Endocrine tumors of the pancreas: Clinical picture, diagnosis, and therapy

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Chapter 61 Endocrine tumors of the pancreas

Clinical picture, diagnosis, and therapy

Overview

Pancreatic endocrine tumors (PETs) are rare neoplasms that comprise 2% to 4% of all clinically detected pancreatic tumors (see Chapter 56). The origin of these tumors is not completely understood. Based on the most recent evidence, it has been suggested that these tumors arise from an endocrine cell–derived gastrointestinal epithelium. The pathogenesis of these tumors is not completely understood. Earlier theorists and modern geneticists have suggested that PETs arise from omnipotent endocrine stem cells present within the gastrointestinal epithelium. PETs are frequently divided into two groups based on the presence or absence of hormone function. Nonfunctioning, or non–hormone producing, tumors account for up to 30% or more of all neuroendocrine tumors; they express neurosecretory granules but are not associated with a clinically evident endocrinopathy, and most are discovered incidentally through the use of imaging studies done for other reasons or because of nonspecific abdominal symptoms. Functional tumors produce hormones that result in well-described endocrinopathies directly attributable to the hormones they secrete. The majority of PETs are sporadic, but they can be associated with hereditary syndromes, such as multiple endocrine neoplasia type 1 (MEN-1), von Hippel–Lindau (VHL) syndrome, tuberous sclerosis complex (TSC), and neurofibromatosis 1 (NF-1). The genetic predisposition for pancreatic endocrine tumors is strongest with MEN-1, which is characterized by the development of multigland parathyroid hyperplasia, pancreatic islet cell tumors, and pituitary adenomas. Almost half of all patients with MEN-1 develop symptomatic pancreatic endocrine tumors, and 100% of patients are shown to harbor small, nonfunctioning pancreatic endocrine neoplasms when the gland is examined histologically (Muscarella & Ellison, 2004).

Clinical management of PETs involves a multidisciplinary approach. Biochemical diagnosis and radiologic localization are the cornerstone of preoperative planning. Surgical resection is the only treatment that is curative, especially in an early stage of disease, but as many as 75% of patients present with advanced disease. Nonoperative therapies include chemotherapy, radiofrequency ablation (RFA), radionuclide therapy, biotherapy, and chemoembolization (see Chapters 81B and 83). These therapeutic modalities are useful for patients with unresectable or metastatic disease in whom symptomatic control of the hormonal effects and arrest of tumor progression can provide palliation and in some instances prolong survival.

Classification and Prognosis

Pancreatic endocrine tumors arise from the islets of Langerhans, and human islet cells display wide varieties in cellular composition and morphology. The molecular pathogenesis of PETs is poorly characterized, but they are associated with genetic syndromes such as VHL, MEN-1, NF-1, and TSC. The genetic makeup of these syndromes may help elucidate the molecular pathways from which PETs arise, although the majority of PETs are sporadic in origin. The broad heterogeneity of these tumors presents a challenge with regard to their correct classification. PETs are commonly classified by the presence or absence of a syndrome caused by hormone hypersecretion; however, neither of these classification systems offers any valuable predictive information regarding the biology or prognosis of these tumors.

The World Health Organization (WHO) developed a classification of pancreatic tumors that predicts malignant behavior based on histologic criteria (Heitz et al, 2004). This classification system assesses tumor localization, extension, proliferative capacity, and the presence of vascular or perineural invasion (Table 61.1). Some authors have challenged the clinical relevance of the WHO classification system (Schindl et al, 2000). Other studies have shown to have strong prognostic value and the ability to predict response to adjuvant treatments (Artale et al, 2005; Bajetta et al, 2005). The tumor-node-metastasis (TNM) staging system for pancreatic exocrine adenocarcinoma has been applied to the staging of PETs and was recently revised to include grades relative to mitotic counts or Ki-67 index (Table 61.2). This was recently validated in a retrospective study looking at 202 foregut neuroendocrine tumors, of which 131 were PETs. This system was found to be equivalent but not superior to the WHO classification system (Pape et al, 2008).

Table 61.1 WHO Classification of Pancreatic Endocrine Tumors

Well-Differentiated Endocrine Tumor
Type 1: Benign Behavior Type 2: Uncertain Behavior
Confined to the pancreas<2 cm in diameter<2 mitoses per high-powered field<2% Ki-67–positive cellsNo vascular or perineural invasion Confined to the pancreas and one of the following:
>2 cm in diameter
>2 mitoses per high-powered field
>2% Ki-67–positive cells
Vascular or perineural invasion
Well-Differentiated Endocrine Carcinoma

Poorly Differentiated Carcinoma

Table 61.2 TNM Classification for Pancreatic Neuroendocrine Tumors

T: Primary Tumor
T0 No evidence of cancer
Tis Carcinoma in situ
T2 Tumor limited to the pancreas, size >2 cm
T3 Tumor extends beyond the pancreas but does not involve the celiac axis or superior mesenteric artery
T4 Tumor involves celiac axis or superior mesenteric artery (unresectable primary tumor)
N: Regional Lymph Nodes
N0 No regional lymph nodes involved
N1 Regional lymph nodes involved
M: Distant Metastases
M0 No distant metastases
M1 Distant metastases
Stages
0 TisN0M0
IA T1N0M0
IB T2N0M0
IIA T3N0M0
IIB T1N1M0, T2N1M0, T3N1M0
III T4, any N, M0
IV Any T, any N, M1

From AJCC Cancer Staging Manual, 7th ed. Chicago, 2010, American Joint Committee on Cancer.

