to help further characterize hepatic lesions. Resolution of some lesions may be slightly better with MRI.

Additionally, certain lesions, such as hemangiomas and cysts, can easily be identified based on MRI

characteristics when the CT characteristics are indeterminate (Fig. 57-16). The disadvantages of MRI are

its increased cost, increased amount of time to perform, inability to quickly screen other organs and

body cavities within the same session, and wide variability in quality from one imaging center to

another.

7 Magnetic resonance cholangiopancreatography (MRCP) is becoming more widely used to

noninvasively view biliary anatomy (Fig. 57-17). The scans are heavily T2 weighted, which maximizes

the signal from the biliary tree. No injection of contrast agent is needed, and under optimal conditions

the resulting imaging can rival that of formal cholangiography. Three-dimensional reconstructions can

be performed to view the biliary tree from multiple angles and can be helpful in distinguishing between

stones, strictures, and neoplasms. Again, these reconstructions are vital to donor selection in live donor

liver transplantation. Rarely is it necessary to proceed with endoscopic retrograde

cholangiopancreatography (ERCP) to define the distal intrahepatic ductal anatomy.

Figure 57-15. Three-dimensional reconstruction of the hepatic vasculature.

Ultrasonography

8 Hepatic ultrasonography can be applied transcutaneously or intraoperatively via open or laparoscopic

surgery. It can be useful in identifying lesions within the hepatic parenchyma, to describe the

consistency (i.e., fatty or cirrhotic) and identify dilation of the biliary tree and any abnormalities or

stones within the gallbladder. In hepatobiliary surgical centers, intra operative ultrasonography is used

routinely to assess the anatomy of the pedicles (portal vein, hepatic artery, and bile duct), the hepatic

veins, and the hepatic parenchyma. It is useful both to further identify and characterize lesions within

the hepatic parenchyma and to delineate their relationships within the eight anatomic segments of the

liver. Additionally, it is often helpful to delineate proximity of lesions to major vascular structures and

to survey for abnormal anatomy in planning a resection.

With ablation therapies more commonly employed, ultrasound has become indispensable in directing

the use of radiofrequency ablation. This ablation therapy can be performed percutaneously,

laparoscopically, and during open surgery.

9 Typically, intraoperative assessment of the liver involves examining the portal pedicles. The main

portal pedicle is identified within the hepatoduodenal ligament. It is followed superiorly to the portal

bifurcation into the main right and left pedicles. The portal pedicles are invested with the Glisson

capsule and have a very echogenic covering to them in contrast to hepatic vein branches. The main right

portal pedicle is followed toward the right where it gives off an anterior branch and a posterior branch

(Fig. 57-18A). The right anterior branch gives off separate pedicles to segment V (caudad) and to

segment VIII (cephalad). The right posterior branch gives off separate pedicles to segment VI (caudad)

and to segment VII (cephalad). The main left pedicle is usually much longer and courses intact to the

base of the umbilical fissure before branching into various segmental pedicles (Fig. 57-18B). At the base

of the umbilical fissure, the main left pedicle courses anteriorly toward the round ligament and gives off

a pedicle to segment IV medially and pedicles to segments II and III laterally. Next, if the falciform

ligament has been divided, the hepatic veins can easily be visualized using intraoperative

ultrasonography (Fig. 57-18C). As described previously, usually a larger right hepatic vein can be

1462

delineated and smaller left and middle hepatic veins joining into a common trunk before emptying into

the IVC are seen. Commonly, an umbilical hepatic vein branch can be identified coursing between the

middle and left hepatic veins and running under the falciform ligament. Not uncommonly, significant

accessory right hepatic veins can be seen emptying from the posterior surface of the right liver directly

into the IVC as it courses posterior to the liver. The identification of these accessory right hepatic veins

is potentially important for both vascular control and preservation of outflow from the liver (in

occasional cases where outflow of the remnant right liver can be supported by a very large accessory

vein). Finally, the hepatic parenchyma is systematically scanned to identify lesions within the liver (Fig.

57-18). It is sometimes useful to adjust the ultrasound settings on a known lesion defined preoperatively

to maximize the echogenicity in the hopes of identifying other occult lesions not identified

preoperatively.

Figure 57-16. A,B: T1-weighted magnetic resonance imaging (MRI) with gadolinium from the same patient as in Figure 57-14

with history of colorectal cancer and three lesions in the liver. Lesion 1 in segment VIII is irregular and rim enhancing and was a

colorectal cancer metastasis. Lesion 2 straddling segments IV and VIII has smooth borders, is not rim enhancing, and was found to

be a cyst. Lesion 3 straddling segments IV and III across the umbilical fissure is irregular, rim enhancing, and was a colorectal

cancer metastasis. C,D: T2-weighted MRI from the same patient with history of colorectal cancer and three lesions in liver. Lesion

1 in segment VIII is irregular and mildly bright and was a colorectal cancer metastasis. Lesion 2 straddling segments IV and VIII

has smooth borders, is very bright, and was found to be a cyst. Lesion 3 straddling segments IV and III across the umbilical fissure

is mildly bright and was a colorectal cancer metastasis. Colorectal metastases and many tumors are mildly bright on T2-weighted

MRI, whereas cysts and hemangiomas are typically very bright.

Positron Emission Tomography

Positron emission tomography (PET), especially when combined with CT (PET-CT), has become a

valuable tool in helping to select patients who will most benefit from aggressive liver resection. This

technique is based on the increased metabolism of glucose in neoplastic tissues. A glucose analog,

fluorodeoxyglucose, that is tagged with fluorine-18 is injected intravenously before scanning and is

retained preferentially in metabolically active tumors over normal tissue. Sometimes PET scans will

identify areas of occult disease within the liver, but more importantly, they can identify areas of

extrahepatic occult disease previously unsuspected. When combined with a CT scanner within the same

machine and the ability to fuse images, the areas of increased activity can be more precisely

anatomically identified (Fig. 57-19).

1463

Figure 57-17. Magnetic resonance cholangiopancreatography (MRCP) of a patient after cholecystectomy with mild dilation of

common hepatic duct (CHD). The pancreatic duct (PD) is also visible.

Correlation of Computed Tomographic Images with Segmental Anatomy

Preoperative CT remains the primary imaging modality used by most surgeons before hepatic resection.

Figure 57-14 is provided to help correlate CT images to the segmental anatomy defined previously. The

segments of the liver are defined using identifiable structures on the CT (Fig. 57-20).

PREOPERATIVE EVALUATION OF HEPATIC RESERVE

Whenever a surgical resection is planned, an important consideration is whether the remnant liver will

be sufficient to regenerate and sustain the patient long term. In patients with relatively normal hepatic

parenchyma (without active hepatitis, cirrhosis, or metabolic defects), up to 75% of the hepatic volume

can be resected with good recovery as long as the remnant liver has adequate portal venous and hepatic

arterial inflow, adequate hepatic venous outflow, and adequate biliary drainage. Many groups around

the world have used various strategies to predict hepatic reserve (Tables 57-1 to 57-3). None of these

tests or strategies has been demonstrated to clearly better predict outcome than another. Many centers

in the United States rely simply on the Child–Pugh or MELD score and the prediction of adequate liver

remnant volume after resection. In select circumstances, it may be of benefit to perform portal vein

embolization to the right or left half (rare) of the liver in the hopes of obtaining compensatory

hypertrophy of the other side before resection. This is especially useful when the predicted liver

remnant after resection is small or if the patient has an underlying hepatic dysfunction that may not

allow the remnant to fully regenerate and sustain the patient long term. To gain maximal growth of the

left lateral section of the liver, some centers will also embolize the portal vein branches to segment IV

in addition to the main right portal vein. The disadvantages of portal vein embolization include the need

to wait 3 to 4 weeks before resection to allow the compensatory hypertrophy to occur and, for more

central lesions, the need to commit to taking out one or the other side with an extended hepatectomy

without the benefit of intraoperative evaluation.

1464

 

Figure 57-8. Variations in hepatic arterial anatomy.

