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

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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

1434

 

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.)

1431

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.)

1432

 

and ATRX mutations were more likely to have CIN and patients with this subtype of PENs had a

reduction in survival.

Table 56-3 Familial Genetic Syndromes Associated with Pancreatic Endocrine

Neoplasms (PENs)

This landmark sequencing work underscored the potential clinical importance of mutations in the

mTOR pathway in a subset of PEN patients. As a reminder, the drug rapamycin targets mTOR, and thus,

this finding should provide the framework in which we may stratify PEN patients for TOR inhibitor–

based therapies (e.g., everolimus).33 As this work demonstrated that mTOR dysregulation may be an

important predictive marker, others have shown that in a large panel of neuroendocrine tumors (195 of

which only 19 where pancreatic) mTOR overexpression and/or its downstream-activated targets were

associated with worse clinical outcomes (i.e., adverse prognostic markers).37 This work provides

another instance where a poor prognostic marker (for even development of disease) may serve

counterintuitively as a positive predictive marker (for everolimus); an established biomarker, BRCA2,

acts in a similar fashion.

Table 56-4 Portal Vein Sampling

Genetic Links and Syndromes Related to PENs

Significant progress has been made in the genetic understanding of the MEN-1 syndrome in relation to

PENs.38 Chromosomal linkage studies have localized the genetic defect to the 11q13 locus, and studies

of DNA markers have localized the MEN-1 gene between PYGM and D11S97. The gene contains 10

exons that code for a 610-amino-acid protein called menin, whose function is unknown, although it is

classically labeled as a tumor suppressor gene. Some studies provide a possible explanation for loss of

this gene in neuroendocrine tumors.39 The menin protein is expressed in diverse tissues and is highly

conserved evolutionarily. Menin is predominately a nuclear protein, which binds to JunD and may

repress JunD-mediated transcription. Studies in patients with MEN-1 have shown allelic deletions at

chromosome 11q13 in nearly 100% of parathyroid tumors, 85% of nongastrinoma islet cell tumors, and

up to 40% of gastrinomas. In patients with sporadic tumors (without MEN-1), 11q13 deletions are seen

in about 25%, 20%, and almost 50% of parathyroid tumors, nongastrinoma PENs, and gastrinomas,

respectively. Recently it has been shown that a comprehensive genetic testing program for patients at

risk for MEN-1 can identify patients harboring a MEN-1 mutation almost 10 years before the

development of clinical signs or symptoms of disease.40 Since MEN-1 loss has been detected in both the

sporadic and the familial forms of PENs, the menin pathway is most likely involved in the overall

pathogenesis of this disease, whether familial or sporadic in nature.39

Less frequently than MEN-1, PENs may be associated with VHL syndrome. VHL syndrome is another

autosomal dominant inheritance disease that includes many clinical disorders

41 including retinal

hemangioblastomas, cerebellar and medullary hemangioblastomas, and PENs. PENs are found in a small

percentage of patients with VHL syndrome. A mutation in the VHL gene, a tumor suppressor located on

chromosome 3p25–26, which regulates hypoxia-induced cell proliferation, is responsible. Although

1428

germline mutations with loss of heterozygosity (LOH) are associated with this disease, it has been

proposed that other tumor suppressors most likely cooperate with VHL in order to form PENs. VHLmutated PENs have been shown to have specific defects in angiogenesis and hypoxia-inducible factor

pathways.42

NF-1 (von Recklinghausen disease) is an autosomal dominant disorder that produces a well-described

clinical syndrome characterized by café-au-lait spots and neurofibromas. These patients may develop

pancreatic somatostatinomas, often near the ampulla of Vater. The NF-1 gene is a tumor suppressor

gene located on 17q11.2 that encodes for neurofibromin, a regulator of the mammalian target of

rapamycin (mTOR) pathway. Loss of NF-1 results in mTOR activation and tumor development.43,44

Complementary Progression Modeling

Based on the data from the Marinoni study that attempted to molecularly subtype PENs,36 a stepwise

progression model of PENs were put forth: (1) initiation occurs (unknown mechanism); (2) DAXX/ATRX

mutations induce transformation; (3) alternative lengthening of telomere (ALT)45 activation and CIN;

(4) clonal heterogeneity and a selection of clones; and (5) metastases.36 Complementary to this work,

Zhang described a “double hit model” of PEN progression35 wherein a first mutational hit (e.g., MEN1

or p53) can induce cell cycle progression, even under harsh tumor microenvironment conditions (low

glucose). Then, the second hit (ATRX and mTOR) can cause cell growth and enhance cell invasion and

metastatic potential,35 even in the absence of cell–cell adhesion. These models highlight our recent and

enhanced knowledge of the molecular etiology of PEN. However, future work will need to define the

main initiating event that sets the stage for PEN transformation. Since KRAS activation appears to be

unnecessary, other nonclassical genetic events (e.g., epigenetics and posttranscriptional gene regulation)

should be surveyed as critical key events in this tumorigenesis process.

Molecular Targeting of PENs

In summary, PENs are becoming easier to characterize molecularly (and clinically) due to large scale

sequencing efforts and a better understanding behind the molecular biologic aspects of these pancreatic

tumors. Ongoing efforts to search for candidate genes and novel pathways that set the stage for CIN and

initiation of tumorigenesis in these tumors will aid in unraveling the molecular etiology of this disease

and perhaps even better druggable targets (see Table 56-4 for molecular pathways to target in PENs vs.

pancreatic ductal adenocarcinoma). Still, the molecular characterization of these tumors have helped to

pave the way for clinical trials targeting tyrosine kinases (e.g., sunitinib) and the mTOR pathways (e.g.,

everolimus). In fact, recent work explored targeting multiple points throughout the dysregulated

pathway (PI3K/AKT/mTOR) in PENs by combining PI3K inhibitors with mTOR inhibitors and

demonstrated that this combination may break initial and acquired drug resistance in PENs.46 Future

molecular interrogation of PENs combined with these types of preclinical targeting approaches should

continue to move the field closer to a personalized approach to treating PENs with better targeted

therapies.

PRESENTATION AND EVALUATION

There are three primary ways by which patients with PENs come to clinical attention: the incidental

discovery of a mass in the pancreas during cross-sectional imaging, symptoms secondary to the mass

effect of a lesion in the pancreas (i.e., obstructive jaundice or pain), and, as a consequence of the

symptoms of a syndrome associated with a functional PEN. As mentioned previously, incidentally

detected nonfunctional PENs currently comprise the majority of clinically relevant tumors. They are

typically hypervascular on imaging studies such as computed tomography (CT) or magnetic resonance

imaging (MRI). In the absence of any clinical syndrome, these lesions can be managed as any other

incidental pancreatic lesion. Typically, the size of a PEN at discovery guides decision making between

three standard options: serial observation, endoscopic ultrasound-guided biopsy, or definitive surgical

resection. Size greater than 2 cm is a standard stratification measure, with lesions larger than this

usually managed in a more aggressive fashion. If a nonfunctional PEN is suspected, baseline serum

levels of chromogranin A and pancreatic polypeptide can be useful diagnostic markers prior to surgical

resection. Chromogranin A is a 49-kDa protein contained within the neurosecretory vesicles of PENs,

whose levels should be measured prior to surgical resection and are expected to significantly decline in

the postoperative period with removal of the tumor burden. The chromogranin A levels can be tracked

over time to document tumor recurrence, often before the lesions become visible on cross-sectional

1429

 

Chapter 56

Neoplasms of the Endocrine Pancreas

Harish Lavu, Jonathan R. Brody, and Charles J. Yeo

Key Points

1 Pancreatic endocrine neoplasms (PENs) originate from multipotential stem cells in pancreatic

ductules. Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged,

in favor of the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.

2 PENs have traditionally been classified according to the size and the mitotic rate of the tumor into

one of three categories: pancreatic endocrine microadenomas, well-differentiated PENs, and poorly

differentiated or high-grade endocrine carcinomas.

3 The most recent World Health Organization classification uses the combination of a proliferative

index (Ki-67) and mitotic rate to grade PENs while incorporating traditional TNM staging taking into

account tumor size, peripancreatic invasion, and metastatic spread to lymph nodes/distant locations,

which result in the classification of carcinoma.

4 The best initial imaging technique for a PEN is a high-quality multidetector computed tomography

(CT) scan.

5 Endoscopic ultrasonography is particularly useful in localizing tumors in patients with gastrinoma

and insulinoma.

6 Insulinomas may present with either neuroglycopenic symptoms (confusion, seizure, obtundation,

and coma) or hypoglycemic-induced symptoms (palpitations, diaphoresis, and tachycardia).