The prognostic value of newer systems has yet to be validated in a prospective way. In a large retrospective study of PET patients from the National Cancer Database, variables predictive of outcomes included age, grade, type of resection, distant metastases, and tumor functionality. Tumor size, nodal status, and margins were not associated with survival (Bilimoria et al, 2008). The limitations of retrospective studies, usually with a small cohort size, and heterogeneity among these tumors likely explain why a standard classification system for PETs still does not exist.

Insulinoma

Insulinomas represent the most common type of functioning pancreatic endocrine tumor. They can occur sporadically or in association with the hereditary MEN-1. Patients typically are women (2 : 1) in the fifth or sixth decade of life. Among the functional PETs, insulinoma has the most favorable prognosis because the majority of these lesions are benign. Sporadic insulinomas are typically unifocal, but MEN-1 patients who develop insulinomas (approximately 10%) may present with multifocal disease.

Diagnosis

The differential diagnosis of hyperinsulinemic hypoglycemia includes postprandial dumping syndromes, insulin receptor gene mutations, factitious hypoglycemia, chronic adrenal insufficiency, and hypopituitarism. In adults with symptoms of hypoglycemia, a 72-hour fast can elucidate the cause of hypoglycemia, defined as a plasma glucose level of 50 mg/dL or less. A monitored fast until symptoms of hypoglycemia develop, or until 72 hours elapse, is commonly performed, with measurement of the plasma concentrations of insulin and glucose at set intervals, especially when the patient becomes symptomatic. An insulin/glucose ratio greater than 0.4 is consistent with an insulinoma.

Insulin is synthesized in the β-cells as a larger molecule called proinsulin. C-peptide is cleaved from proinsulin to make the active form of insulin. Elevated levels of insulin with undetectable proinsulin and C-peptide indicate factitious hypoglycemia from the exogenous administration of insulin. Factitious hypoglycemia can also be caused by the ingestion of sulfonylureas, which cause elevated levels of all the β-cell polypeptides. Factitious hypoglycemia often occurs in health care workers who have access to insulin or oral hypoglycemics. So, during a monitored 72-hour fast, both C-peptide and sulfonylureas should also be measured in the patient’s plasma and urine. Monitored testing can detect up to 99% of insulinomas (Table 61.3; Service et al, 2000). Provocative testing with tolbutamide, glucagon, or intravenous calcium is rarely required for the diagnosis of insulinoma; furthermore, their use can cause harmful hypoglycemia with permanent neurologic damage. Autoimmune syndromes are rare causes of hypoglycemia that result from elevated levels of insulin in the presence of antiinsulin antibodies or antiinsulin receptor antibodies. Screening for these rare conditions can be done with serum measurements of the respective antibodies. Treatment is nonsurgical and sometimes warrants plasmapheresis.

Table 61.3 Diagnostic Criteria for Insulinoma

Localization

Imaging for preoperative localization of insulinomas should take place only after the biochemical diagnosis has been confirmed. Most patients with insulinomas have a solitary benign adenoma (Friesen, 1982). Patients with familial syndromes, however, are more likely to have multifocal disease. Adenomas occur with equal frequency in the head, body, and tail of the pancreas. The majority of lesions are less than 1.5 cm in size and can be below the limit of detection for many conventional imaging modalities. Localization of insulinomas preoperatively remains a challenge for present-day clinicians. Traditional imaging techniques include ultrasound (US), computed tomography (CT) (see Chapter 16), and magnetic resonance imaging (MRI) (see Chapter 17). Transabdominal US, although widely available and used routinely, has low sensitivity in detecting insulinomas because of limitations from body habitus, surrounding intraabdominal organs, and the retroperitoneal depth of the pancreatic head.

Endoscopic ultrasound (EUS) (see Chapter 14) has substantially improved preoperative imaging of pancreatic neoplasms, but it is invasive. The sensitivity of EUS for localizing insulinomas has been reported to be 65% to 94%, with a mean sensitivity of 84% to 89% (Sotoudehmanesh et al, 2007). EUS visualization of the pancreatic head and uncinate process is superior to that of conventional US and provides the option of image-guided biopsy. The sensitivity of EUS is variable and depends on the location of the tumor. Sotoudehmanesh and colleagues (2007) reported sensitivity of EUS for detection of lesions in the pancreatic head, body, and tail as 92.6%, 78.9%, and 40.0%, respectively. This is understandable because of a blind spot in the distal body and tail where the stomach does not directly overly the pancreas.