Hepatic Arteries

3 There is much variability in the hepatic arterial supply to the liver. The most common anatomy is a

common hepatic artery that arises from the celiac trunk and courses near the superior border of the

neck of the pancreas. After the origins of the gastroduodenal, supraduodenal, and right gastric arteries,

the proper hepatic artery courses in the left anterior aspect of the hepatoduodenal ligament in front of

the portal vein and to the left of the common hepatic duct. The proper hepatic artery usually bifurcates

into right and left hepatic arteries outside the liver. The anatomy of the hepatic artery is variable and

should be familiar to surgeons operating in this area (Fig. 57-8). Approximately 45% of people have

variant hepatic arterial anatomy.9 The right hepatic artery usually courses posterior to the common

hepatic duct but anterior to the right portal vein to supply the right liver. The left hepatic artery usually

remains extrahepatic until near the base of the umbilical fissure, where it enters the liver to give off

branches to segments II, III, and IV. Small branches from near the bifurcation of the proper hepatic

artery also supply segment I. A middle hepatic artery branch may arise from either the right or left

hepatic arteries after bifurcation. Although this anatomy is described as normal, it is found only in

approximately 50% to 60% of patients. A replaced or accessory right hepatic artery may arise off of the

superior mesenteric artery near its origin and course posteriorly or through the head of the pancreas to

lie along the right posterior border of the hepatoduodenal ligament. A replaced or accessory left hepatic

artery may arise off of the left gastric artery and course transversely toward the base of the umbilical

fissure in the lesser omentum. In general, within the hepatic parenchyma, the hepatic arterial branches

course closely with bile duct branches and fairly closely with portal venous branches, but not always,

and anatomic variations should be suspected. The descriptions and frequency of hepatic arterial variants

have been well characterized by Michels.9

Intrahepatic Biliary Tree

The right and left livers are respectively drained by the right and left hepatic ducts, whereas the caudate

(segment I) is drained by several small ducts joining the confluence and the first several centimeters of

1457

both hepatic ducts. The intrahepatic ducts are tributaries of the corresponding hepatic ducts, which

penetrate the liver invaginating the Glisson capsule at the hilus. Bile ducts are usually located above the

corresponding portal branches, whereas hepatic arterial branches run inferiorly to the veins. The left

hepatic duct directly drains the bile ducts to segments II, III, and IV, which constitute the left liver. The

right hepatic duct drains the bile ducts from segments V, VI, VII, and VIII, which constitute the right

liver. Usually, the bile ducts from segments V and VIII join to first form the anterior sectoral duct and

the bile ducts from segments VI and VII join to first form the posterior sectoral duct prior to forming

the right hepatic duct (Fig. 57-9).

Figure 57-9. Intrahepatic divisions of the bile ducts and hepatic arteries.

Gallbladder

4 The gallbladder is a reservoir for bile located on the undersurface of the liver at the confluence of the

right and left halves of the liver. It is separated from the hepatic parenchyma by a cystic plate, which is

constituted of connective tissue applied to the Glisson capsule. The gallbladder may be deeply imbedded

into the liver or occasionally presents on a mesenteric attachment, but usually lays in a gallbladder

fossa. The gallbladder varies in size and consists of a fundus, a body, and an infundibulum. The tip of

the fundus usually reaches the free edge of the liver and is closely applied to the cystic plate. The

infundibulum of the gallbladder makes an angle with the body and may obscure the common hepatic

duct, constituting a danger point during cholecystectomy. The cystic duct arises from the infundibulum

of the gallbladder and extends to join the common hepatic duct. The lumen measures between 1 and 3

mm in diameter, and its length varies depending on the type of union with the common hepatic duct

(Fig. 57-10). Callot triangle is bounded by the common hepatic duct on the left, the cystic duct

inferiorly, and the cystic artery superiorly. Arterial blood reaches the gallbladder via the cystic artery,

which usually originates from the right hepatic artery. Several known variations in the origin and

course of the cystic artery are illustrated in Figure 57-11. The venous drainage of the gallbladder is

directly into the liver parenchyma or into the common bile duct plexus.

1458

Figure 57-10. Variations in the junction of the cystic duct and common hepatic duct.

Figure 57-11. Variations of the cystic artery.

Common Bile Duct

The cystic and common hepatic ducts join to form the common bile duct. The common bile duct is

approximately 8 to 10 cm in length and 0.4 to 0.8 cm in diameter. The common bile duct can be divided

into three anatomic segments: supraduodenal, retroduodenal, and intrapancreatic (Fig. 57-12). The

supraduodenal segment resides in the hepatoduodenal ligament lateral to the hepatic artery and anterior

1459

to the portal vein (Fig. 57-13). The course of the retroduodenal segment is posterior to the first portion

of the duodenum, anterior to the IVC, and lateral to the portal vein. The pancreatic portion of the duct

lies within a tunnel or groove on the posterior aspect of the pancreas. The common bile duct then enters

the medial wall of the duodenum, courses tangentially through the submucosal layer for 1 to 2 cm, and

terminates in the major papilla in the second portion of the duodenum (Fig. 57-12). The distal portion

of the duct is encircled by smooth muscle that forms the sphincter of Oddi. The common bile duct

usually joins the pancreatic duct to form a common channel before entering the duodenum at the

ampulla of Vater. Some patients will have an accessory pancreatic duct emptying into the duodenum.

5 The blood supply of the common bile duct is segmental in nature and consists of branches from the

cystic, hepatic, and gastroduodenal arteries. These meet to form collateral vessels that run in the 3 and

9 o’clock positions. The venous drainage forms a plexus on the anterior surface of the common bile duct

that enters the portal system. The lymphatic drainage follows the course of the hepatic artery to the

celiac nodes.

LIVER IMAGING

Computed Tomography

Computed tomography (CT) is widely available and quick and has become the main modality to initiate

the assessment of hepatic processes. It also has the advantage of being able to quickly assess other

organs within the abdominal cavity and chest. With the introduction of multidetector spiral CT, the

resolution of hepatic lesions is quite good. This scanning technique allows total hepatic imaging in

arterial, portal venous, and delayed phases after a rapid intravenous contrast bolus during a single

breath hold by the patient (Fig. 57-14). In addition, three-dimensional reconstructions can be created to

construct high-quality hepatic artery angiograms, portal venograms, and hepatic venograms. These

reconstructions play a vital role in the selection of appropriate donors for live donor liver

transplantation (Fig. 57-15). Drip infusion cholangiography with CT can provide distal intrahepatic duct

cholangiograms that with the three-dimensional arteriograms and venograms are vital in planning donor

hepatectomies and avoiding serious complications.

Figure 57-12. Anatomy of the extrahepatic biliary tree and pancreatic duct.

1460

Figure 57-13. Relationship of structures within the hepatoduodenal ligament.

Figure 57-14. Portal venous phase of computed tomography (CT) scan from a patient with a history of colorectal cancer and three

lesions in the liver. Lesion 1 in segment VIII is irregular and rim enhancing and was a colorectal cancer metastasis. Lesion 2

straddling segments IV and VIII has smooth borders, is not rim enhancing, and was found to be a cyst. Lesion 3 straddling segments

IV and III across the umbilical fissure is irregular and rim enhancing and was a colorectal cancer metastasis.

Magnetic Resonance Imaging

6 Magnetic resonance imaging (MRI) of the liver with gadolinium as a contrast agent is commonly used

1461

 

dividing loose areolar tissue (Fig. 57-2). Neoplastic or inflammatory conditions may obliterate these

planes. Superiorly and anteriorly, the diaphragm or abdominal wall and liver may jointly be involved in

a pathologic process. Posteriorly, the right adrenal gland or upper pole of the right kidney may involve

or be involved by the liver. Inferiorly, the gallbladder, colon, duodenum, or periportal lymphatics may

be involved. Cancers of the stomach or gastroesophageal junction may involve the left liver or vice

versa.

