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Chapter 5 / Pancreatic Cysts Including Intraductal Pancreatic Mucinous Neoplasm (IPMN) 61
more intensive surveillance approach. Even patients without evidence of
residual disease in the remnant gland are at risk of de novo development
of IPMN or progression of disease that was radiologically occult at the time
of resection. For these reasons, surveillance with cross-sectional imaging
should be undertaken at routine intervals. Finally, numerous reports have
described an elevated risk of concomitant gastrointestinal malignancy in
patients with MCN or IPMN of the pancreas. ese patients should be vigi-
lant with the American Cancer Society recommendations about screening
for prostate, colon, breast, and lung cancer. e clinician should maintain a
high index of suspicion for nonpancreatic neoplasia in these patients.
CONCLUSIONS
Cystic neoplasms of the pancreas are an increasingly recognized entity
with important clinical implications. e accurate diagnosis and charac-
terization of these lesions with clinical history, cross-sectional imaging (CT,
MRCP, EUS), as well as cytopathologic sampling are critical in oncologic
risk stratication and subsequent clinical decision making. e subset of
cysts with little to no malignant potential should only be considered for
resection in the setting of substantial size, mass eect, or refractory symp-
toms. Cysts with malignant features or high malignant potential should
be considered for operative resection in t patients. Primary surveillance
strategies may be acceptable for low-risk lesions, as pancreatic resection
carries substantial morbidity. Surveillance of the pancreatic remnant after
resection is dictated based on cyst diagnosis and dysplastic grade. In the
setting of IPMN, surveillance should be conducted indenitely as these
lesions are commonly multicentric and may recur or develop de novo in
the remnant gland.
Suggested Readings
Cauley CE, Waters JA, Dumas RP. Outcomes of primary surveillance for intraductal
papillary mucinous neoplasm. J Gastrointest Surg 2012;16(2):258–267; discussion
266.
D’Angelica M, Brennan MF, Suriawinata AA, et al. Intraductal papillary mucinous neo-
plasms of the pancreas: an analysis of clinicopathologic features and outcome.
Ann Surg 2004;239:400.
Katabi N, Klimstra DS. Intraductal papillary mucinous neoplasms of the pan-
creas: clinical and pathologic features and diagnostic approach. J Clin Pathol
2008;61;1303–1313.
Schmidt CM, White PB, Waters JA, et al. Intraductal papillary mucinous neoplasms:
predictors of malignant and invasive pathology. Ann Surg 2007;246(4):644–654.
Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the
pancreas: an updated experience. Ann Surg 2004;239:788–797.
Tanaka M, Fernández-del Castillo C, Adsay V, et al . International Consensus Guidelines
2012 for the Management of IPMN and MCN of the Pancreas. Pancreatolog y
2012;12(3):183–197.
Wargo JA, Fernandez-del-Castillo C, Warshaw AL. Management of pancreatic serous
cystadenomas. Adv Surg 2009;43:23–34.
Waters JA, Schmidt CM. Intraductal papillary mucinous neoplasm—when to resect?
Adv Surg 2008;42:87–108.
62
INTRODUCTION
Pancreatic neuroendocrine neoplasms are relatively rare. e incidence of clin-
ically detected cases is approximately 4 cases per million people per year in the
United States. Like the more common exocrine pancreatic adenocarcinoma,
they are capable of regional and distant metastatic dissemination. But, they
can also be relatively indolent. Indeed, autopsy studies suggest that the actual
incidence of pancreatic neuroendocrine neoplasms may be as high as 1.5%.
is combination of relative rarity and indolence has challenged the ability of
investigators to denitively characterize the natural history and optimal treat-
ment of this disease. However, recent studies to be outlined in this chapter have
yielded important new insights for the hepato-pancreatico-biliary surgeon.
ETIOLOGY
Initially believed to arise from the endocrine islets of Langerhans, recent
studies suggest that these neoplasms originate from pluripotent cells
within pancreatic ductules. As a result, previous descriptors like “islet cell
tumors” and “islet cell carcinomas” have been dropped in favor of “pancre-
atic neuroendocrine neoplasms.” Pancreatic neuroendocrine neoplasms
have been categorized into “functioning” variants (those that overproduce
pancreatic endocrine hormones capable of inducing specic clinical signs
and symptoms) and “nonfunctioning” variants (those that exhibit no clear
pattern of symptomatic hormonal overproduction).