7 Ninety percent of insulinomas are solitary, 90% are sporadic, and 90% are benign with their location

evenly distributed throughout the pancreas.

8 Seventy-five percent of gastrinomas are sporadic (25% are associated with multiple endocrine

neoplasia type 1 syndrome), and all should be considered to be of malignant potential.

9 Most gastrinomas are located in the gastrinoma triangle and may be intrapancreatic, within the wall

of the duodenum, or in a peripancreatic lymph node, and in most cases local resection (enucleation)

may be adequate therapy.

10 Glucagonomas usually present with a characteristic severe dermatitis (termed necrolytic migratory

erythema) and are typically large and bulky and often with metastatic disease.

1 Pancreatic endocrine neoplasms (PENs) are rare tumors that account for 3% of pancreatic neoplasms

and 7% of all neuroendocrine tumors.1 Their incidence has increased nearly fivefold over the past 30

years, corresponding to the dramatic rise in the use of cross-sectional imaging in modern medicine. This

has led to an increase in the rate of incidental diagnoses in asymptomatic patients.2 First described by

Nicholls in 1902 as a tumor arising from pancreatic islet cells, these “islet cell adenomas” were long

thought to arise from the islets of Langerhans.3 Recent investigations have revealed that PENs more

likely originate from multipotential stem cells in pancreatic ductules.4,5 This non–islet cell origin has

been further demonstrated in tumors arising in patients with multiple endocrine neoplasia type1.6

Therefore, use of the older terms islet cell tumor and islet cell carcinoma is now discouraged, in favor of

the terms pancreatic endocrine neoplasms or pancreatic endocrine tumors.7,8

2 Traditionally, PENs were classified according to their size and the mitotic rate of the tumor. This

system placed PENs into one of three categories: pancreatic endocrine microadenomas, welldifferentiated PENs, and poorly differentiated or high-grade endocrine carcinomas. PENs are also

differentiated by the presence (i.e., functional tumors) or absence (i.e., nonfunctional tumors) of a

syndrome due to hormone production, with nonfunctional PENs (91%) being much more common than

functional tumors (9%).9,10 The production of certain hormones by the functional tumors and their

resulting symptoms lead to well-described clinical syndromes, which are detailed later in this chapter.

PENs less than 0.5 cm in diameter are classified as pancreatic endocrine microadenomas.

1425

Oncologically, they are considered to be benign lesions. Their prevalence is estimated to be as high as

10% of the population in autopsy series.11,12 Most pancreatic endocrine microadenomas are noted as

incidental findings in pancreata resected for other indications and, by definition, produce no neoplastic

syndromes (i.e., are nonfunctional). Functional PENs less than 0.5 cm are classified with welldifferentiated PENs.

PENs measuring greater than 0.5 cm in diameter and having a low mitotic rate of less than 10 mitoses

per 10 high-power fields are referred to as well-differentiated PENs. This group comprises the large

majority of clinically relevant PENs. They are uncommon, with an estimated incidence of approximately

1 out of 100,000 people.13,14 Although rare in children, cases have been described at all ages, and the

peak incidence occurs between the ages of 40 and 60 years.7 Overall distribution is equal between men

and women with some differences in ratio among different functional types.

3 The classification of PENs has in the past been controversial, with no single dominant staging

system in existence.15 Multiple varying staging schemes (including those by the European

Neuroendocrine Tumor Society (ENETS) and the American Joint Committee on Cancer (AJCC))16,17

have been put forward, attempting to establish prognostic characteristics such as size, mitotic count,

presence of necrosis, extrapancreatic invasion, vascular and perineural invasion, nuclear polymorphisms,

and nodal involvement.18–21 The most recent World Health Organization (WHO) classification attempts

to standardize PEN grading by using a proliferation-based system together with classical histopathologic

diagnostic criteria. This new classification takes into account the increasing importance of the

proliferative index Ki-67 as a prognostic marker for PENs. In this schema, PENs are graded into one of

three categories based upon their Ki-67 proliferation index and mitotic rate. These include two

categories of well-differentiated endocrine tumors and a third category of poorly differentiated

endocrine carcinomas. In this system, the well-differentiated tumors include those which are grade 1

(Ki-67 <3%, <2 mitoses per 10 hpf) and grade 2 (Ki-67 3% to 20%, 2 to 20 mitoses per 10 hpf).

Whereas, grade 3 (Ki-67 >20%, >20 mitoses per 10 hpf) tumors are considered poorly differentiated

carcinomas.22,23 By convention, the tumor is assigned the higher grade if the Ki-67 index and mitotic

rate differ. Any local invasion beyond the pancreas or metastatic spread to lymph nodes or distant

locations results in the classification of carcinoma (Table 56-1).

Table 56-1 WHO 2010 Classification of Well-Differentiated Pancreatic Endocrine

Tumors

Well-differentiated PENs can also be classified as functional or nonfunctional based on the presence or

absence of an associated clinically recognizable syndrome (Table 56-2). These syndromes are the result

of the secretion of biologically active hormones by the tumors and are confirmed by measurable

elevations of the hormones in the blood. The most common functional PENs include insulinomas,

gastrinomas, vasoactive intestinal polypeptide-omas (VIPomas), glucagonomas, and somatostatinomas.

The incidence of these lesions ranges from 1 per 1 million for insulinomas to 1 per 40 million for

somatostatinomas.24 Even less common PENs secreting calcitonin,25,26 parathyroid hormone–related

protein,27 growth hormone–releasing factor, and adrenocorticotropic hormone28 have been reported.

Nonfunctional PENs are classified as such due to their lack of an associated clinical syndrome. Some of

the tumors in this group do secrete elevated amounts of hormones, including chromogranin A, which

can be detected in either the serum or in surgical specimens using immunohistochemistry.29 These

secreted hormones either produce no clinical syndromes, as is seen with tumors that secrete pancreatic

polypeptide,30 or secrete hormones in subclinical amounts or inactive forms. Traditionally, functional

PENs were reported to comprise the majority of PENs. As methods of detecting these lesions and

patterns of presentation have evolved, due primarily to the widespread use of high-quality cross1426

sectional imaging, nonfunctional PENs now comprise the vast majority of surgically resected cases.18,31

The least common group of PENs is the poorly differentiated or high-grade endocrine carcinomas.

These are aggressive tumors characterized by their high mitotic count and proliferation index (>20

mitotic figures per 10 high-powered fields, Ki-67 >20%).23,32 These tumors primarily occur in adults

and have a male predominance. Some have been reported to be functional, producing varied clinical

syndromes (commonly gastrinoma, VIPoma, glucagonoma, and, less frequently, insulinoma). Prognosis

is often poor, with the clinical course varying from a rapid decline to a more indolent, prolonged

survival.

Table 56-2 Classification of Functional Pancreatic Endocrine Tumors

MOLECULAR GENETICS

The majority of PENs are sporadic. Some of them, however, occur as part of inherited familial

syndromes such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel–Lindau (VHL) syndrome,

neurofibromatosis (NF-1), and tuberous sclerosis (TSC) (see section below on genetic syndromes) (Table

56-3). Recent advances in high throughput DNA sequencing techniques have provided new insights into

the genesis of PENs and possible reasons why certain tumors behave more aggressively than others as

well as why tumors may respond more favorable to specific therapies (i.e., a more personalized

approach to therapy of PENs).

Whole-Exome Sequencing of PENs

Specifically, in a 2011 landmark paper, Jiao et al. sequenced ∼18,000 coding genes of 10 clinically

well-characterized PENs.33 Technically, this work dovetailed eloquently and aligned with the group’s

previous work of sequencing and analyzing multiple pancreatic ductal adenocarcinoma genomes.34

Importantly, the investigators microdissected the samples in an effort to achieve a high purity and

quality of DNA from neoplastic tissue. In the PENs cancer genomes compared to pancreatic ductal

adenocarcinoma genomes a number of differences were discovered including >50% fewer mutations in

PENs compared to pancreatic adenocarcinoma genomes; and commonly mutated genes such KRAS were

not mutated in PENs (Table 56-4).35 These genetic data support the notion that the chromosomal

instability (CIN) and tumorigenesis process between these two pathologically distant pancreatic

neoplasms are initiated by unique molecular and/or environmental events. The study went on to

validate the common findings in the 10 PENs (labeled a discovery set) with an additional 58 PENs.