MORPHOLOGIC AND FUNCTIONAL ANATOMY

The description and definition of the anatomic divisions of the liver have been revised and written

about numerous times in the past 100 years.1–8 At present, there is still confusion between the various

hepatic anatomic nomenclatures in the English and French literature. Based only on morphologic criteria

and surface anatomy, the liver can be divided into right and left halves by forming a plane through the

gallbladder fossa (Cantlie line) and inferior vena cava (IVC) (Fig. 57-3). As will be shown later, this

plane approximates the true division between the right and left halves using the more strict definition of

a plane through the middle hepatic vein and IVC, but the middle hepatic vein is not obvious based

solely on morphology and without ultrasound. Further subdivisions of the right half of the liver into a

right anterior sector and a right posterior sector are not possible based only on surface anatomy. The

left half of the liver can be further subdivided into a left medial section and left lateral section based on

the umbilical fissure and falciform ligament. The caudate (tail-shaped) process of the liver is identified

as lying posterior to the gastrohepatic ligament and emanating from a process of liver situated posterior

to the main portal pedicle and anterior to the IVC.

Figure 57-1. Posterior view of the liver, showing the level of peritoneal reflections.

Figure 57-2. Posterior view of the liver, showing organs that produce impressions on its inferior surface.

1453

Figure 57-3. Anatomic division of the liver into right and left halves by a plane extending from the gallbladder fossa posteriorly to

the inferior vena cava.

Figure 57-4. Functional divisions of the liver and liver segments according to Couinaud nomenclature with the liver in the natural

position (A) and after it is mobilized (B).

1 The most widely accepted nomenclature is based on Couinaud’s description of the discrete anatomic

segments of the liver (Fig. 57-4).6 The eight segments of a liver can be determined using surface

anatomy and location of the three main hepatic veins, the portal pedicle bifurcation into right and left,

and the umbilical fissure and falciform ligament. As described, the right and left halves of the liver are

delineated by a plane through the middle hepatic vein and IVC. Segments II, III, and IV lie to the left of

this plane and form the left half of the liver. Segments V, VI, VII, and VIII lie to the right of this plane

and form the right half of the liver. Segment I, or the caudate process, is morphologically distinct from

the two halves of the liver and emanates from a process of liver lying posterior to the portal pedicle and

anterior to the IVC. Whereas the right and left halves of the liver derive blood supply from the

corresponding right and left portal veins and hepatic arteries, segment I derives blood supply from both.

Additionally, the right half of the liver has venous drainage primarily through the right and middle

hepatic veins, and the left half of the liver primarily through the left and middle hepatic veins. Segment

I, however, drains directly via small branches into the IVC. The left liver and especially the right liver

usually have small accessory hepatic venous branches draining directly into the IVC. Occasionally on the

right, the accessory branch is significant in size.

The right half of the liver can be further subdivided using a plane through the right hepatic vein and

the IVC. Liver anterior to this plane forms the right anterior sector, and liver posterior to this plane

forms the right posterior sector. The right anterior sector of the liver is composed of segment V

(inferior to the portal bifurcation) and segment VIII (superior to the portal bifurcation). The right

posterior sector of the liver is composed of segment VI (inferior to the portal bifurcation) and segment

VII (superior to the portal bifurcation).

The left half of the liver can be further subdivided using a plane through the umbilical fissure and

falciform ligament. Liver medial to this plane forms the left medial section of the liver or segment IV,

and liver lateral to this plane forms the left lateral section of the liver. The left medial section of the

liver is sometimes divided into two halves, with IVa closer to the IVC and IVb farther. The left lateral

section of the liver is further subdivided into segment II (which is superior) and segment III (which is

inferior).

Hepatic Veins

2 Three major hepatic veins carry blood from the liver to the IVC. Most patients have a right hepatic

1454

vein that joins the right anterior wall of the IVC and middle and left hepatic veins that converge into a

common trunk about 1 cm from the IVC that enters the left anterior wall of the IVC (Fig. 57-5). In some

patients, the three main hepatic veins join the IVC via three distinct trunks. These hepatic veins usually

lie within the hepatic parenchyma. Usually, a definable extraparenchymal segment of the hepatic veins,

especially the right, can be dissected out before it empties into the IVC, which makes outflow control

safer and easier. Usually, multiple accessory right hepatic veins empty from the right half of the liver

directly into the IVC as it courses posterior to the liver (Fig. 57-6). On occasion, these accessory right

hepatic veins are sizable and may even support venous outflow should the native right hepatic vein

need to be taken. Additionally, sometimes an umbilical vein can be appreciated running to the falciform

ligament between the middle and left hepatic veins and emptying into the terminal portion of the left

hepatic vein.

Portal Veins

The superior mesenteric and splenic veins join posterior to the neck of the pancreas to form the main

portal vein. It receives pyloric and coronary vein branches as it courses cephalad and obliquely to the

right to form the most posterior structure within the hepatoduodenal ligament (portal triad). In the

hilus of the liver, the main portal vein bifurcates into a short oblique right portal vein and a longer,

more transverse, and more superficial left portal vein (Fig. 57-7). These branches then enter the

parenchyma and become invested along with the other components of the portal triad by extensions of

the Glisson capsule. Both the right and left portal veins give off small branches to dually supply segment

I. The right portal vein usually enters the hepatic parenchyma immediately and is quick to divide into a

right anterior portal vein supplying segments V and VIII and a right posterior portal vein supplying

segments VI and VII. The left portal vein may remain near the surface of the left half of the liver in the

hilar plate for a significant distance as it courses to the umbilical fissure to give off medial branches to

segment IV and lateral branches to segments II and III.

Figure 57-5. Three major hepatic veins drain the liver. The caudate segment of the liver usually drains directly into the inferior

vena cava.

1455

Figure 57-6. Retraction of right liver medially exposes small venous tributaries that drain the right liver directly into the

retrohepatic vena cava. Several branches are ligated.

Figure 57-7. Intrahepatic divisions of the portal vein.

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SECTION H: HEPATOBILIARY AND PORTAL VENOUS SYSTEM

1451

Chapter 57

Hepatobiliary Anatomy

Trevor L. Nydam and Richard D. Schulick

Key Points

1 The most widely accepted nomenclature for liver anatomy is based on Couinaud’s description of

eight anatomic segments of the liver.

2 There are three major hepatic veins, with most patients having a right hepatic vein that joins the

right anterior wall of the inferior vena cava (IVC) and middle and left hepatic veins that converge

into a common trunk before joining the IVC.

3 Classic hepatic arterial anatomy exists in only approximately 50% of patients, with a replaced or

accessory right hepatic artery arising from the superior mesenteric artery and a replaced or

accessory left hepatic artery arising from the left gastric artery being the most common variants.

4 Callot triangle is bounded by the common hepatic duct on the left, the cystic duct inferiorly, and the

cystic artery superiorly.

5 The blood supply of the common bile duct is segmental in nature and consists of branches from the

cystic, hepatic, and gastroduodenal arteries, which meet to form collateral vessels that run in the 3

and 9 o’clock positions.

6 Multiphase computed tomography (CT) and magnetic resonance imaging (MRI) with intravenous

contrast are commonly used to characterize hepatic lesions.

7 Magnetic resonance cholangiopancreatography (MRCP) is often used to view biliary anatomy as it

involves no contrast agent and optimally can provide images that rival formal cholangiography.

8 Intraoperative ultrasonography is used routinely to assess the anatomy of the hepatic pedicles

(portal vein, hepatic artery, and bile duct) and hepatic veins and to identify and characterize hepatic

lesions within the parenchyma and their relationships within the eight anatomic segments.

9 The portal pedicles are invested with the Glisson capsule and have a very echogenic covering to

them on ultrasound in contrast to hepatic vein branches.

10 The steps involved in major hepatectomy include optimal exposure, vascular inflow control, vascular

outflow control, and parenchymal transection.