Pancreatic neuroendocrine neoplasms can occur sporadically or as a
component of inherited genetic syndromes. Genetic and epigenetic altera-
tions of the p16/MTS1 tumor suppressor gene have been implicated in the
development of sporadic pancreatic neuroendocrine neoplasms. Whereas
loss of heterozygosity at chromosome 11q appears to be associated with
functional lesions, loss of heterozygosity at chromosome 6q has been asso-
ciated with nonfunctional neoplasms. e inherited genetic syndrome
most commonly associated with pancreatic neuroendocrine neoplasms
is multiple neuroendocrine neoplasia type 1 (MEN 1), an autosomal domi-
nant trait associated with mutations of the presumed tumor suppressor
gene menin. In addition, von Hippel-Lindau disease and neurobromatosis
type 1 are also associated with pancreatic neuroendocrine neoplasms.
DIAGNOSIS
Clinical Presentation
Historically, it was believed that functioning variants comprised the major-
ity of pancreatic neuroendocrine neoplasms; however, as more diagnoses
are being made by imaging and not by symptoms, most contemporary
series suggest that nonfunctioning neoplasms comprise the large majority.
Nevertheless, the often bizarre and characteristic behavior of functional
neoplasms warrants discussion of their various subtypes (Table 6.1).
Pancreatic Neuroendocrine
Neoplasms
Rebecca A. Busch and Clifford S. Cho
6
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 63
Neoplasm Common Clinical Characteristics Secretory Product Symptoms Diagnostic Criteria
Insulinoma Small (< 2 cm)
90% solitary
Evenly distributed throughout
pancreas
90% benign
Seen in 5%–8% of MEN1
Insulin
(promotes hypoglycemia)
Whipple triad:
1. Hypoglycemic symptoms
during monitored fast
2. Blood glucose < 50 mg/dL
with symptoms
3. Symptom relief after admin-
istration of glucose
During 72-hour fast:
Glucose < 50 mg/dL
Insulin > 5 μ/mL
Insulin: glucose ratio > 0.4
Elevated C-peptide, proinsulin
Gastrinoma Sporadic form: solitary
MEN1: multifocal
90% within gastrinoma triangle
50% malignant
30% present with metastases
15%–35% associated with MEN1
Gastrin
(promotes gastric acid
production)
Zollinger-Ellison syndrome:
90% gastroduodenal
ulcerations
75% epigastric pain
75% diarrhea
Gastrin > 10 × upper limit normal
Gastrin increase > 200 pg/mL
after secretin stimulation
Glucagonoma Large Glucagon “4 Ds”: Fasting glucagon > 1,000 pg/mL
Solitary
Body/tail of the pancreas
75% malignant
(promotes hyperglycemia,
amino acid metabolism)
Diabetes
Dermatitis (necrolytic
migratory erythema)
Deep venous thrombosis
Depression
Skin biopsy of necrolytic
migratory erythema
Summary of Functioning Pancreatic Neuroendocrine Neoplasms
TABLE
6.1
(Continued)
Section I / Pancreas64
Neoplasm Common Clinical Characteristics Secretory Product Symptoms Diagnostic Criteria
VIPoma Large
Solitary
Body/tail of the pancreas
Malignant
50% present with metastases
Vasoactive intestinal
polypeptide (VIP)
(promotes intestinal
secretion and motility
and inhibits intestinal
absorption)
Verner-Morrison/WDHA
syndrome:
Watery diarrhea
Hypokalemia
Achlorhydria/hypochlorhydria
Fasting VIP > 500 pg/mL
Somatostatinoma Large
Solitary
Head of the pancreas
Malignant
Commonly present with
metastases
Associated with von
Recklinghausen disease
(NFtype 1)
Somatostatin
(inhibits pancreatic
endocrine and exocrine
secretion and gallbladder
contractility)
Diabetes
Malabsorption
Cholelithiasis
Fasting somatostatin > 100 pg/mL
Summary of Functioning Pancreatic Neuroendocrine Neoplasms (Continued)
TABLE
6.1
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 65
Insulinomas are the most common type of functional pancreatic
neuroendocrine neoplasm. ey tend to be small (<
2
cm), solitary, benign
lesions that can arise anywhere within the pancreas and can be associated
with MEN1 (although less commonly than gastrinomas). e diagnosis
of insulinoma can be made by the classic Whipple triad of clinical nd-
ings: (1)symptoms of hypoglycemia during monitored fasting or exercise;
(2)blood glucose levels of less than 50mg/dL during these symptomatic epi-
sodes; and (3) relief of these symptoms following administration of glucose.
