior therapies and surgeries, patient functional
status and comorbidities, extent and location of disease, health and volume of
liver, and patient and provider preference. Systemic therapies include SSA, cytotoxic chemotherapy, molecular targeted therapies (everolimus, small molecule
tyrosine kinase inhibitors, and bevacizumab), and PRRT.For liver-dominant metastatic disease, a number of transarterial embolization approaches may be used to
limit tumor growth, including bland embolization, transarterial chemoembolization (TACE), and transarterial radioembolization (TARE). Percutaneous or surgical-assisted ablation (radiofrequency ablation, microwave ablation, cryoablation)
may also be used to manage smaller lesions, generally <3cm, that may be unresectable or in patients unable to undergo liver resection. Liver transplantation is
not generally considered an available option for patients with unresectable metastatic NET.
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J. Kearney et al.
Debulking andPalliative Resections
Metastases from PNETs typically involve regional lymph nodes and the liver. Bulky
primary lesions of the pancreas or regional lymph nodes are often symptomatic and
can lead to acute or subacute life-threatening complications in patients who may
otherwise live for years with metastatic disease. Such complications include gastric
outlet and bowel obstructions, bowel perforations, biliary obstructions and cholangitis, pancreatitis, and hemorrhage. Palliative resection of the primary tumor may
increase survival through local control [8, 56–58]. Debulking may prolong life not
only by preventing anatomic complications but may decrease the rate of future
metastasis and increase the sensitivity to systemic therapies, including PRRT [59].
For metastatic functional tumors, effective debulking, generally greater than
70% of tumor load, may offer symptomatic relief from medically refractory hypersecretion syndromes and improve survival. Patient selection in this setting is difcult as patient factors, rate of disease progression, number and size of liver lesions,
anatomic distribution, prior therapies, and sites of extrahepatic disease may inuence the decision to proceed with therapy. In addition, other local and regional therapies must be considered in addition to or instead of surgery.
Other Operative Considerations
Cholecystectomy
Cholecystectomy should be considered at the time of resection in all patients and
should be performed in patients anticipated to receive somatostatin analogue therapy unless there exists a specic contraindication. Somatostatin analogues are associated with a signicant increase in the risk of cholelithiasis and related complications
[60]. Additionally, patients who may undergo hepatic artery-directed therapies also
have a signicant risk of cholecystitis [61]. Cholecystectomy at the time of PNET
resection is associated with a signicant decrease in the rate of subsequent biliary
complications [60]. There are no data to support prophylactic cholecystectomy as a
separate operation in otherwise asymptomatic patients.
Perioperative Somatostatin Analogues
Somatostatin analogues are more frequently used during surgery for small bowel
NETs to prevent carcinoid crisis. Serotonin secretion has been reported during
resection of both functional and nonfunctional PNETs, and there are case reports of
carcinoid syndrome in PNET, but there is no unambiguous evidence of surgery
prompting carcinoid crisis in PNETs [62–64]. For functional PNETs, it is more
critical to manage the clinical hypersecretory syndromes to optimize patients for
15 Surgical Treatment ofPancreatic Islet Cell Tumors
surgery, which may include the use of SSAs in addition to syndrome-specic management (discussed in a prior chapter). There is no role for perioperative SSAs for
the prevention of carcinoid crisis.
223
Postoperative Care andComplications after
Pancreatic Resections
Postoperative Care
Over the past decade, there has been a nationwide trend among institutions toward
the adoption of enhanced recovery after surgery (ERAS) pathways after abdominal
surgery, including pancreatic resections. ERAS is a multipronged, evidence-based
approach to optimize patient care before, during, and after surgery to optimize outcomes for patients, including shorter lengths of stay, lower complication rates, and
better symptomatic management. These pathways often vary between institutions
but typically involve several core components [65]. In the preoperative period,
attention is given to identifying and optimizing comorbidities, functional status, and
nutrition using objective, validated tools. Patients are also counseled on what to
expect with their perioperative course so that patient expectations are in line with
both the expected postoperative course as well as potential complications.
Perioperative care includes utilizing objective measures to guide uid resuscitation,
using of multimodal analgesia including neuraxial techniques, and pursuing minimally invasive operative techniques as a given procedure allows. Postoperative care
focuses on expediting a return to functional recovery including early removal of
drains and tubes, reinstitution of enteral nutrition, early ambulation, and multidisciplinary discharge planning to ensure an optimal transition out of the hospital that
may prevent the need for readmission [65, 66].
Although the evidence supporting drain placement after pancreaticoduodenectomy
is mixed, recent retrospective studies support drain placement and following drain
amylase levels for the early detection of clinically relevant postoperative pancreatic
stula (CR-POPF) [67, 68]. In a recent retrospective analysis, postoperative hemorrhage requiring either reoperation or endovascular repair occurred in 3.3% of cases in
the postoperative period. The complications most commonly requiring re-intervention
include GI complications from anastomotic issues and incisional hernias [69].