A precise knowledge of the anatomy of the liver and biliary tract and their relationship to associated

blood vessels is essential for the performance of hepatobiliary surgery. Every surgeon caring for a

patient with a hepatobiliary problem should have a thorough understanding of the general anatomy and

an absolute understanding of each individual patient’s anatomy, because variations are common.

TOPOGRAPHIC ANATOMY

The normal adult liver is a large, wedge-shaped organ that occupies much of the right upper quadrant of

the abdomen. Most of the liver bulk lays to the right of the midline where it molds to the undersurface

of the right diaphragm, and where the lower border coincides with the right costal margin. The liver

extends as a wedge to the left of the midline between the anterior surface of the stomach and the left

dome of the diaphragm. The anterior surface of the liver is invested by visceral peritoneum that extends

to the anterior abdominal wall in the midline from the ligamentum teres, or round ligament (the

obliterated umbilical vessels), and by an obliquely oriented fusion of peritoneum known as the falciform

ligament. Posteriorly, the investing peritoneum is contiguous with the peritoneum of the diaphragm and

covers the liver, except for a bare area bounded by the right and left triangular ligaments (Fig. 57-1). The

Glisson capsule is a thin, fibrous covering that envelops the liver deep to the peritoneum, sending

fibrous septa into the hepatic parenchyma investing the portal structures.

Ordinarily, the liver can be separated from adjacent organs and structures by simply moving it or

1452

 

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73. Norton JA, Shawker TH, Doppman JL, et al. Localization and surgical treatment of occult

insulinomas. Ann Surg 1990;212(5):615–620.

74. Vinik AI, Moattari AR, Cho K, et al. Transhepatic portal vein catheterization for localization of

sporadic and MEN gastrinomas: a ten-year experience. Surgery 1990;107(3):246–255.

75. Pedrazzoli S, Pasquali C, Miotto D, et al. Transhepatic portal sampling for preoperative localization

of insulinomas. Surg Gynecol Obstet 1987; 165(2):101–106.

76. Vinik AI, Delbridge L, Moattari R, et al. Transhepatic portal vein catheterization for localization of

insulinomas: a ten-year experience. Surgery 1991; 109(1):1–11; discussion 111.

77. Fraker DL, Norton JA. Localization and resection of insulinomas and gastrinomas. JAMA

1988;259(24):3601–3605.

78. Imamura M, Takahashi K, Adachi H, et al. Usefulness of selective arterial secretin injection test for

1446

 

treated without surgery. These data provide compelling evidence that patients with sporadic gastrinoma

benefit from surgical exploration and complete tumor resection.

The management of gastrinoma in MEN-1 is not as clear. The surgical treatment of hypercalcemia

caused by parathyroid hyperplasia should precede any surgery for hypergastrinemia in patients with

MEN-1. In these patients, gastrin-secreting tumors are often multicentric and associated with lymph

node metastases. Although some groups have favored exploration only when MEN-1 gastrinoma tumors

exceed 3 cm, it seems that earlier intervention may be warranted.125,126 Unfortunately, more data from

an appropriate clinical trial are needed to better define the timing of surgery for MEN-1 gastrinoma.

In the 1950s and 1960s, most gastrinomas were diagnosed late in the course of the disease, when the

tumor burden was already significant. At that time, effective medical therapy did not exist, nor did

sophisticated radiographic localization and staging techniques. Patients often suffered multiple ulcer

complications, required total gastrectomy to control the ulcer diathesis, and typically succumbed to

continued tumor growth following gastrectomy. Recent reviews of patients with surgically treated

gastrinoma provide room for optimism.127–130 Currently, up to 35% of patients who undergo resection

with curative intent have been rendered eugastrinemic at follow-up. Cure rates approach 60% to 70%

when the extent of disease allows a complete resection.

Most patients with incurable metastatic disease eventually die of tumor growth and dissemination.

Multiple modalities have been used to treat such patients. Chemotherapy including streptozocin, 5-

fluorouracil, and doxorubicin provides response rates of less than 50%.131 Hormonal therapy with

octreotide may relieve symptoms, reduce hypergastrinemia, and diminish hyperchlorhydria.132,133 In

patients with hepatic metastases, aggressive resection for debulking,134–137 hepatic transplantation,138

hepatic artery embolization, and interferon therapy have all been used, with variable results.

VIPOMA (VERNER–MORRISON SYNDROME)

Synonyms for VIPoma include WDHA syndrome (watery diarrhea, hypokalemia, and either achlorhydria

or acidosis) and pancreatic cholera syndrome (Table 56-8). Verner and Morrison139 characterized this

secretory diarrheal syndrome in a 1958 report. Patients characteristically present with intermittent,

severe, watery diarrhea averaging up to 5 L/d. Hypokalemia results from fecal loss of large amounts of

potassium. Low serum potassium levels lead to lethargy, muscle weakness, and nausea. A metabolic

acidosis may be present, due to loss of bicarbonate in the diarrhea. Half of the patients may have

hyperglycemia or hypercalcemia, and cutaneous flushing can be observed in a minority. The diagnosis

of VIPoma is made after other common causes of diarrhea have been excluded (Table 56-9)140 and an

elevated serum VIP level is documented.

Table 56-8 VIPoma

Table 56-9 Differential Diagnosis of Verner–Morrison Syndrome

1439

Figure 56-9. Several computed tomographic images from a patient with a primary vasoactive intestinal polypeptide-oma (VIPoma)

in the tail of the pancreas. The tumor is nearly spherical. Its location is posterior to the stomach and adjacent to the spleen.

VIP secretion can be episodic, so repeated fasting levels should be measured if there is a strong

clinical suspicion. Preoperative tumor localization is critical, because 10% of patients may have

extrapancreatic tumors located in the retroperitoneum or chest. Most tumors are located in the distal

pancreas where they are amenable to resection via distal pancreatectomy (Fig. 56-9). In most cases,

hepatic metastases accompany the primary tumor. Therapies directed at debulking these metastases

such as resection or ablative strategies are appropriate.

Surgical excision is appropriate in nearly all patients with Verner–Morrison syndrome. Prior to

surgery, fluid and electrolyte imbalances must be corrected. Octreotide can serve as a treatment

adjunct, reducing the levels of circulating VIP, with a resultant decrease in the volume of diarrhea.

Octreotide is also useful for symptom control in the setting of unresectable disease. Chemotherapy

specific for this disease has not been well studied.

GLUCAGONOMA

10 The most common findings in the glucagonoma syndrome are severe dermatitis, mild diabetes,

stomatitis, anemia, and weight loss (Table 56-10). The dermatitis manifests as a characteristic skin rash

1440

termed necrolytic migratory erythema. This rash exhibits cyclic migrations, and it has been theorized that

the hypoaminoacidemia accompanying glucagonoma is the cause.

Table 56-10 Glucagonoma

The diagnosis of glucagonoma is suggested by the clinical presentation and biopsy of the skin lesions

but is secured by the documentation of high fasting levels of serum glucagon. Most glucagonomas are

located in the body and tail of the gland. These tumors are typically large and bulky, and surgical

resection requires distal pancreatectomy (Fig. 56-10). Metastases are found in most patients and safe

debulking of these should be considered.141 As in patients with VIPoma and insulinoma, octreotide can

be useful in controlling the signs and symptoms (hyperglycemia and dermatitis) associated with

incurable glucagonoma.

SOMATOSTATINOMA

The somatostatinoma syndrome is the least common of the five generally accepted functional pancreatic

endocrine neoplasia syndromes, occurring in less than 1 in 40 million people. The clinical features are

nonspecific including steatorrhea, diabetes, hypochlorhydria, and cholelithiasis (Table 56-11). Fasting

plasma somatostatin levels of greater than 100 pg/mL can be used to confirm the diagnosis.

Most somatostatinomas are located in the pancreatic head or periampullary region.142 Tumors are of

variable size and are often easily localized. Metastatic disease may be present at the time of diagnosis.

Safe resection of the primary tumor (often via pancreaticoduodenectomy) and careful debulking of

hepatic metastases are indicated.