To detect the Whipple triad, patients with suspected insulinoma are closely
monitored during a 72-hour inpatient fast. Following measurement of base-
line serum glucose and insulin levels, blood glucose levels are measured
every 2 hours, and insulin levels are measured at the onset of hypoglyce-
mic symptoms or when blood glucose levels become lower than 50mg/dL.
Nearly all patients with insulinoma will have inappropriately elevated
plasma insulin levels (> 5 μU/mL) in the setting of hypoglycemia. Elevated
levels of C peptide and proinsulin are also typically present and help to dif-
ferentiate insulinoma from factitious hypoglycemia; the onset of symptoms
during fasting helps to dierentiate insulinoma from postprandial reactive
hypoglycemia.
Gastrinomas are the second most common type of functional pancre-
atic neuroendocrine neoplasm. Unlike insulinomas, 90% of gastrinomas
are found within the gastrinoma triangle: an anatomical region dened by
the cystic and common bile ducts superiorly, the second and third portions
of the duodenum inferiorly, and the pancreatic neck and body medially
(Fig.6.1). Two-thirds of gastrinomas are located within the pancreas, and a
third may be found within the duodenum. In sporadic, noninherited forms
of gastrinoma, tumors tend to be solitary. However, gastrinomas arising in
the context of MEN1 are multifocal and highly prone to recurrence. Because
of the ability of gastrin to induce gastric acid secretion, gastrinomas typi-
cally present with the classic and often refractory signs and symptoms of
Zollinger-Ellison syndrome, consisting of gastroduodenal ulcerations (90%),
epigastric pain (75%), diarrhea associated with the large-volume gastric
acid secretion (75%), and malabsorption leading to weight loss. e inci-
dence of gastrinoma among patients presenting with peptic ulcer disease
has been estimated to be approximately 1%, and this diagnosis should be
entertained in patients presenting with advanced or refractory peptic ulcer
disease. Unlike insulinomas, gastrinomas are often malignant, with about
50% of patients presenting with evidence of hepatic metastases.
Patients with suspected gastrinoma should undergo serum gastrin
measurement. e upper limit of normal gastrin level is approximately
100pg/mL; serum gastrin levels ten times greater than the upper limit
of normal in the presence of gastric pH less than 5.0 are diagnostic of
gastrinoma. However, patients with gastrinoma often present with more
subtle degrees of hypergastrinemia. e dierential diagnosis for mod-
erate hypergastrinemia includes achlorhydria (as can occur with proton
pump inhibitor therapy), retained antrum following partial gastrectomy,
gastric outlet obstruction, and renal insuciency. e secretin stimula-
tion test is a means of increasing the sensitivity of detecting gastrinoma.
Following intravenous administration of 2μg/kg secretin, a paradoxical
rise in serum gastrin by greater than 200pg/mL is considered positive
for gastrinoma. Similarly, a paradoxical rise in serum gastrin of greater
than 50% following infusion of calcium gluconate is also indicative of
gastrinoma.
Unlike insulinomas and gastrinomas, glucagonomas are characteristi-
cally larger lesions that tend to be localized along the body and tail of the
pancreas. Like gastrinomas, they exhibit a proclivity for aggressive behavior,
Section I / Pancreas66
with approximately 50% of cases harboring evidence of distant metastatic
disease. e ability of glucagon to promote gluconeogenesis and amino acid
oxidation explains the characteristic clinical ndings of diabetes (resulting
from hyperglycemia) and dermatitis (resulting from amino acid deciency).
Skin manifestations of dermatitis include necrolytic migratory erythema,
characterized by painful blistering plaques along the face, abdomen, lower
extremities, and mucous membranes. Interestingly, up to a third of patients
with glucagonoma develop deep venous thrombosis, warranting consider-
ation of anticoagulation therapy.
Serum glucagon levels greater than 1,000 pg/mL can be diagnostic
for glucagonoma. However, as with gastrinoma, more subtle elevations
can be seen in patients with glucagonoma. Unlike gastrinoma, provocative
testing is not available to help distinguish glucagonoma from potentially
confounding conditions that can induce hyperglucagonemia such as pan-
creatitis, sepsis, Cushing syndrome, fasting, renal insuciency, and hepatic
failure.