Postoperative Complications
Complications after complex resections involving the liver, biliary tree, and pancreas are not unexpected and frequently result after what would be considered a
technically optimal procedure. Complications in this setting are anticipated and
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J. Kearney et al.
proactively managed. The use of ERAS protocols and consolidation of technically
challenging procedures in high-volume centers helps to diminish rates of complications and improve outcomes [70].
Pancreatic Fistula
A common complication after pancreatic resection, with an average preoperative
risk of 15%, although varying greatly depending on operative risk factors, is the
development of clinically relevant postoperative pancreatic stula [71, 72]. After
pancreatic resection, including both anatomic resection and enucleation, there is a
risk of failure of the transected pancreatic ducts to seal, allowing pancreatic uid
with digestive proteases to leak. These leaks delay healing of the pancreas, impair
initiation of adequate nutrition, and may also result in prolonged drainage of pancreatic uid. Factors associated with pancreatic leak include intraoperative blood
loss, gland texture (rm/soft), history of pancreatitis, and main pancreatic duct size
[71, 73]. Risks of pancreatic leak after enucleation approach those of pancreaticoduodenectomy and distal pancreatectomy in some series [74, 75].
Leaks are categorized by clinical severity and range from asymptomatic (grade
A; detected on biochemical analysis of drain uid), to involving escalation of postoperative care (grade B; requiring drainage and medical management), to requiring
reoperation or resulting in single or multisystem organ failure (grade C) [76]. Grades
B and C leaks may cause infected intra-abdominal uid collections, hemorrhage,
ileus and delayed gastric emptying, malnutrition, and wound complications.
Pancreatic stula is most commonly managed with percutaneous drain placement,
if a drain was not left at the time of surgery; nutritional management with an effort
to reduce stimulation of pancreatic secretion through low-fat and low-protein diets
or total parenteral nutrition; and use of somatostatin analogues to decrease pancreatic uid production [77, 78]. Additional care, such as antibiotics, gastric drainage,
and wound management, is frequently required. Drain placement at the time of
surgery is a controversial topic; drains are typically left at the time of surgery in an
effort to mitigate the effects of a pancreatic leak, particularly in high-risk patients,
although the absolute benet of this approach has not been demonstrated [79].
Uncommonly, refractory leaks that continue after a period of weeks may be managed with further intervention, including pancreatic duct stent placement or additional surgery.
Pancreatic Insufciency
Following pancreatic resection, patients may develop exocrine pancreatic insufciency and/or endocrine pancreatic insufciency. The risk of pancreatic insufciency is related to the preoperative function of the pancreas, which may be
diminished in the setting of prior pancreatitis, metabolic syndrome, and/or resection, and the extent of pancreatic resection. Concern for pancreatic insufciency
15 Surgical Treatment ofPancreatic Islet Cell Tumors
225
contributes to the decision for parenchyma-sparing enucleation in tumors at a low
risk of malignancy or in patients at high risk of multiple surgical resections (MEN-1).
Exocrine pancreatic insufciency, dened by inadequate production of pancreatic juice containing alkaline uid and digestive enzymes in response to a food
bolus, may occur in up to three-fourths of patients after pancreaticoduodenectomy
or distal pancreatectomy [80]. This typically results in malabsorption manifest by
bloating, cramping, steatorrhea, and, in severe cases, malnutrition and vitamin deciency. Management includes dietary modication with low-fat meals, administration of exogenous pancreatic enzymes, supplementation of fat-soluble vitamins, and
consideration for supplementation with medium-chain triglycerides. Inadequate
endocrine pancreatic function results in pancreatogenic diabetes mellitus (type 3c)
and is managed with treatment of concomitant exocrine insufciency, dietary modication, close blood glucose monitoring, and exogenous insulin. Treatment with
metformin, insulin sensitizers, secretagogues, incretin-based therapies, or other specic medications should be considered by endocrinologists in the appropriate setting [81]. In one series, the risk of developing insufciency is approximately 16%
after pancreaticoduodenectomy and 21% after distal pancreatectomy [82].
Conclusion
The surgical management of PNETs is dependent on the tumor’s functional status,
location, histology/grade, and genetic predisposition. The approach chosen is
dependent on both the tumor type and predisposition for malignancy, as well as the
location of the tumor. All of these procedures have risks and potential complications
that need to be weighed against patient’s comorbidities and the goals of resection
(i.e., curative or palliative). These patients are best managed and treated in coordination with a multidisciplinary team at high-volume centers.
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