Figure 56-10. Computed tomography with oral and intravenous contrast in a patient with a glucagonoma. The large tumor

appears to be posterior to the stomach and to the right of the aorta from the viewer’s perspective.

Table 56-11 Somatostatinoma

1441

NONFUNCTIONAL PANCREATIC ENDOCRINE NEOPLASMS

Currently, the majority of patients with neoplasms of the endocrine pancreas have no defined clinical

syndrome and no elevated functional hormone levels. Pancreatic PP and chromogranin A levels may be

elevated, though neither is associated with a clinical syndrome. A study by Mutch et al.143 determined a

relationship between fasting plasma PP levels in patients with MEN-1 and the presence of

radiographically detectable pancreatic endocrine tumor. A PP level that is more than three times the

age-specific normal value is 95% sensitive and 88% specific for a PEN that can be imaged. The majority

of patients with nonfunctional endocrine tumors are asymptomatic, however, those who present with

symptoms will typically complain of abdominal pain, weight loss, or jaundice, caused by the spaceoccupying nature of the mass in the pancreas. Overall, nonfunctional tumors tend to grow more slowly

and have a more indolent course than the highly lethal pancreatic ductal adenocarcinoma, yet the 5-year

survival rate for PENs after resection remains only 65%, with a 10-year survival of 45%.10

Patients with operable disease should undergo formal surgical resection for potential cure via

pancreaticoduodenectomy or distal pancreatectomy, depending on tumor location. Tumor enucleation,

without formal resection may be appropriate for patients with small tumors (<2 cm), significant

medical comorbidities, or those documented to have a low proliferative index (Ki-67). Patients with

locally advanced disease involving the mesenteric vasculature may be candidates for radical mesenteric

vascular resection (Fig. 56-11). With successful treatment, these patients can expect to enjoy a median

survival in excess of 5 years.144,145

METASTATIC PANCREATIC ENDOCRINE TUMORS

At least one-third of patients with malignant PENs present with synchronous liver metastases at the time

of diagnosis.146 A subset of these patients remain asymptomatic and experience prolonged survival even

without aggressive therapy.104 However, overall 5-year survival with liver metastases is less than

50%.147 PENs are one of the few tumors for which a survival advantage for surgical debulking has been

shown.135,146,148–150 In those selected patients where safe surgical resection of greater than 90% of the

tumor burden can be achieved, 5-year survival rates of 60% to 75% have been reported.

Those with unresectable disease to the liver may be candidates for a variety of hepatic directed

therapies for locoregional control and symptom palliation. These include hepatic artery embolization,

radiofrequency/microwave ablation, and infusional chemotherapy.151 Metastatic PENs have shown

partial responses to chemotherapy. In 1992, the results of a trial conducted by the Eastern Cooperative

Oncology Group (ECOG) were published.104 In this study, 105 patients with advanced nonfunctional

endocrine tumors were randomly assigned to one of three groups. The lowest response rate (30%) was

seen in patients receiving chlorozotocin alone, an intermediate response rate (45%) was seen in patients

receiving the combination of streptozotocin plus 5-fluorouracil, and the highest response rate (69%) was

noted in patients receiving streptozotocin plus doxorubicin. The last regimen also showed significant

survival advantage in comparison with the other two treatments. More recent attempts to replicate

these results have been disappointing.152

1442

Figure 56-11. Computed tomography of a patient with a large PEN(*) replacing the pancreatic body and tail(*), with splenic vein

occlusion, perigastric varices (blue line), and tumor thrombus (red line) growing into the portal vein. This patient underwent a distal

pancreatectomy, splenectomy, and partial portal vein resection with tumor thrombectomy, with complete surgical extirpation of

the malignancy.

Somatostatin analogs are another approach to treating metastatic PENs. Results are more favorable in

tumors that have high-affinity receptors (gastrinomas, VIPomas, glucagonomas, and some nonfunctional

tumors) as compared to insulinomas. Symptomatic improvement occurs in 60% to 90% of patients.

However, an objective tumor response is seen in only 5% to 15% of patients, with stabilization of

disease in 50% or more of patients.153–155 In patients who fail to respond to traditional somatostatin

analogs, such as octreotide and lanreotide, the novel multireceptor-targeted somatostatin analog

pasireotide has shown the ability to offer symptom reduction, primarily because of its ability to bind to

four of the five known somatostatin receptor subtypes.156

Two new targeted therapies have been approved for use in the setting of advanced metastatic PENs

based upon the results of large multicenter phase 3 clinical trials. The first is the agent sunitinib malate

(Sutent, Pfizer Inc.), an oral, small molecule, multitargeted tyrosine kinase inhibitor initially approved

for the treatment of advanced renal cell carcinoma and refractory gastrointestinal stromal tumors. It has

activity against VEGF and PDGF. In a large (171 patients) multinational, randomized, double-blind,

placebo-controlled phase 3 trial in patients with advanced, well-differentiated PENs, patients receiving

sunitinib had a median progression-free survival of 11.4 months compared with 5.5 months in the

placebo group (p < 0.001).157 The second agent everolimus, an oral inhibitor of the mammalian target

of rapamycin (mTOR) was also tested in a large (410 patients) international, randomized, double blind,

placebo-controlled phase 3 trial (RADIANT-3), in patients with advanced low- and intermediate-grade

PEN. The median progression free survival of patients in the everolimus arm was 11 months compared

to 4.6 months in the placebo arm (p < 0.001). Both of these oral agents have a favorable side-effect

profile, and further studies to delineate their role in the treatment of PENs are currently underway.158

References

1. Lawrence B, Gustafsson BL, Chan A, et al. The epidemiology of gastroenteropancreatic

neuroendocrine tumors. Endocrinol Metab Clin North Am 2011;40(1):1–18.

2. Yao JC, Hassan M, Phan A, et al. One hundred years after “carcinoid”: epidemiology of and

prognostic factors for neuroendocrine tumors in 35,825 cases in the United States. J Clin Oncol

2008;(18):3063–3072.

3. Nicholls AG. Simple adenoma of the pancreas arising from an island of Langerhans. J Med Res

1902;8:385–395.

4. Pour PM, Schmied B. The link between exocrine pancreatic cancer and the endocrine pancreas. Int J

Pancreatol 1999;25(2):77–87.

5. Apel RL, Asa SL. Endocrine tumors of the pancreas. Pathol Annu 1995; 30:305–349.

6. Vortmeyer AO, Huang S, Lubensky I, et al. Non-islet origin of pancreatic islet cell tumors. J Clin

1443

 

the withholding of exogenous glucose). During a monitored fast, blood is sampled for glucose and

insulin determinations every 4 to 6 hours and when symptoms appear. Hypoglycemic symptoms

typically occur when glucose levels are below 50 mg/dL, with concurrent serum insulin levels often

exceeding 25 microunits/mL. Additional support for the diagnosis of insulinoma comes from the

calculation of the insulin-to-glucose ratio at different times during the monitored fast. Normal persons

have insulin-to-glucose ratios below 0.3, whereas patients with insulinoma typically demonstrate

insulin-to-glucose ratios above 0.4 after a prolonged fast. Other measurable β-cell products synthesized

in excess in patients with insulinoma include C peptide and proinsulin. Elevated levels of both are

typically found in the peripheral blood of patients with insulinoma.

The possibility of the surreptitious administration of insulin or oral hypoglycemic agents should be

considered in all patients with suspected insulinoma. Levels of C peptide and proinsulin are not elevated

in patients who self-administer insulin. Additionally, patients self-administering either bovine or porcine

insulin may demonstrate anti-insulin antibodies in circulating blood. The ingestion of oral hypoglycemic

agents, such as sulfonylureas, can be assessed by means of standard toxicologic screening.