Like glucagonomas, VIPomas often present as large, solitary lesions
localized to the pancreatic body and tail and often present with evidence
of metastatic disease. Rare extrapancreatic VIPomas have been observed
in the colon, bronchus, liver, adrenal glands, and para-aortic ganglia.
Vasoactive intestinal polypeptide (VIP) promotes intestinal secretion and
FIGURE 6.1 Most gastrinomas are found within the gastrinoma triangle. (From: Mulholland
MW, Lillemoe KD, Doherty GM, et al. Greeneld’s surgery: scientic principles & practice,
5th ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2011.)
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 67
motility while inhibiting intestinal absorption of water and electrolytes.
As a result, the classic Verner-Morrison syndrome of VIPomas is also referred
to by the acronymic WDHA syndrome (consisting of massive watery diar-
rhea, hypokalemia, and achlorhydria). In patients presenting with profuse
secretory diarrhea, the diagnosis of VIPoma can be made by measuring
elevated fasting serum VIP levels (typically >
500 pg/mL).
In contrast to glucagonomas and VIPomas, the majority of somatostati-
nomas are found within the pancreatic head. Like gastrinomas and
VIPomas, somatostatinomas can present outside of the pancreas (most
commonly in the duodenum and ampulla). Duodenal somatostatinomas
are a common manifestation of von Recklinghausen disease (neurobroma-
tosis type 1). Pancreatic somatostatinomas tend to present as larger tumors
with metastatic disease. Somatostatin inhibits secretion of pancreatic insu-
lin and exocrine enzymes and inhibits gallbladder contractility; as a result,
somatostatinomas often present with symptoms of diabetes, malabsorp-
tion, and cholelithiasis. e diagnosis of somatostatinoma among patients
presenting with these symptoms is supported by elevated serum levels of
somatostatin greater than 100pg/mL.
Nonfunctioning pancreatic neuroendocrine neoplasms tend to pres-
ent evenly throughout all regions of the pancreas. Taken as a whole, they
were previously characterized as generally rarer, larger, and more aggres-
sive than functioning pancreatic neuroendocrine neoplasms. However,
these characterizations may have been historical artifacts of diagnosis.
As more and more pancreatic neuroendocrine neoplasms are being diag-
nosed incidentally with imaging evaluations rather than by symptoms
referable to hormonal production or tumor mass, the prevalence of small,
asymptomatic, nonfunctioning pancreatic neuroendocrine neoplasms
appears to be increasing. us, the extent to which functioning and non-
functioning pancreatic neuroendocrine neoplasms dier in term s of inher-
ent tumor biology and behavior is unclear. Nonfunctioning lesions can
occasionally secrete measurable levels of proteins that do not induce sig-
nicant symptomatology, but often do not express any known hormones.
As a result, elevated serum levels of proteins like pancreatic polypeptide,
neuron-specic enolase, and neurotensin can have high specicity but
very poor sensitivity in the diagnosis of nonfunctioning pancreatic neuro-
endocrine neoplasms.
Imaging and Localizing Studies
Diagnostic imaging for pancreatic neuroendocrine neoplasms takes advan-
tage of some of their unique biologic characteristics. e majority of pancre-
atic neuroendocrine neoplasms are markedly well vascularized. As a result,
contrast-enhanced imaging by computed tomography (CT) or magnetic
resonance imaging (MRI) should employ both early arterial and delayed
portal-phase imaging sequences, as they tend to appear very bright during
early arterial-phase administration of contrast (Fig. 6.2) or on portal-phase
imaging (Fig. 6.3). Radiographic diagnosis can be further enhanced with
MRI, as pancreatic neuroendocrine neoplasms tend to exhibit low signal
intensity on T1-weighted imaging and high signal intensity on T2-weighted
imaging (Fig. 6.4). ese imaging characteristics can also be used in the
detection of extrapancreatic metastases.
Another relevant biologic characteristic of pancreatic neuroendocrine
neoplasms is that they tend to grow as rounded, well-circumscribed l esions.
e ability of endoscopic ultrasonography (EUS) to clearly recognize these
morphologic characteristics (Fig. 6.5) may explain its heightened sensitiv-
ity in the detection of smaller lesions as compared with cross-sectional CT
and MRI. Intraoperative ultrasonography with direct probe application on
Section I / Pancreas68
the surface of the pancreas or duodenum can be especially useful in the
detection of occult and multifocal lesions (as can be seen with insulinomas
or with duodenal or pancreatic gastrinomas arising in a setting of MEN1).