Validating previous work and also underscoring the importance of the disruption in the chromatinremodeling pathway in PENS, a majority of PENs harbored a tumor-specific inactivating mutation in

MEN-1. Additional genes functionally important in a chromatin-remodeling complex, DAXX (deathdomain–associated protein) and ATRX (alpha thalassemia/mental retardation syndrome X-linked), were

frequently mutated in PENs as well. Correlating the clinical outcomes of these tumors, the study

demonstrated that patients in this cohort with MEN-1, DAXX, and ATRX mutated tumors had unique

outcomes compared to the other PENs. More recent work published in 2014, correlated DAXX and ATRX

mutations, activation of alternative lengthening of telomeres, and global chromosomal alterations with

pathologic features and outcome data.36 Interestingly, this study identified that PENs harboring DAXX

1427

 

with pancreatoduodenectomy in the surgical treatment of adenocarcinoma of the head of the

pancreas: a multicenter, prospective, randomized study. Lymphadenectomy Study Group. Ann Surg

1998;228:508–517.

19. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy with or without distal

gastrectomy and extended retroperitoneal lymphadenectomy for periampullary adenocarcinoma,

part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg

2002;236:355–366; discussion 366–368.

20. Farnell MB, Pearson RK, Sarr MG, et al. A prospective randomized trial comparing standard

pancreatoduodenectomy with pancreatoduodenectomy with extended lymphadenectomy in

resectable pancreatic head adenocarcinoma. Surgery 2005;138:618–630.

21. Nimura Y, Nagino M, Takao S, et al. Standard versus extended lymphadenectomy in radical

pancreatoduodenectomy for ductal adenocarcinoma of the head of the pancreas: long-term results

of a Japanese multicenter randomized controlled trial. J Hepatobiliary Pancreat Sci 2012;19:230–241.

22. Jang JY, Kang MJ, Heo JS, et al. A prospective randomized controlled study comparing outcomes

of standard resection and extended resection, including dissection of the nerve plexus and various

lymph nodes, in patients with pancreatic head cancer. Ann Surg 2014;259:656–664.

23. Traverso LW, Longmire WP Jr. Preservation of the pylorus in pancreaticoduodenectomy. Surg

Gynecol Obstet 1978;146:959–962.

24. Kozuschek W, Reith HB, Waleczek H, et al. A comparison of long term results of the standard

Whipple procedure and the pylorus preserving pancreatoduodenectomy. J Am Coll Surg 1994;

178:443–453.

25. Takada T, Yasuda H, Amano H, et al. Results of a pylorus-preserving pancreatoduodenectomy for

pancreatic cancer: a comparison with results of the Whipple procedure. Hepatogastroenterology

1997;44:1536–1540.

26. Tran KT, Smeenk HG, van Eijck CH, et al. Pylorus-preserving pancreaticoduodenectomy versus

standard Whipple procedure a prospective randomized multicenter analysis of 170 patients with

pancreatic and periampullary tumors. Ann Surg 2004;240:738–745.

27. Kooby D, Gillespie T, Bentrem D, et al. Left-sided pancreatectomy: a multicenter comparison of

laparoscopic and open approaches. Ann Surg 2008;248:438–446.

28. Palanivelu C, Jani K, Senthilnathan P, et al. Laparoscopic pancreaticoduodenectomy: technique and

outcomes. J Am Coll Surg 2007;205:222–230.

29. Kendrick ML, Cusati D. Total laparoscopic pancreaticoduodenectomy: feasibility and outcome in an

early experience. Arch Surg 2010;145:19–23.

30. Asbun HJ, Stauffer JA. Laparoscopic vs open pancreaticoduodenectomy: overall outcomes and

severity of complications using the accordion severity grading system. J Am Coll Surg

2012;215:810–819.

31. Chalikonda S, Aguilar-Saavedra JR, Walsh RM. Laparoscopic robotic-assisted

pancreaticoduodenectomy: a case-matched comparison with open resection. Surg Endosc

2012;26:2397–2402.

32. Zureikat AH, Moser AJ, Boone BA, et al. 250 Robotic pancreatic resections: safety and feasibility.

Ann Sur 2013;258:554–562.

33. Yeo CJ, Cameron JL, Lillemoe KD, et al. Pancreaticoduodenectomy for cancer of the head of the

pancreas: 201 patients. Ann Surg 1995;221:721–733.

34. Richter A, Neidergethmann M, Sturm JW, et al. Long-term results of partial

pancreaticoduodenectomy for ductal adenocarcinoma of the pancreatic head: 25-year experience.

World J Surg 2003;27:324–329.

35. Schmidt CM, Powell ES, Yiannoutsos CT, et al. Pancreaticoduodenectomy: a 20-year experience in

516 patients. Arch Surg 2004;139:718–725; discussion 725–727.

36. Sosa JA, Bowman HM, Gordon TA, et al. Importance of hospital volume in the overall management

of pancreatic cancer. Ann Surg 1998;228:320–330.

37. Winter JM. Cameron JL. Campbell KA, et al. 1423 pancreaticoduodenectomies for pancreatic

cancer: a single-institution experience. J Gastrointest Surg 2006;10:1199–1210.

38. Gastrointestinal Tumor Study Group. Further evidence of effective adjuvant combined radiation and

chemotherapy following curative resection of pancreatic cancer. Cancer 1987;59:2006–2010.

1423

39. Kinkenbijl JH, Jeekel J, Sahmoud T, et al. Adjuvant radiotherapy and 5-fluorouracil after curative

resection of cancer of the pancreas and periampullar region. Ann Surg 1999;230:776–782; discussion

782–784.

40. Neoptolemos JP, Stocken DD, Freiss H, et al. A randomized trial of chemoradiotherapy and

chemotherapy after resection of pancreatic cancer. N Engl J Med 2004;350:1200–1210.

41. Regine WF, Winter KW, Abrams R, et al. RTOG 9704 a phase III study of adjuvant pre and post

chemoradiation (CRT) 5-FU vs. gemcitabine (G) for resected pancreatic adenocarcinoma. J Clin

Oncol 2006;24:18S.

42. Oettle H, Post S, Neuhaus P, et al. Adjuvant chemotherapy with gemcitabine vs. observation in

patients undergoing curative-intent resection of pancreatic cancer: a randomized controlled trial.

JAMA 2007;297:267–277.

43. Spitz FR, Abbruzzese JL, Lee JE, et al. Preoperative and postoperative chemoradiation strategies in

patients treated with pancreaticoduodenectomy for adenocarcinoma of the pancreas. J Clin Oncol

1997;15:928–937.

44. Hoffman JP, Lipsitz S, Pisansky T, et al. Phase II trial of preoperative radiation therapy and

chemotherapy for patients with localized, resectable adenocarcinoma of the pancreas: an Eastern

Cooperative Oncology Group Study. J Clin Oncol 1998;16:317–323.

45. Pisters PW, Wolff RA, Janjan NA, et al. Preoperative paclitaxel and concurrent rapid-fractionation

radiation for resectable pancreatic adenocarcinoma: toxicities, histologic response rates, and eventfree outcome. J Clin Oncol 2002;20:2537–2544.

46. Wolff RA, Evans DB, Crane CH. Initial results of preoperative gemcitabine-based chemoradiation

for resectable pancreatic Adenocarcinoma (abstract). Proc Am Soc Clin Oncol 2002;21:130a.

47. Talamonti MS, Small W Jr, Mulcahy MF, et al. A multi-institutional phase II trial of preoperative

full-dose gemcitabine and concurrent radiation for patients with potentially resectable pancreatic

carcinoma. Ann Surg Oncol 2006;13:150–158.

48. Evans DB, Varadhachary GR, Crane CH, et al. Preoperative gemcitabine-based chemoradiation for

patients with resectable adenocarcinoma of the pancreatic head. J Clin Oncol 2008;26(21):3496–

3502.

49. Turrini O, Viret F, Moureau-Zabotto L, et al. Neoadjuvant 5 fluorouracil-cisplatin chemoradiation

effect on survival in patients with resectable pancreatic head adenocarcinoma: a ten-year single

institution experience. Oncology 2009;76(6):413–419.

50. Sohn TA, Lillemoe KD, Cameron JL, et al. Surgical palliation of unresectable periampullary

carcinoma in the 1990s. J Am Coll Surg 1999;188:658–666; discussion 666–659.

51. Sarr MG, Cameron JL. Surgical management of unresectable carcinoma of the pancreas. Surgery

1982; 91:123–133.

52. Lillemoe KD, Cameron JL, Hardacre JM, et al. Is prophylactic gastrojejunostomy indicated for

unresectable periampullary cancer? Ann Surg 1999;230:322–328; discussion 328–330.

53. Van Heek NT, De Castro SM, van Eijck CH, et al. The need for a prophylactic gastrojejunostomy for

unresectable periampullary cancer: a prospective randomized multicenter trial with special focus on

assessment of quality of life. Ann Surg 2003;238:894–902; discussion 902–905.

54. Lillemoe KD, Cameron JL, Kaufman HS, et al. Chemical splanchnicectomy in patients with

unresectable pancreatic cancer: a prospective randomized trial. Ann Surg 1993;217:447–455;

discussion 456–457.