7 Insulinomas are evenly distributed throughout the pancreas, with one-third found in the head and

uncinate process, one-third in the body, and one-third in the tail of the gland.85 Less than 3% are located

outside the pancreas, with these lesions located in the peripancreatic area.86 Ninety percent are found to

be benign solitary adenomas amenable to surgical cure. Ninety percent of insulinomas are sporadic,

with approximately 10% being associated with the MEN-1 syndrome. In patients with MEN-1, the

possibility of multiple insulinomas must be considered, and recurrence rates are higher. In

approximately 10% of patients, insulinoma is metastatic to the peripancreatic lymph nodes or liver,

making the diagnosis of malignant insulinoma.

Figure 56-6. The technique for enucleating a benign pancreatic endocrine neoplasm with scissors (A) or electrocautery (B). C:

After enucleation, the site of excision is drained.

After the diagnosis of insulinoma has been confirmed biochemically, the appropriate localization and

staging studies described earlier are performed (typically CT and EUS). Once the lesion has been

localized,87 patients undergo surgical exploration, where the pancreas is assessed not only by operative

palpation but also by intraoperative ultrasonography. This allows for confirmation of preoperative

localization and evaluates for the presence or absence of multiple primary tumors. Small, benign tumors

that are not close to the main pancreatic duct can be removed by enucleation88 (Fig. 56-6), regardless of

their location in the gland. Larger tumors in the neck or proximal body may be resected via central

pancreatectomy.89–91 In the body and tail of the pancreas, insulinomas more than 2 cm in diameter and

those close to the pancreatic duct are most commonly removed via distal pancreatectomy. Large lesions

in the head or uncinate process of the gland may not be amenable to local resection and may

occasionally require pancreaticoduodenectomy for complete excision.92,93 Increasingly, experienced

surgeons are utilizing a laparoscopic approach to these tumors. Both laparoscopic pancreatectomy and

1435

enucleation are now performed on a routine basis with excellent results.94–98

In rare instances, preoperative localization studies and intraoperative ultrasound fail to identify the

tumor. Intraoperative biopsy of the pancreatic tail may help make the diagnosis of nesidioblastosis as

the cause of hyperinsulism. Some authors have recommended a “blind” distal pancreatic resection to the

level of the superior mesenteric vein (60% to 70% pancreatectomy), in the hope of excising an

unidentified insulinoma in the body and tail. Others have suggested blind pancreaticoduodenectomy,

because the thickness of the gland in this region makes it more likely to harbor an occult neoplasm. The

favored approach at the current time is to defer any blind resection, close the patient without

pancreatectomy, and perform postoperative selective arterial calcium stimulation with hepatic venous

insulin sampling to allow for specific tumor localization and directed surgical excision at a second

operation.99

Approximately 10% of insulinomas are malignant, presenting with lymph node or liver metastases. In

the presence of hepatic metastases, resection of the primary tumor and accessible metastases should be

considered if it can be performed safely.100–102 Such tumor debulking can be helpful in reducing

hypoglycemic symptoms and improving long-term survival. In patients with unresectable disease,

medications such as diazoxide and octreotide can be used to reduce insulin secretion from the tumor,

minimizing hypoglycemia. One promising new treatment is everolimus, an oral rapamycin analog that

inhibits mammalian target of rapamycin (mTOR). In a pilot study of patients with refractory

hypoglycemia due to metastatic insulinoma, everolimus resulted in improved glycemic control.103

Dietary manipulations, including judicious spacing of carbohydrate-rich meals and the consumption of

nighttime snacks, can also reduce the number of hypoglycemic episodes. Multiple chemotherapeutic

regimens have been used including streptozocin, dacarbazine, doxorubicin, and 5-fluorouracil.104–106

Combination chemotherapy has yielded the highest response rates but has not been shown to be

curative.

GASTRINOMA (ZOLLINGER–ELLISON SYNDROME)

8 In 1955, Zollinger and Ellison described two patients with severe peptic ulcer disease and pancreatic

endocrine tumors and postulated that an ulcerogenic agent originated from the pancreatic tumor.107–109

It has been estimated that approximately 1 in 1,000 patients with primary duodenal ulcer disease and 2

in 100 patients with recurrent ulcer after ulcer surgery harbor gastrinomas.110 Seventy-five percent of

gastrinomas occur sporadically, and 25% are associated with the MEN-1 syndrome. Historically, the

majority of gastrinomas were found to be malignant, with metastatic disease present at the time of

initial workup. With increased awareness and screening for hypergastrinemia, the diagnosis of

gastrinoma is made earlier and a higher percentage of patients present with benign and potentially

curable neoplasms.111

Table 56-6 Gastrinoma

The clinical symptoms of patients with gastrinoma are a direct result of increased levels of circulating

gastrin (Table 56-6). Abdominal pain and peptic ulceration of the upper gastrointestinal (UGI) tract are

seen in up to 90% of patients. Diarrhea is seen in 50% of patients, with 10% having diarrhea as their

only symptom. Esophageal symptoms or endoscopic abnormalities resulting from gastroesophageal

reflux are seen in up to half of patients. The diagnosis of gastrinoma should be suspected in several

clinical settings, including the initial diagnosis of peptic ulcer disease, recurrent ulcer after medical or

surgical therapy, postbulbar ulcer, family history of ulcer disease, ulcer with diarrhea, prolonged

undiagnosed diarrhea, MEN-1 kindred, nongastrinoma pancreatic endocrine tumors (high association of

secondary hormone elevations), and prominent gastric rugal folds on UGI examination. Serum gastrin

1436

levels should be obtained in all of these settings.

In most patients with gastrinoma, the fasting serum gastrin level is greater than 200 pg/mL. Gastrin

levels greater than 1,000 pg/mL in the setting of documented hyperacidity and ulcer disease are

virtually pathognomonic for gastrinoma. Because hypergastrinemia can occur in other pathophysiologic

states (Table 56-7), fasting hypergastrinemia alone is not sufficient for the diagnosis of gastrinoma.

Gastric acid analysis (or at least gastric pH testing) is critical in differentiating between ulcerogenic

(high levels of acid) and nonulcerogenic (low levels of acid) causes of hypergastrinemia. To obtain an

accurate gastric acid analysis, patients must not be taking antisecretory medications including histamine

(H2

)-receptor antagonists or proton pump inhibitors (PPIs). The diagnosis of gastrinoma is supported by

a basal acid output above 15 mEq/hr in nonoperated patients, a basal acid output exceeding 5 mEq/hr

in patients with previous vagotomy or ulcer operations, or a ratio of basal acid output to maximal acid

output exceeding 0.6.

Table 56-7 Disease States Associated With Hypergastrinemia

Figure 56-7. Results of intravenous secretin stimulation tests in patients with atrophic gastritis (triangles), gastric outlet obstruction

(squares), and gastrinoma (circles). A positive test result, consistent with the presence of gastrinoma, is indicated by an increase

over basal serum gastrin levels of at least 200 pg/mL. (Adapted from Wolfe MM, Jensen RT. Zollinger-Ellison syndrome: current

concepts in diagnosis and management. N Engl J Med 1987;317:1200–1209.)

After documenting that hypergastrinemia and excessive acid secretion exist, provocative testing with

secretin should be performed to differentiate between gastrinoma, antral G-cell hyperplasia or

hyperfunction, and the other causes of ulcerogenic hypergastrinemia. This is achieved with a secretin

stimulation test (Fig. 56-7). A baseline gastrin level is drawn. The patient is then stimulated with 2

units/kg of secretin as an intravenous bolus and subsequent gastrin samples are collected at 5-minute

intervals for 30 minutes. An increase in the gastrin level by more than 200 pg/mL above the basal level

supports the diagnosis of gastrinoma.

After the biochemical diagnosis of gastrinoma has been made, the gastric acid hypersecretion should

be pharmacologically controlled. The PPIs are now considered the drugs of choice for doing so.112,113

The dose is adjusted to achieve a nonacidic pH during the hour immediately before the next dose of the

drug. Typically, PPI doses needed for acid control exceed usual dosing levels. After the initiation of

antisecretory therapy, all patients should undergo imaging studies to localize the primary tumor and to

assess for metastatic disease.