Somatostatin receptor scintigraphy (octreotide scanning) takes
advantage of the fact that many pancreatic neuroendocrine neoplasms
FIGURE 6.2 CT imaging of neuroendocrine neoplasm arising from the uncinate process
demonstrates brisk uptake of contrast on early arterial-phase imaging (white arrow).
FIGURE 6.3 CT imaging of neuroendocrine neoplasm arising from the pancreatic head
demonstrates contrast enhancement on portal-phase imaging with areas of central necrosis
(white arrow).
Chapter 6 / Pancreatic Neuroendocrine Neoplasms 69
FIGURE 6.4 A. MRI imaging of neuroendocrine neoplasm arising from the pancreatic body
demonstrates a rounded lesion of low signal intensity on T1-weighted sequences (white
arrow). B. MRI imaging of the same neuroendocrine neoplasm arising from the pancreatic
body demonstrates high signal intensity on T2-weighted sequences (white arrow).
FIGURE 6.5 EUS imaging of the neuroendocrine neoplasm arising from the pancreatic tail
demonstrates a rounded and well-circumscribed lesion (black arrow).
Section I / Pancreas70
overexpress somatostatin receptor proteins. Octreotide is a somatostatin
analogue (and somatostatin receptor ligand) that can be radiolabeled
with
111
In and administered intravenously. Scintigraphic localization of
radiolabeled octreotide uptake, especially when used in conjunction with
single-photon emission computed tomography, can identify both primary
pancreatic neuroendocrine neoplasms and foci of metastatic disease with
high sensitivity. Recent analyses, however, suggest that they rarely yield
additional information beyond that which can be obtained with traditional
cross-sectional imaging studies alone. Of note, insulinomas typically do
not overexpress somatostatin receptor and are thus poorly visualized with
somatostatin receptor scintigraphy.
Venous sampling is a means of tumor localization that takes advantage
of pancreatic neuroendocrine neoplasm’s ability to secrete hormones into
the portal venous circulation. Now largely of historic interest, venous sam-
pling involves the placement of percutaneous transhepatic catheters into
the portal venous circulation. ese catheters can be positioned within the
portal vein, splenic vein, or superior mesenteric vein and are used to collect
venous blood samples for insulin or gastrin measurement. Identifying the
venous basin in which hormone levels are elevated may facilitate the local-
ization of radiographically occult insulinomas and gastrinomas. e utility
of this technique is enhanced with the addition of selective arterial stimula-
tion. In this approach, a percutaneous transarterial catheter is positioned
within the common hepatic artery, splenic artery, or gastroduodenal artery
and used for selective infusion of either secretin or calcium. e ability of
these agents to stimulate hormonal production can then be used to localize
tumors to various locations (e.g., pancreatic tail or body vs. pancreatic head
or neck, hepatic metastases) based on their arterial supply.
MANAGEMENT
Until recently, safe and eective chemotherapeutic agents were not avail-
able for the treatment of pancreatic neuroendocrine neoplasms. As a
result, surgical resection has been the mainstay of therapy for this disease.
Complete surgical resection remains the only potentially curative inter-
vention for pancreatic neuroendocrine neoplasms. However, because the
course of this disease can be gradual and indolent, operative intervention
has also been employed in the attempt to palliate symptoms and possibly
prolong survival for patients with metastatic disease.
Localized Disease
Surgical resection is the standard treatment intervention for patients
with localized and resectable pancreatic neuroendocrine neoplasm. The
specific type of resection is tailored to the location and distribution of
disease and to the patient’s ability to tolerate a major pancreatic resec-
tion. The standard operative approach for resection of tumors within
the pancreatic head or uncinate process is pancreaticoduodenectomy,
whereas left or distal pancreatectomy is reserved for tumors within the
pancreatic body or tail. Total pancreatectomy is typically reserved for
large or multifocal tumors involving the pancreatic head, neck, and
body. Central pancreatectomy has been advocated as a means of pre-
serving functional pancreatic parenchyma for patients with tumors
localized to the pancreatic neck or body; however, any potential advan-
tage in endocrine function must be counterbalanced by the risk of fistula
at the site of the pancreaticojejunostomy or pancreaticogastrostomy
that must be constructed to drain the pancreatic tail remnant. For small
tumors in locations not involving the main pancreatic duct, enucleation