55. Burris HA 3rd, Moore MJ, Andersen J, et al. Improvements in survival and clinical benefit with

gemcitabine as first-line therapy for patients with advanced pancreas cancer: a randomized trial. J

Clin Oncol 1997;15(6):2403–2413.

56. Rothenberg ML, Moore MJ, Cripps MC, et al. A phase II trial of gemcitabine in patients with 5-FU

refractory pancreas cancer. Ann Oncol 1996;7:347–353.

57. Conroy T, Desseigne F, Ychou M, et al. FOLFIRINOX versus gemcitabine for metastatic pancreatic

cancer. NEJM 2011;364(19):1817–1825.

58. Von Hoff DD, Ervin T, Arena FP, et al. Increased survival in pancreatic cancer with nab-paclitaxel

plus gemcitabine. NEJM 2013;369(18):1691–1703.

1424

 

matter of debate. Surgeons who do not perform a prophylactic bypass feel that it needlessly increases

the postoperative length of stay and can be associated with delayed gastric emptying and increased

morbidity and mortality. However, data from a prospective, randomized trial of prophylactic

gastrojejunostomy in patients with unresectable cancer do not support this view.52 In this study, 44

patients were randomized to a gastrojejunostomy, and 43 did not undergo gastric bypass. No mortality

occurred in either group. No difference was observed in either the complication rate or the

postoperative length of stay (Table 55-16). However, late duodenal obstruction developed in 19% of the

patients who did not undergo bypass. A recent multicenter prospective randomized controlled trial has

confirmed these results.53 Therefore, we believe that a prophylactic gastrojejunostomy should be

performed in patients undergoing surgical palliation for unresectable pancreatic carcinoma.

Pain

Tumor-associated pain can be incapacitating in patients with unresectable pancreatic cancer. The

postulated causes of tumor-associated pain are many and include tumor infiltration into the celiac

plexus, increased parenchymal pressure caused by pancreatic duct obstruction, pancreatic inflammation,

gallbladder distention resulting from biliary obstruction, and gastroduodenal obstruction. The

management of pain in patients dying of carcinoma of the pancreas is one of the most important aspects

of their care. The appropriate use of oral agents can be successful in most patients. Patients with

significant pain should receive their medication on a regular schedule and not on an “as-needed” basis.

The use of long-acting morphine derivative compounds appears to be best suited for such treatment.

Percutaneous neurolytic block of the celiac axis, performed under either fluoroscopic or CT guidance, is

also successful in the majority of patients at eliminating pain. Patients with unresectable cancer at the

time of surgical exploration should receive a chemical splanchnicectomy, with 20 mL of 50% alcohol

injected on either side of the aorta at the level of the celiac axis.54

MANAGEMENT

Table 55-16 Prospective Randomized Trial of Prophylactic Gastrojejunostomy in

Patients with Unresectable Periampullary Cancer

SUMMARY

8 The decision to perform nonoperative versus surgical palliation for pancreatic cancer is influenced by

a number of factors, including the patient’s symptoms, overall health status, predicted procedure-related

morbidity and mortality, and projected survival. Surgical palliation can be completed with acceptable

perioperative morbidity and mortality and postoperative length of stay. The avoidance of late

complications of recurrent jaundice, duodenal obstruction, and disabling pain would strengthen the

argument in favor of surgical palliation in those patients expected to survive 6 months or more.

Nonoperative methods of palliation should be considered for patients in whom preoperative staging

suggests distant metastatic disease or a locally unresectable tumor, patients who are not candidates for

operative intervention, and those not expected to survive more than 3 months.

Radiation and Chemotherapy for Unresectable Pancreatic Carcinoma

Specific antitumor therapies in patients with advanced pancreatic carcinoma have been studied for

years, with limited success. Trials evaluating the use of chemotherapy and radiation therapy both alone

and in combination have shown a marginal improvement in survival, often with relatively high toxicity

rates and some negative impact on quality of life. Recently gemcitabine, a deoxycytidine analog capable

of inhibiting DNA replication and repair, has become increasingly popular. When gemcitabine was

compared with bolus 5-FU in a randomized phase III trial, it was shown to confer a significant survival

benefit in advanced pancreatic cancer, increasing median survival from 4.4 to 5.7 months and increasing

1-year survival from 2% to 18%, respectively.55 A key end-point in this study was “clinical benefit

1421

response,” based on reducing pain, improving performance status, and inducing weight gain, which was

attained in 24% of patients receiving gemcitabine compared with 5% for those receiving 5-FU. In

patients with metastatic pancreatic cancer that had progressed with 5-FU and then been treated with

gemcitabine, the median survival (in 63 of 74 patients enrolled) was 3.9 months.56 Seventeen patients

(27%) attained a clinical benefit response with a median duration of 14 weeks. Gemcitabine is generally

well tolerated with a low incidence of significant toxicity and therefore seems to be a reasonable choice

for palliative therapy.

Long before gemcitabine was established as an option for adjuvant therapy, it was approved in the

metastatic setting based on clinical benefit in patients who had symptomatic advanced disease.55 Over

the last two decades, several combinations of gemcitabine based chemotherapy have failed to improve

outcome in patients with metastatic disease. Recently, both FOLFIRINOX (5-FU, leucovorin, irinotecan,

and oxaliplatin) and nab-paclitaxel/gemcitabine were proven superior to gemcitabine alone in patients

with metastatic pancreatic cancer leading to improvement in response rate (RR), progression-free

survival (PFS) and OS.57,58 Objective response rates have improved by nearly fivefold with these newer

systemic regimens.

In addition to gemcitabine, other agents are currently being studied for a role in the palliation of

patients with pancreatic adenocarcinoma. Examples of such agents are paclitaxel (Taxol), matrix

metalloproteinase inhibitors (e.g., marimastat and perillyl alcohol), and inhibitors of angiogenesis, such

as TNP-470. The results of such studies are eagerly awaited.

References

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outcomes, and prognostic indicators. J Gastrointest Surg 2000;4:567–579.

3. Yeo CJ, Cameron JL. Pancreatic cancer. Curr Probl Surg 1999;36:61–152.

4. Chari ST, Leibson CL, Rabe KG, et al. Probability of pancreatic cancer following diabetes: a

population based study. Gastroenterology 2005;129:504–511.

5. Takai E, Yachida S. Genomic alteration in pancreatic cancer and their relevance to therapy. World J

Gastrointest Oncol 2015;7:250–258.

6. Brune KA, Kliein AP. Familial pancreatic cancer. In: Lowy Am, Leach SD, Philip PA, eds. Pancreatic

Cancer. New York, NY: Springer Science + Buisness; 2008:65–79.

7. Brosens LA, Hackeng WM, Offerhaus GJ, et al. Pancreatic adenocarcinoma pathology: changing

“landscape.” J Gastrointest Oncol 2015;6:358–374.

8. Schmidt CM, Matos JM, Bentrem DJ, et al. Acinar cell carcinoma of the pancreas in the United

States: prognostic factors and comparison to ductal adenocarcinoma. J Gastrointest Surg

2008;12:2078–2086.

9. Farrell JJ. Prevalence, diagnosis and management of pancreatic cystic neoplasms: current status and

future directions. Gut and Liver 2015;9:571–589.

10. Sohn TA, Yeo CJ, Cameron JL, et al. Intraductal papillary mucinous neoplasms of the pancreas an

updated experience. Ann Surg. 2004;239:788–797; discussion 797–799.

11. Tanaka M, Fernandez-del Castillo C, Adsay V, et al. International consensus guidelines 2012 for the

management of IPMN and MCN of the pancreas. Pancreatology 2012;12:183–197.

12. Ritts RE, Pitt HA. CA 19–9 in pancreatic cancer. Surg Oncol Clin North Am 1998;7:93–101.

13. Dye CE, Waxman I. Endoscopic ultrasound. Gastroenterol Clin North Am 2002; 31:863–879.

14. Conlon KC, Dougherty E, Klimstra DS, et al. The value of minimal access surgery in the staging of

patients with potentially resectable peripancreatic malignancy. Ann Surg 1996;223:134–140.

15. Barreiro CJ, Lillemoe KD, Koniaris LG, et al. Diagnostic laparoscopy for periampullary and

pancreatic cancer: what is the true benefit? J Gastrointest Surg 2002;6:75–81.

16. Kausch W. Das Carcinom der papilla duodeni and seine radikale entfeinung. Beitrage zur Klinische

Chirurgie 1912;78:439.

17. Whipple AO, Parsons WB, Mullins CR. Treatment of carcinoma of the ampulla of Vater. Ann Surg

1935;102:763–779.