If localization studies reveal unresectable hepatic metastases, the patient should undergo

percutaneous or laparoscopic-directed liver biopsy to obtain a definitive histologic diagnosis. These

patients should be maintained on long-term PPI therapy. Virtually all patients can be rendered

achlorhydric with an appropriate dose of PPIs. Patients noncompliant with antisecretory therapy who

experience complications related to their ulcer diathesis may require removal of the end organ (total

1437

gastrectomy) if tumor resection is not possible. However, total gastrectomy, once the operation of

choice for gastrinoma, is now only rarely used.

9 If unresectable disease is not identified by staging studies, patients should be offered surgical

exploration with curative intent. On exploration, the entire abdomen should be assessed for areas of

extrapancreatic and extraduodenal gastrinomas. Most gastrinomas are found in the gastrinoma

triangle85,114 (Fig. 56-8), the area to the right of the superior mesenteric vessels, in the head of the

pancreas or in the duodenal wall. Both intraoperative ultrasound and intraoperative upper endoscopy

may be helpful in tumor localization. Transillumination of the duodenum may help identify small

duodenal gastrinomas.115,116 Well-encapsulated tumors less than 2 cm in size and distant from the

pancreatic duct can be enucleated. Those situated deep in the parenchyma may require partial resection

by pancreaticoduodenectomy or distal pancreatectomy. If no pancreatic tumor is identified, a

longitudinal duodenotomy should be performed at the level of the second portion of the duodenum in

search of duodenal microgastrinomas.117,118 Small gastrinomas in the duodenal wall can be locally

resected with primary closure of the duodenal defect. The routine use of duodenotomy increases the

short- and long-term cure rates in patients with sporadic gastrinoma, because such a duodenotomy

allows detection of more duodenal gastrinomas.119 Duodenotomy did not impact the occurrence of

hepatic metastases or disease-related mortality. In a small percentage of patients, gastrinoma is found

only in peripancreatic lymph nodes, with these lymph nodes harboring the apparent primary tumor.

Resection of these apparent lymph node primary gastrinomas has been associated with long-term

eugastrinemia and biochemical cure in up to half of cases.120 A review from the National Institutes of

Health identified likely primary lymph node gastrinomas in 26 of 176 gastrinoma patients (14.7%),

with 69% being eugastrinemic at a mean of 10 years after resection.121

Figure 56-8. Most gastrinomas are found within the gastrinoma triangle.

Occasionally, preoperative localization studies may identify the tumor in the gastrinoma triangle, but

at the time of exploration, the tumor is not demonstrable. Several surgical options are available at this

point. First, a parietal cell vagotomy has been proposed as a way to reduce antisecretory drug dose

requirements in patients on high-dose antisecretory drug therapy but without prior life-threatening

complications.122 However, this approach leaves behind potentially resectable gastrinoma and has lost

favor as an option. A second option is total gastrectomy; however, the availability of PPIs has

drastically reduced the need to perform this operation for gastrinoma. It may have a limited role in

patients whose tumors cannot be localized, if they cannot or will not take their PPIs. Like parietal cell

vagotomy, this leaves tumor behind. A third, controversial option in patients with localization to the

gastrinoma triangle is blind pancreaticoduodenectomy. Some argue this should include distal

gastrectomy, as duodenal gastrinomas may arise close to the pylorus and be left behind during a

pylorus-preserving resection.

Patients with sporadic gastrinomas tend to fare better following resection than those with MEN-1. In

a series of 151 patients reported by Norton et al.,123 123 had sporadic gastrinoma and 28 had MEN-1–

associated gastrinoma. Of those with sporadic gastrinoma, 34% were free of disease 10 years following

resection. None of the MEN-1 patients were free of disease at 10 years. A more recent review of 195

patients from the same institution demonstrated clear superiority of surgical intervention over other

treatment strategies.124 The rate of disease-related death was increased 23-fold in the group of patients

1438

 

Figure 56-4. Schematic depiction of data from percutaneous transhepatic portal venous sampling (PTPVS) in a patient with an

insulinoma. Insulin levels are given in microunits per milliliter. These data localize the neoplasm to the head of the pancreas.

(Adapted from Norton JA, Sigel B, Baker AR, et al. Localization of an occult insulinoma by intraoperative ultrasonography. Surgery

1985;97:381–384.)

Venous Sampling

Percutaneous transhepatic portal venous sampling (PTPVS) and arterial stimulation with venous

sampling (ASVS) are two techniques that are used exclusively for the diagnosis and localization of PENs.

In a small number of cases, CT, MRI, SRS, and EUS are unsuccessful at localizing a PEN. When

insulinoma or gastrinoma are suspected, PTPVS may help in localizing the occult neoplasm.73–77 The

technique involves placing a catheter percutaneously through the liver into the portal vein and then

sequentially sampling for hormone levels in the splenic vein, superior mesenteric vein, and portal vein,

thereby regionalizing the location of hormone production (Fig. 56-4). The overall accuracy of this test

ranges from 70% to greater than 95% depending on the number of samples obtained, the persistence of

autonomous hormone production by the tumor, and the careful handling and assaying of all samples.

ASVS involves the selective visceral arterial injection of secretin or calcium with concurrent hepatic

venous sampling for either gastrin or insulin.78,79 Gastrinoma cells are known to respond to secretin by

releasing gastrin,80,81 and insulinoma cells are known to respond to calcium by releasing insulin. The

provocative secretogogue is serially injected through an arterial catheter into at least three sites – the

splenic, gastroduodenal, and inferior pancreaticoduodenal arteries. Samples are drawn from a hepatic

vein catheter before and immediately after each injection. The arterial supply to the occult tumor can

then be deduced based on which selective secretogogue injection is followed by a large increase in

hepatic vein hormone concentration (Fig. 56-5). This technique, particularly when combined with

intraoperative ultrasonography, results in a sensitivity of greater than 90%, essentially obviating the

need for blind resection in unlocalized insulinomas.71,82 Additionally, ASVS can differentiate the 5% of

patients with nesidioblastosis from those with insulinoma.83

SURGICAL EXPLORATION

At the time of surgical exploration for PEN, a complete evaluation of the pancreas and peripancreatic

regions is performed. The body and tail of the pancreas are exposed by dividing the gastrocolic ligament

and entering the lesser sac. This portion of the pancreas can be partially elevated out of the

retroperitoneum by dividing the inferior retroperitoneal attachments to the gland. After the second

portion of the duodenum has been elevated out of the retroperitoneum by means of the Kocher

maneuver, the pancreatic head and uncinate process are palpated bimanually. The liver is carefully

assessed for evidence of metastatic disease. Potential extrapancreatic sites of tumor are evaluated in all

cases, with particular attention paid to the duodenum, splenic hilum, small intestine and its mesentery,

peripancreatic lymph nodes, and reproductive tract in women. The goals of surgical therapy for PENs

include controlling the symptoms of hormone excess, safely resecting maximal tumor mass, and

preserving maximal pancreatic parenchyma. Management strategies, including preoperative,

intraoperative, and postoperative considerations, vary for the different types of endocrine neoplasms of

the pancreas.

1433

Figure 56-5. Graphic depiction of the results of arterial stimulation with venous sampling (ASVS) in a patient with gastrinoma.

The rise in hepatic vein gastrin concentration (gastrin gradient) is plotted on the y-axis, and basal values are plotted on the x-axis:

1, 100% rise; 2, 200% rise; and so forth. A rise in the hepatic vein gastrin concentration observed after the injection of secretin into

the superior mesenteric artery (SMA) and gastroduodenal artery (GDA) localizes the neoplasm to the head of the pancreas or

duodenum. SPL, splenic artery. (Adapted from Thom AK, Norton JA, Doppman JL, et al. Prospective study of the use of intraarterial secretin injection and portal venous sampling to localize duodenal gastrinomas. Surgery 1992;112:1002–1028; discussion

1008–1009.)