18. Pedrazzoli S, DiCarlo V, Dionigi R, et al. Standard versus extended lymphadenectomy associated

1422

 

postchemoradiation). Although the study showed no overall difference in aggregate survival, when

pancreatic head lesions only were considered (eliminating study results from resected lesions in the

pancreatic body or tail), both median survival (16.7 vs. 18.8 months) and overall survival at 3 years

(21% vs. 31%) favored the gemcitabine arm (p = 0.047). The study concluded that the addition of

adjuvant gemcitabine to postoperative 5-FU chemoradiation was superior to the addition of 5-FU.

Figure 55-8. Survival of patients with pancreaticoduodenectomy based on tumor size (A), lymph node status (B), margin status

(C), histologic grade (D), and historical context (E). From Winter JM. Cameron JL. Campbell KA, et al. 1423

pancreaticoduodenectomies for pancreatic cancer: a single-institution experience. J Gastrointest Surg 2006; 10:1199–210, with

permission.

TREATMENT

Table 55-14 Randomized Prospective Trials of Adjuvant Therapy for Pancreatic

Cancer

1418

The CONKO-1 trial,42 conducted in Germany and Austria, represented a randomization of 368 patients

following R0 or R1 resection to either observation or an experimental arm of gemcitabine. After a

median follow-up time of 53 months, the median disease-free survival was 13.9 months in the

gemcitabine arm versus 6.9 months in the observation arm (p <0.001). There was no difference in

overall survival for the gemcitabine arm versus the control group – median survival was 22 versus 20

months. Although survival was not different, the authors concluded that postoperative gemcitabine

significantly delayed the development of recurrent disease after complete resection of pancreatic cancer

compared with observation alone and, thus, was supported as adjuvant therapy in resectable pancreatic

cancer.

At present, many centers are utilizing preoperative neoadjuvant chemoradiation for the treatment of

pancreatic cancer (Table 55-15). Neoadjuvant therapy offers several potential benefits including: (1)

delivery of treatment to well-oxygenated tissue which enhances efficacy of chemoradiation, (2)

downstaging can enhance ability to achieve a negative-margin resection and thereby reduce local

recurrence, and (3) avoidance of surgery in patients with rapidly progressive disease. Neoadjuvant

therapy can be completed without increasing the subsequent morbidity and mortality of surgical

resection. The group from the M.D. Anderson Cancer Center reported on the multimodality treatment of

142 consecutive patients with localized adenocarcinoma of the pancreatic head.43 A subset of 41 patients

treated by preoperative chemoradiation and pancreatoduodenectomy were compared with 19 patients

receiving pancreatoduodenectomy and postoperative adjuvant chemoradiation. Surgery was not delayed

for any patient who received preoperative chemoradiation because of chemoradiation toxicity, but 24%

of the eligible patients did not receive their intended postoperative chemoradiation because of delayed

recovery following PD. The patients treated with rapid fractionation were reported to have a

significantly shorter duration of treatment (median, 62.5 days) than patients who received

postoperative chemoradiation (median, 98.5 days). In early follow-up, no patient who received

preoperative chemoradiation experienced a local recurrence, and peritoneal recurrence developed in

only 10% of these patients. Local or regional recurrence developed in 21% of patients who received

postoperative chemoradiation. The overall survival curves were similar for both cohorts.

Wolff et al.46 examined 86 patients treated with weekly gemcitabine at a dose of 400 mg/m2 and 30

Gy of radiation. Sixty-one patients ultimately underwent resection (71%). The median survival in the

resected patients was 36 months which is significantly longer than those seen in regimens using 5-FU or

paclitaxel as the radiation sensitizer. Analysis of the specimens revealed two pathologic complete

responses and more than 50% nonviable tumor cells in 36 (59%). A gemcitabine-based regimen was also

used in a multi-institutional study of 20 patients reported by Talamonti et al.47 This group used full-dose

gemcitabine and limited field radiation to 36 Gy (2.4 Gy/fraction). The authors described 14 patients as

resectable and six as borderline resectable. Ultimately, all patients were explored and 17 resected

(85%), again representing a very high rate of resectability. A single pathologic complete response was

observed and, in 24% of tumors, greater than 90% of the tumor cells were felt to be nonviable. Also

notable was the low incidence (6%) of margin positivity in this trial. The median survival in the

resected patients was 26 months. Based on the results of these initial trials, gemcitabine-based

neoadjuvant regimens remain of considerable interest.

TREATMENT

Table 55-15 Selected Neoadjuvant Trials for Potentially Resectable Pancreatic

Cancer

1419

PALLIATION

7 Unfortunately, it has been the experience nationwide that only a minority of patients with carcinoma

of the pancreas can undergo resection for possible cure at the time diagnosis is made. Therefore, the

optimal palliation of symptoms to maximize quality of life is of primary importance in most patients

with pancreatic cancer. Both operative and nonoperative options are available for the palliation of

pancreatic cancer.

Jaundice

Obstructive jaundice is present in most patients who have pancreatic cancer. If left untreated, it can

result in progressive liver dysfunction, hepatic failure, and early death. In addition, the pruritus

associated with obstructive jaundice can be debilitating and usually does not respond to medication.

When patients undergo exploration for possible cure and are found to have unresectable disease, a

biliary bypass should be performed.

Traditionally, surgeons have performed either choledochojejunostomy or cholecystojejunostomy for

the relief of malignant biliary obstruction. Both procedures are effective in relieving jaundice, but it

appears that the rate of recurrent jaundice after cholecystojejunostomy is approximately 10%.

Therefore, our preference for the palliation of obstructive jaundice is a hepaticojejunostomy or

choledochojejunostomy reconstructed with a Roux-en-Y limb of jejunum. The surgical palliation of

jaundice can be accomplished safely, with a mortality rate of less than 3% and an overall morbidity rate

of 30% to 40%.50 In recent years, nonoperative palliation has become available as an option for

managing patients who are deemed unresectable by preop staging. Plastic or metal stents can be placed

across the biliary obstruction by either an endoscopic or a percutaneous technique. For pancreatic

cancer, the endoscopic approach is usually preferred. The overall morbidity rate for endoscopic stenting

ranges up to 35%, but the rate of major procedure-related morbidity is less than 10%. Early

complications include cholangitis, pancreatitis, and bile duct or duodenal perforation. The major late

complications of stent placement are cholecystitis, duodenal perforation, and stent migration. Stent

occlusion can result in episodes of cholangitis and recurrent jaundice. For most patients, an exchange of

stents is required every 3 to 6 months. The newer metal stents appear to remain patent for longer

periods.

Nonoperative palliation appears to be associated with lower complication rates, lower procedurerelated mortality rates, and shorter initial periods of hospitalization in comparison with surgical

palliation. However, the rate of recurrent jaundice is higher. No advantage with respect to long-term

survival has been noted for either approach. Therefore, nonoperative palliation should be offered to

patients with advanced disease or poor performance status. Surgical palliation should be considered for

patients with an anticipated life expectancy of at least 6 months.

Duodenal Obstruction

At the time that pancreatic cancer is diagnosed, approximately one-third of patients have symptoms of

nausea or vomiting. Although true mechanical obstruction of the duodenum seen by radiologic or

endoscopic examination is much less frequent, duodenal obstruction develops in almost 20% of patients

before they die as the disease progresses.51 Duodenal obstruction can be caused in the C-loop by cancers

of the head or at the ligament of Trietz by cancers of the body and tail. In patients with evidence of

duodenal obstruction or impending obstruction, a gastrojejunostomy is indicated for palliation. This is

typically performed as a retrocolic, isoperistaltic loop gastrojejunostomy with a loop of jejunum 20 to

30 cm distal to the ligament of Trietz.

In patients with unresectable pancreatic cancer who do not have symptoms of gastric outlet

obstruction, whether or not to perform a prophylactic gastric bypass at the time of biliary bypass is a

1420

 

placement of clips for postoperative radiation therapy. If, as in most cases, the tumor cannot be

resected, a tissue biopsy should be performed, in addition to a chemical splanchnicectomy with alcohol

for pain management. In some cases, a prophylactic gastrojejunostomy may be indicated because of the

potential for obstruction by tumor at the ligament of Treitz.

Postoperative Results

4 During the 1960s and 1970s, many centers reported operative mortality following PD in the range of

20% to 40%, with postoperative morbidity rates as high as 40% to 60%. During the last three decades, a

dramatic decline in operative morbidity and mortality following PD has been reported at a number of

centers, with operative mortality rates in the range of 2% to 3%.33–35 The reasons behind this decline

appear to be the following: (a) fewer, more experienced surgeons are performing the operation on a

more frequent basis, (b) preoperative and postoperative care has improved, (c) anesthetic management

has improved, and (d) large numbers of patients are being treated at high-volume centers.36

Although the operative mortality rates for pancreatic cancer have been reduced significantly, the

complication rates approach 40% (Table 55-13). Pancreatic fistula remains the most frequent serious

complication following PD, with an incidence ranging from 5% to 15%. In the past, the development of

pancreatic fistula after PD was associated with mortality rates of 10% to 40%. Although the incidence of

pancreatic fistula following PD remains stable, the overall associated mortality rate has diminished

owing to improved management. Important supportive measures include careful maintenance of fluid

and electrolyte balance, parenteral nutrition, and controlling the pancreatic leak with percutaneous or

intraoperative drainage.

Table 55-12 Results for Minimally Invasive Pancreatoduodenectomy

COMPLICATIONS

Table 55-13 Complications After Pancreaticoduodenectomy

Long-Term Survival

5 Historically, 5-year survival rates for patients undergoing resection for adenocarcinoma of the head of

1416

the pancreas were reported to be in the range of 5%. However, recent studies have suggested an

improved survival for patients following PD. In 2006, Winter et al.37 reported on 1,175 patients who

underwent operative resection for pancreatic adenocarcinoma. The actuarial 5-year survival for these

patients was 18%, with a median survival of 18 months (Fig. 55.8). In this study, factors found to be

important predictors of survival included tumor diameter (<3 cm), negative resection margin status,

well/moderate tumor differentiation, and postoperative chemoradiation treatment. Patients who

underwent resection with negative margins had a median survival of 20 months and a 5-year survival of

21%, whereas those with positive margins fared significantly worse, with a median survival of 14

months and a 5-year survival of 12%. The outcome was particularly favorable in the subgroup of

patients with small tumors (<3 cm) who underwent margin-negative, node-negative resections; the

median survival was 44 months and the 5-year survival was 43%.

ADJUVANT AND NEOADJUVANT THERAPY

6 At present, the general consensus of most surgeons treating patients with pancreatic carcinoma is that

any future improvement in survival for this disease will involve improvements in systemic therapy.

Despite advances in surgery and perioperative care that have resulted in markedly reduced

postoperative mortality after pancreatoduodenectomy, the median survival for pancreatic cancer

patients has changed minimally over the past two decades. Even with optimal surgical management, 5-

year survival averages 15% to 20% for resectable disease and 3% for all stages combined.

Approximately 85% of patients with resected pancreatic cancer will ultimately recur and die of their

disease. These outcomes suggest that in most cases pancreatic cancer is a systemic disease at the time of

diagnosis, making surgical resection alone inadequate therapy. The results of the most important

randomized prospective trials of adjuvant therapy for pancreatic cancer are summarized in Table 55.14.

In 1985, the Gastrointestinal Tumor Study Group reported encouraging results from a prospective,

randomized trial to evaluate the efficacy of adjuvant radiation and chemotherapy following curative

resection for adenocarcinoma of the head of the pancreas.38 Forty-three patients were randomized to

either adjuvant therapy with radiation and 5-fluorouracil (5-FU) or no adjuvant therapy. The median

survival for the 21 patients who received adjuvant therapy was 20 months, and three (14%) survived 5

years or longer. For the 22 patients who received no adjuvant therapy, the median survival was 11

months, and only 1 patient (4.5%) survived 5 years.

The randomized trial conducted by the European Organization for Research and Treatment of Cancer

(EORTC),39 sought to recapitulate the results of the GITSG study in 114 patients with pancreatic head

lesions (observation, n = 54 and adjuvant treatment, n = 60). However, chemotherapy (5-FU) given

during radiation was given as a continuous infusion (rather than via bolus) during each radiation

sequence, depending on toxicity, for up to 5 days. No chemotherapy was given postchemoradiation.

Fifty-six percent of patients received the intended chemotherapy dose during radiation. Patients in the

chemoradiation arm had a median survival of 17.1 months versus 12.6 months in the observation arm (p

= 0.099); 2- and 5-year overall survivals were 37% and 20%, respectively, for the experimental arm

and 23% and 10%, respectively, for the control arm.

The ESPAC-1 trial published in 2004 analyzed 289 patients recruited from 53 hospitals in a 2 × 2

factorial design.40 The four study groups included (1) surgery only (n = 69); (2) chemotherapy only (n

= 73) consisting of 5-FU, 425 mg/m2, and leucovorin, 20 mg/m2, given daily for 5 days every 4 weeks

for six cycles of treatment; (3) radiation therapy and 5-FU given (n = 75) according to the original

GITSG method; and (4) both treatments (n = 73, chemoradiation followed by chemotherapy). The

major study conclusions were that the 5-year overall survival comparisons between patients who

received chemotherapy versus those that did not (21% vs. 8%, p = 0.009) and those that received

radiation therapy versus those that did not (10% vs. 20%, p = 0.05). The authors concluded that

adjuvant chemotherapy had a beneficial effect in resected pancreatic cancer, whereas chemoradiation

had a deleterious effect. A quality-of-life questionnaire showed no difference between those that

received chemotherapy and those that did not, and those that received chemoradiation and those that

did not. Thus, the survival benefit of adjuvant chemoradiation for pancreatic cancer patients remains

unclear, and the optimal regimen has yet to be determined.

The RTOG 9704 trial, presented in abstract form in 2006,41 contained 442 eligible patients who

received adjuvant chemoradiation (5,040 cGy) given as continuous fractions with radiosensitizing doses

of 5-FU. The comparisons were with the addition of either three cycles of 5-FU (one prechemoradiation,

two postchemoradiation for 12 weeks) versus four cycles of gemcitabine (one prechemoradiation, three

1417

 

There are a number of techniques for restoring gastrointestinal continuity after a pancreaticoduodenal

resection. Our preferred technique is to bring the end of the divided jejunum through the transverse

mesocolon in a retrocolic fashion and perform an end-to-side pancreaticojejunostomy. The anastomosis

is begun by placing a series of interrupted 3-0 silk sutures between the side of the jejunum and the

posterior capsule of the end of the pancreas. A small enterotomy is then made in the jejunum to match

the size of the pancreatic duct and an inner layer of interrupted 5-0 absorbable monofilament sutures

are used to create a duct-to-mucosa anastomosis. Some surgeons prefer to stent this anastomosis with

either a short indwelling pancreatic stent or an externalized pancreatic stent. The anastomosis is

completed with an outer layer of 3-0 silk sutures placed between the anterior pancreatic capsule and the

jejunum. An alternative to this duct-to-mucosa technique is to create an enterotomy approximately the

same size as the pancreatic neck and to complete a running anastomosis circumferentially around the

entire gland. This technique then allows invagination of the neck 1 to 2 cm into the lumen of the bowel

by the outer anterior layer of the anastomosis. The biliary–enteric anastomosis is performed 10 cm

distal to the pancreaticojejunostomy. An end-to-side hepaticojejunostomy is performed with a single

interrupted layer of 4-0 absorbable synthetic suture material. No T tube or stent is generally necessary.

Approximately 20 cm distal to the biliary–enteric anastomosis, an end-to-side duodenojejunostomy is

performed in an antecolic manner with an inner continuous layer of 3-0 absorbable synthetic suture

material and an outer interrupted layer of 3-0 silk. The final reconstruction is shown in Figure 55-6C.

Extent of Resection

Several technical aspects of PD remain controversial. These controversies include: (1) whether or not a

radical lymph node dissection is necessary, (2) should a pylorus preserving or classic PD be performed,

and (3) is there a role for laparoscopic pancreatic resections.

Several nonrandomized retrospective studies have advocated adding a radical (extended)

retroperitoneal lymph node dissection to PD in an attempt to improve survival. However, results from

four randomized prospective trials (Table 55-11)18–22 have shown extended lymph node dissections not

to be beneficial. The prospective trial performed by Pedrazzoli et al.18 suggested a survival advantage

to extended retroperitoneal lymph node dissection in patients with positive lymph nodes. Eighty-one

patients with pancreatic adenocarcinoma were randomized to either standard or radical

lymphadenectomy over 3 years at six different institutions. While the two groups were similar with

respect to preoperative parameters, operative morbidity, and overall survival, a subgroup analysis of

the 48 patients with positive lymph nodes showed a statistically significant survival advantage for

patients undergoing the extended lymph node dissection. However, the largest prospective randomized

trial from the Johns Hopkins Hospital failed to demonstrate a survival advantage for a radical resection

as compared with a classic PD.19 Two hundred and ninety-four patients undergoing resection for

periampullary adenocarcinoma were randomized between a standard resection (pylorus preserving PD

with en bloc resection of the anterior and posterior pancreaticoduodenal lymph nodes, lower

hepatoduodenal lymph nodes, and nodes along the right lateral aspect of the superior artery and vein)

and a radical resection (standard resection plus distal gastrectomy and retroperitoneal lymph node

dissection extending from the right renal hilum to the left lateral border of the aorta and from the

portal vein to the inferior mesenteric artery). The groups did not differ with respect to age, gender, site

of primary tumor, lymph node status, or margin status. There were no significant differences in 1-, 3-,

or 5-year and median survival when comparing the standard and radical groups (Fig. 55-7). However,

the radical group had a higher overall morbidity (43% vs. 29%) with significantly higher rates of

delayed gastric emptying and pancreatic fistula in addition to a longer postoperative hospital stay.