INSULINOMA

Insulinoma is the most common functional neoplasm of the endocrine pancreas (Table 56-5). The

insulinoma syndrome is associated with the following features, known as Whipple triad84:

1. Symptoms of hypoglycemia during fasting

2. Documentation of hypoglycemia, with a serum glucose level typically below 50 mg/dL

3. Relief of hypoglycemic symptoms following administration of exogenous glucose

6 Autonomous insulin secretion in insulinomas leads to spontaneous hypoglycemia, with symptoms

that can be classified into two groups (Table 56-5). Neuroglycopenic symptoms include confusion,

seizure, obtundation, personality change, and coma. Hypoglycemia-induced symptoms, related to a

surge in catecholamine levels, include palpitations, trembling, diaphoresis, and tachycardia. In most

cases, patients consume carbohydrate-rich meals and snacks to relieve or prevent these symptoms.

Table 56-5 Insulinoma

Whipple triad is not specific for insulinoma. The differential diagnosis of adult hypoglycemia is

extensive and includes the following: reactive hypoglycemia, functional hypoglycemia associated with

gastrectomy or gastroenterostomy, nonpancreatic tumors, pleural mesothelioma, sarcoma, adrenal

carcinoma, hepatocellular carcinoma, carcinoid, hypopituitarism, chronic adrenal insufficiency,

extensive hepatic insufficiency, and surreptitious self-administration of insulin or ingestion of oral

hypoglycemic agents.

A common error made in evaluating a patient with suspected insulinoma is to begin with an oral

glucose tolerance test. Instead, insulinoma is most reliably diagnosed by means of a monitored fast (via

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imaging studies.47 Pancreatic polypeptide is secreted by the PP cells of the islets of Langerhans and can

also be used to track patients with PENs, though its sensitivity (63%) is lower than that of

chromogranin A.48 Neuron-specific enolase is another tumor marker that is elevated in approximately

50% of PENs, most commonly in patients with pulmonary metastases.49

PENs presenting due to mass effect on surrounding structures resulting in jaundice, pain, or gastric

outlet obstruction are uncommon. These lesions should be addressed as any other symptomatic

pancreatic lesion with definitive surgical resection if clinically appropriate.

Patients presenting with symptoms from a functional PEN can be a diagnostic challenge. Three

general principles apply to the diagnosis and treatment of patients with suspected functional neoplasms

of the endocrine pancreas. One must first recognize the abnormal physiology or characteristic

syndrome. Patients are often misdiagnosed or have their symptoms disregarded for years before an

accurate diagnosis is reached. Characteristic clinical syndromes are well described for insulinoma,

gastrinoma, VIPoma, and glucagonoma. The somatostatinoma syndrome is nonspecific, much more

difficult to recognize, and exceedingly rare. Second is the detection of hormone elevations in the serum

by radioimmunoassay. Such assays are readily available for measuring insulin, gastrin, vasoactive

intestinal peptide (VIP), and glucagon. Assays for somatostatin, pancreatic polypeptide (PP),

prostaglandins, and other hormonal markers are less commonly available but can be obtained from

certain laboratories. The third step involves localizing and staging the tumor in preparation for possible

operative intervention (Algorithm 56-1).

LOCALIZATION AND STAGING

Computed Tomography

4 The initial imaging technique used to localize a PEN and stage the disease is high-quality

multidetector three-dimensional CT.50 The accuracy of CT in detecting primary PENs ranges from 64%

to 82% and depends largely on the size of the tumor.51,52 PENs are typically hyperdense (bright) on

arterial phases of imaging. Lesions that are obvious during the early arterial phase can become isodense

on later phases of imaging. Therefore, a multiphase approach is typically recommended.53,54 CT is

useful in assessing size and location of the primary tumor, proximity to visceral vessels, peripancreatic

lymph node involvement, and the presence or absence of liver metastases (Fig. 56-1).

Magnetic Resonance Imaging

MRI is increasingly used in the detection of PENs, particularly small lesions. They are especially well

visualized on T1- and T2-weighted images with fat suppression. MRI has the advantage of increased soft

tissue contrast without the administration of intravenous contrast when compared to CT.42 PENs

characteristically have high signal intensity on T2-weighted images.55 On dynamic contrast-enhanced

T1-weighted images, the tumors show the same typical enhancement pattern as on CT scan. The

sensitivity of MRI has been reported to be between 74% and 100%.51,52

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Algorithm 56-1. Diagnosis and management of pancreatic endocrine neoplasms.

Somatostatin Receptor Scintigraphy (Octreoscan)

Somatostatin receptor scintigraphy (SRS) also plays an important role in imaging patients with

pancreatic endocrine tumors.56–62 In this technique, the octapeptide analog of somatostatin (Octreotide)

labeled with indium-111 is administered intravenously to patients in whom a PEN is suspected. Because

neuroendocrine tumors often express large numbers of somatostatin receptors on their cell surfaces (Fig.

56-2), the tracer preferentially identifies tumors. The overall sensitivity of SRS has been reported to

range from 74% to near 100% depending on the functional type of PEN.63 There is a significant falsenegative rate, indicating that negative SRS findings in patients with PENs should be viewed with

caution. Nonfunctional tumors and insulinomas seem to be localized less frequently by SRS, while SRS

performs well for gastrinoma, VIPoma, and glucagonoma. In addition, SRS appears to play a role in the

evaluation of patients with metastatic pancreatic endocrine tumors, especially in identifying

extrahepatic tumor spread. In a study by Frilling et al.,62 54% of patients with liver metastases had

extrahepatic tumor spread detected by SRS that was not detected by alternate imaging techniques.

Figure 56-1. Computed tomography with oral and intravenous contrast in a patient with biochemical evidence of insulinoma. The

neoplasm (arrow) is seen as a contrast-enhancing structure, 3 cm in diameter, in the tail of the pancreas posterior to the stomach

(S). (From Yeo CJ. Islet cell tumors of the pancreas. In: Niederhuber JE, ed. Current Therapy in Oncology. St. Louis, MO: Mosby;

1993:272, with permission.)

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Figure 56-2. Octreotide scan (anterior view) in a patient with a large endocrine tumor in the tail of the pancreas (large dark mass,

upper right) and several hepatic metastases (upper left quadrant). A small amount of the tracer is seen in the bladder (lower

midline).

Endoscopic Ultrasound

5 Endoscopic ultrasonography (EUS) has also shown utility in localizing PENs.64–68 Rosch et al.67 were

able to localize 32 of 39 tumors (82%) correctly with EUS after CT had failed to locate the tumor (Fig.

56-3). In their experience, EUS was more sensitive than the combination of CT and visceral

angiography. A more recent study by Proye et al.69 evaluated preoperative EUS and SRS in 41 patients

with insulinoma and gastrinoma. The sensitivity and positive predictive value of EUS were 77% and

94%, respectively, for pancreatic tumors; 40% and 100%, respectively, for duodenal gastrinomas; and

58% and 78%, respectively, for metastatic lymph nodes. These results indicate that EUS is best at

detecting lesions in the head of the pancreas. It is less successful at evaluating the distal pancreas and

the duodenal wall. Additionally, the procedure is operator dependent.70 These results have been

duplicated by others and have led some to suggest that EUS should serve as the initial localization

procedure in patients with insulinoma and gastrinoma. Of note, the drawback to EUS is that it does not

evaluate accurately for hepatic metastatic disease; rather, it is more sensitive than CT for imaging the

duodenal wall, pancreatic parenchyma, and peripancreatic lymph nodes.

Intraoperative Ultrasound

Historically, the primary methods of localizing PENs intraoperatively have been visualization and

palpation. With the advent of laparoscopic exploration for PENs, intraoperative ultrasound has been

substituted for palpation. Results have been promising, with sensitivities reported between 75% and

90%.71,72

Figure 56-3. Endoscopic ultrasonographic image from a patient with an insulinoma (arrows) in the body of the pancreas. SV,

splenic vein. (From Rosch T, Lightdale CJ, Botet JF, et al. Localization of pancreatic endocrine tumors by endoscopic

ultrasonography. N Engl J Med 1992;326:1721–1726, with permission.)

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