In 1978, Traverso and Longmire23 popularized the pylorus-preserving modification of the Whipple

procedure. Preserving antral and pyloric function, the pylorus-preserving Whipple procedure reduces

1414

the incidence of troublesome postgastrectomy symptoms. A number of studies have documented that

gastrointestinal function is better preserved in the pylorus-sparing modification than in the traditional

operation. In addition, compared with the classic Whipple operation, the pylorus-preserving procedure

is less time-consuming and technically easier to perform. Concerns exist in the use of the pyloruspreserving Whipple procedure for the management of periampullary tumors because of the possibility

of compromising the already small proximal surgical margin of resection. This question has been

addressed by a number of authors, and no difference appears to be found in survival among those

patients treated with the pylorus-sparing Whipple procedure and those managed by the traditional

Whipple resection.24–26 Therefore, many pancreatic surgeons favor pylorus-preserving PD because it

shortens the operative time, retains the entire stomach as a reservoir, and has a similar survival rate as

compared with the classic PD.

Figure 55-7. Actuarial survival for standard versus radical pancreaticoduodenectomy. From Yeo CJ, Cameron JL, Lillemoe KD, et

al. Pancreaticoduodenectomy with or without distal gastrectomy and extended retroperitoneal lymphadenectomy for

periampullary adenocarcinoma, part 2: randomized controlled trial evaluating survival, morbidity, and mortality. Ann Surg

2002;236:355–366; discussion 366–368, with permission.

In recent years, significant advances have been made in the application of minimally invasive

techniques to the management of both benign and malignant pancreatic disorders. Initially, laparoscopic

pancreatic surgery was limited to diagnostic staging in patients with pancreatic cancer prior to

resection. More recently, minimally invasive techniques have been used to manage benign and

malignant lesions of the pancreas. While laparoscopic distal pancreatic resections are being performed

with increasing frequency,27 the role of minimally invasive PD remains controversial. Laparoscopic or

robotic PD is a technically demanding procedure due to the retroperitoneal location of the pancreas, its

intimate association with surrounding gastrointestinal and major vascular structures, and the need for

three separate anastomoses to complete the reconstruction. In addition, it is unclear whether an

adequate cancer operation can be performed with respect to lymph node harvest and margin status in

patients with malignancy. Currently, laparoscopic PD is only performed in a handful of specialized

centers (Table 55-12). The procedures are performed as either robotic, pure laparoscopic, hand assisted,

or as laparoscopic-assisted procedures with the resection being performed laparoscopically and the

reconstruction being completed via a “mini” laparotomy or through a hand port.

Carcinoma of the Body and Tail

The surgical management of adenocarcinoma of the body and tail of the pancreas is much more limited

than that of the head of the pancreas because of the extent of the disease usually present at the time of

symptomatic presentation. Most patients are unable to undergo resection, based on findings of major

vascular involvement on CT or peritoneal or liver metastases on laparoscopy. If an attempt at open

exploration for possible cure is undertaken, the exploration should be started with a search for evidence

of either metastatic disease to the liver or peritoneal implants. If this is not the case, the lesser sac is

opened, and the SMV is identified as it passes under the neck of the pancreas. If this vessel is normal,

and if the splenic vein does not appear to be obstructed preoperatively, a distal pancreatectomy with

splenectomy is performed. The spleen is mobilized, as is the distal pancreas, and an en bloc resection of

the structure, including the mass, is obtained. The resection should be extended as proximally as

possible, with the transected pancreas simply oversewn. The tumor bed should be marked with the

1415

 

and therefore may not be routinely detected. Moreover, peritoneal and omental metastases are usually

only 1 to 2 mm in size and frequently can be detected only by direct visualization. With the recent

improvements in CT imaging, the rate of unsuspected positive peritoneal findings approaches 10% to

15% for all patients. The percentage however varies with tumor location. Patients presenting with

obstructive jaundice secondary to tumors in the head of the pancreas typically have only a 15% to 20%

incidence of unexpected intraperitoneal metastasis after routine staging studies. In contrast, unexpected

peritoneal metastasis is found in up to 50% of patients with cancer of the body and tail of the

pancreas.15

Selective use of staging laparoscopy should be considered for patients at high risk of occult metastatic

disease (Table 55-10). The information gained from preoperative staging provides the basis for planning

therapy for each individual patient. If the results of preoperative staging with CT/MRI and laparoscopy

show localized disease, resectability rates may approach 90% for tumors in the head of the pancreas.

Table 55-9 Preoperative Staging based on CT Findings

Algorithm 55-2. Management strategy based on CT criteria for resectability of pancreatic cancer.

RESECTION OF PANCREATIC CARCINOMA

Carcinoma of the Head, Neck, or Uncinate Process

In 1912, Kaush16 reported the first successful resection of the duodenum and a portion of the pancreas

for an ampullary cancer. In 1935, Whipple et al.17 described a technique for radical excision of a

periampullary carcinoma. The operation was originally performed in two stages. A

cholecystogastrostomy to decompress the obstructed biliary tree and a gastrojejunostomy to relieve

gastric outlet obstruction comprised the first stage. The second stage was performed several weeks later

when the jaundice had resolved and the nutritional status had improved. During the second stage, an en

bloc resection of the second portion of the duodenum and head of the pancreas was performed without

reestablishing pancreatic–enteric continuity. Although earlier contributions had been made, the report

1411

by Whipple et al. began the modern-day approach to the treatment of pancreatic carcinoma.

DIAGNOSIS

Table 55-10 Signs of High Risk of Occult Metastatic Disease

The operative management of pancreatic cancer consists of two phases: first, assessing tumor

resectability and then, if the tumor is resectable, completing a PD and restoring gastrointestinal

continuity. After the abdomen has been opened through an upper midline or bilateral subcostal incision,

a careful search for tumor outside the limits of a pancreaticoduodenal resection should be carried out.

The liver, omentum, and peritoneal surfaces are inspected and palpated, and suspect lesions are sampled

and specimens submitted for frozen-section analysis. Next, regional lymph nodes are evaluated for

tumor involvement. The presence of tumor in the periaortic lymph nodes of the celiac axis indicates that

the tumor is beyond the limits of normal resection. However, the presence of tumor-bearing lymph

nodes that normally would be incorporated within the resection specimen does not constitute a

contraindication to resection.

Once distant metastases have been excluded, the primary tumor is assessed in regard to resectability.

Local factors that preclude pancreaticoduodenal resection include retroperitoneal extension of the tumor

to involve the inferior vena cava or aorta or direct involvement or encasement of the superior

mesenteric artery, hepatic artery, and celiac axis. Involvement of the superior mesenteric vein (SMV),

or portal vein can be managed with venous resection and reconstruction in select cases. The technical

aspects of determining local resectability begin with a Kocher maneuver and mobilization of the

duodenum and head of the pancreas from the underlying inferior vena cava and aorta. Once the

duodenum and head of the pancreas are mobilized sufficiently, the surgeon’s hand can be placed under

the duodenum and head of the pancreas to palpate the relationship of the tumor mass to the superior

mesenteric artery. Inability of the surgeon to identify a plane of normal tissue between the mass and the

arterial pulsation indicates direct tumor involvement of the superior mesenteric artery, and the

possibility of complete tumor resection is eliminated.

The final step to determine resectability involves dissection of the superior mesenteric and portal

veins to rule out tumor invasion. Identification of the portal vein can be simplified greatly if the

common hepatic duct is divided and reflected early in the dissection. Once the hepatic duct has been

divided, the posteriorly located portal vein can be identified easily. After the anterior surface of the

portal vein is dissected posterior to the neck of the pancreas, the next step is to identify the SMV and

dissect its anterior surface. This is done most easily by extending the Kocher maneuver past the second

portion of the duodenum to include the third and fourth portions of the duodenum. During this

extensive kocherization, the first structure that one encounters anterior to the third portion of the

duodenum is the SMV. Alternatively the SMV may also be identified by tracing either the middle colic

vein or the right gastroepiploic vein back to the SMV after entering the lesser sac thru the gastrocolic

ligament. The anterior surface of the SMV then can be cleaned rapidly and dissected under direct vision

by retracting the neck of the pancreas anteriorly. The dissection is continued until it connects to the

portal vein dissection from above.

Most experienced pancreatic surgeons, at this point, proceed with a PD without obtaining a tissue

diagnosis. The clinical presentation, results of preoperative CT and cholangiography, and operative

findings of a palpable mass in the head of the pancreas surpass the ability of an intraoperative biopsy to

define the diagnosis of malignancy.

Having excluded regional and distant metastases and demonstrated no tumor involvement in major

vascular structures, the surgeon can proceed with PD with a high degree of certainty that the tumor is

1412

resectable. In the pylorus-preserving modification of PD, the duodenum is first mobilized and divided

approximately 2 cm distal to the pylorus. If a classic Whipple procedure is to be performed, the stomach

is divided to include approximately 40% to 50% of the stomach with the resected specimen. The

gastroduodenal artery is exposed, ligated, and divided near its origin at the common hepatic artery. It is

always important to confirm, before ligation, that the structure to be ligated is indeed the

gastroduodenal artery and not a replaced right hepatic artery. Next, the neck of the pancreas is divided,

with care taken to avoid injury to the underlying superior mesenteric and portal veins. The portal and

superior mesenteric veins are then dissected from the uncinate process and head of the pancreas. At this

point, the fourth portion of the duodenum and the proximal jejunum are mobilized, with the proximal

jejunum divided approximately 10 cm distal to the ligament of Treitz. The proximal jejunum and fourth

portion of the duodenum are passed under the superior mesenteric vessels to the right, and the uncinate

process is dissected from the superior mesenteric artery clearing all of the tissue along the right border

of the artery. The course of the superior mesenteric artery should be clearly identified to avoid injury to

this structure. At this point, the specimen consisting of the gallbladder and common bile duct; the head,

neck, and uncinate process of the pancreas; the entire duodenum; and the proximal jejunum (and the

distal stomach for a traditional Whipple procedure) is freed completely and removed from the operative

field (Fig. 55-6). Margins should be inked to facilitate pathologic analysis of the specimen.

Figure 55-6. Pancreaticoduodenectomy. A: The tissue to be resected in a standard pancreaticoduodenectomy. B: Reconstruction

after a standard pancreaticoduodenectomy. C: Reconstruction after the pylorus-sparing variation.

Table 55-11 Randomized Prospective Trials of Standard Versus Extended

Lymphadenectomy for Pancreatic Cancer

1413

 

In general, MRI offers no significant advantages over CT because of a low signal-to-noise ratio,

motion artifacts, lack of bowel opacification, and low spatial resolution. MRI can be considered an

alternative preoperative staging examination in patients with allergies to iodinated contrast agents and

in patients with renal insufficiency. On MRI, a typical pancreatic adenocarcinoma appears hypointense

on T1-weighted, unenhanced images, and has a variable appearance on T2-weighted sequences. The T2

signal of the tumor is often dependent on the amount of desmoplastic response associated with the

tumor. On dynamic imaging following a gadolinium contrast injection, an adenocarcinoma enhances

relatively less than the background pancreatic parenchyma in the early phase and then reveals

progressive enhancement in the subsequent phases. Magnetic resonance imaging with MRCP is currently

indicated for noninvasive diagnostic imaging to evaluate the biliary and pancreatic ducts and may be

the optimal method to survey patients with IPMN and the pancreatic remnant after surgery.

Traditionally, the next step in the evaluation of the jaundiced patient has been cholangiography,

either by the endoscopic or by the percutaneous route. If the endoscopic approach is used, the

duodenum and ampulla can be visualized and biopsy specimens obtained if necessary. In addition, ERCP

allows for direct imaging of the pancreatic duct. The sensitivity of ERCP for the diagnosis of pancreatic

cancer approaches 90%. The finding of a long, irregular stricture in an otherwise normal pancreatic duct

is highly suggestive of a pancreatic cancer (Fig. 55-4). Often, the pancreatic duct will be obstructed with

no distal filling. Although ERCP is reliable in confirming the presence of a clinically suspected

pancreatic cancer, it should not be used routinely. Diagnostic ERCP should be reserved for patients with

presumed pancreatic cancer and obstructive jaundice in whom no mass is demonstrated on CT,

symptomatic but nonjaundiced patients without an obvious pancreatic mass, and patients with chronic

pancreatitis who develop jaundice.

EUS is a minimally invasive technique in which a high-frequency ultrasonographic probe is placed

into the stomach and duodenum endoscopically and the pancreas is imaged. Tumors appear as

hypoechoic areas in the pancreatic substance (Fig. 55-5). The strengths of EUS techniques for pancreatic

cancer are the clarification of small lesions (<2 cm) when CT findings are questionable or negative,

detection of malignant lymphadenopathy, detection of vascular involvement, and the ability to perform

EUS-guided FNA for definitive diagnosis and staging. EUS is not effective in assessing metastatic disease

to the liver. In patients for whom a tissue diagnosis is required (poor operative candidates or

undergoing neoadjuvant therapy), EUS-guided FNA has been used to acquire tissue samples for cytologic

analysis. This approach may avoid the risks of tumor seeding from percutaneous biopsy. The accuracy of

EUS without FNA averages 85% for determining T-stage and 70% for determining N-stage diseases. The

combination of EUS and FNA has a sensitivity of 93% and a specificity of 100% for T stage and an

accuracy of 88% for N stage.13 At the time of diagnosis, only 10% of patients have tumors confined to

the pancreas, 40% have locally advanced disease, and more than 50% have distant spread.

Figure 55-4. Endoscopic retrograde cholangiopancreatography in a patient with adenocarcinoma of the pancreas demonstrates a

stricture of both the distal common bile duct and the pancreatic duct (arrow).

1409

Figure 55-5. Endoscopic ultrasonogram of a 2.2-cm mass in the head of the pancreas. The transducer tip is located in the

duodenum. The dilated common bile duct and gallbladder (GB) can be seen at the top of the image. The pancreatic duct (PD) is

also dilated. The mass involves the portal vein (PV).

Percutaneous FNA of pancreatic masses is helpful in selected patients. The technique is safe and

generally reliable but is of limited use in patients in whom surgical exploration for attempted resection

or palliation is planned. The reasons for not using FNA or percutaneous biopsy in potentially resectable

lesions are twofold. First, even after repeated sampling, a negative result does not exclude malignancy;

in fact, it is the smaller and likely more curable tumors that are likely to be missed by the needle. The

second concern is the potential for seeding of the tumor, either along the needle tract or with

intraperitoneal spread. Percutaneous biopsy is primarily indicated in patients with unresectable cancers

based on preoperative staging to direct palliative chemoradiation therapy or in patients with cancer in

the head of the pancreas in whom neoadjuvant protocols are being considered. Currently, however, EUS

is the preferred technique when possible in either situation.

PREOPERATIVE STAGING

The goal of preoperative staging of pancreatic cancer is to determine the feasibility of surgery and the

optimal treatment for each individual patient. Specific anatomy-based CT criteria can stratify patients

into four distinct groups (Table 55-9): (1) Resectable, (2) Borderline, (3) Locally advanced, or (4)

Metastatic. The extent of further staging to be performed depends on the individual patient and the

surgeon’s preference. Historically, patients with resectable CT criteria were offered operation as the

first modality of therapy followed by adjuvant chemotherapy or chemoradiotherapy. Recent advances in

the efficacy of systemic chemotherapy agents have further supported the hypothetical benefits of

preoperative neoadjuvant chemotherapy even for resectable tumors. Patients with borderline or locally

advanced pancreatic cancer based on CT criteria should receive preoperative chemotherapy or

chemoradiotherapy. Ideally, patients in these high-risk categories of disease should be offered

enrollment in clinical trials investigating novel treatment agents. Algorithm 55-2 outlines an algorithm

for approaching patients with pancreatic cancer after complete staging and determination of

resectability based on local vascular involvement according to CT findings.

STAGING LAPAROSCOPY

The use of diagnostic laparoscopy in pancreatic cancer remains controversial. Proponents believe that

laparoscopy can identify a substantial number of unresectable patients with advanced disease and,

therefore, should be uniformly applied to all patients with potentially resectable tumors.14 On the other

hand, opponents believe that the inherent cost of such a practice far outweighs the benefit to the small

number of patients in whom diagnostic laparoscopy is useful. The liver and peritoneum are the most

common sites of distant spread of pancreatic carcinoma. Once distant metastases have developed,

survival is so limited that a conservative approach is usually indicated. Liver metastases larger than 1

cm in diameter can usually be detected by CT, but approximately 30% of these metastases are smaller

1410