Because of its wide availability, CT is usually the first localizing study performed; it can detect up to two thirds of lesions. When available, multidetector-row CT has been shown to be more sensitive for detecting small insulinomas (Liu et al, 2009). Most insulinomas are vascular and can be visualized on arterial phase imaging. One series comparing the use of CT, EUS, and the two in combination found the sensitivity of CT with EUS was superior to either modality done separately (Gouya et al, 2003). MRI alone or in combination with other imaging modalities has demonstrated higher sensitivity and rates of detection than were originally reported. More recent use of rapid tri-phase breath-holding imagery allows better fat suppression and reduction in motion artifact in both the arterial and venous phases (Catalano et al, 1999; Thoeni et al, 2000). At present, MRI is considered a second-line modality in the evaluation of insulinomas because of its greater expense and more limited availability.

Because only 30% of insulinomas possess somatostatin type II receptors, the value of somatostatin receptor scintigraphy (SRS) is limited in this tumor type (Kisker et al, 1997). Intraarterial calcium stimulation with hepatic venous sampling is one of the most sensitive localization modalities but also one of the most invasive (Guettier et al, 2009). It is a modification of the selective arterial secretin injection test developed by Imamura and colleagues (1993) and used to localize gastrinomas. This technique involves selective infusion of calcium into branches of the celiac axis and superior mesenteric artery with sampling of the hepatic venous effluent for insulin. It is an invasive, expensive, time-consuming, and technically difficult procedure that should be reserved for patients with persistent or recurrent disease, or when other tests are unsuccessful.

Despite these advances, preoperative localization may still not be successful in up to a third of patients. Current research suggests that future improvements will continue. A recent study showed that glucagon-like peptide-1 (GLP-1) receptor was expressed in more than 90% of insulinomas and at twice the density of somatostatin receptors (Reubi et al, 2003). Exendin-3, the analogue of GLP-1, is known to enhance insulin secretion in β-cells and has been introduced in the treatment of type 2 diabetes (Gallwitz et al, 2006). In a pilot trial of six patients, scintigraphy done with GLP-1 radioligands was able to identify all the insulinomas prior to operative exploration (Christi et al, 2009).

The extent of imaging necessary to ensure operative cure has not been clearly defined. Some institutions have suggested that preoperative localization is not necessary beyond the evaluation for metastatic disease (Hashimoto et al, 1999). This philosophy is based on the observation that the combination of surgical exploration and intraoperative US can identify more than 90% of insulinomas.

Therapy

Although the definitive treatment for patients with insulinomas is resection of the tumor, presurgical therapy to alleviate the symptoms and neurologic affects of hypoglycemia should be instituted. The medical management of insulinomas consists of dietary measures to minimize the occurrence of dangerous hypoglycemia. This involves taking small, frequent meals and closely monitoring blood glucose levels throughout the day. A number of insulin antisecretagogues can be used, such as diazoxide, verapamil, octreotide, or dilantin. Diazoxide, the most commonly prescribed drug, works by directly inhibiting the release of insulin from β-cells by stimulating their α-adrenergic receptors. Diazoxide also promotes glycogenolysis by inhibiting cyclic adenosine monophosphate phosphodiesterase. It can offer symptom control in up to 50% to 60% of patients (Boukhman et al, 1998). Octreotide, a somatostatin analogue, has had variable results and alleviates symptoms in approximately 40% of patients (Arnold et al, 2002). Its use is limited by side effects such as bloating, malabsorption, cholelithiasis, and eventual tachyphylaxis. Dilantin and verapamil have been used alone or in combination with other drugs, but their duration of action and side effects limit their efficacy for long-term medical therapy.

Definitive treatment for an insulinoma is operative removal of the tumor. Before proceeding to surgery, it is important to exclude the presence of any familial syndromes and their other associated problems, such as pituitary tumors and hyperparathyroidism. Intraoperative glucose monitoring is done to ensure normoglycemia. Dextrose infusions should be stopped just prior to surgical resection to permit intraoperative glucose measurements as an indicator of biochemical cure. The glucose levels should be monitored frequently to be sure hypoglycemia does not persist.

Most sporadic adenomas are amenable to enucleation regardless of their location. Surgical exploration starts by gaining access to the pancreas in the lesser sac. Lesions located in the head of the pancreas should be explored via a wide kocherization of the duodenum. In experienced hands, intraoperative US in combination with palpation detects up 98% of insulinomas (Norton et al, 1988). Care must be taken not to injure the pancreatic duct when performing an enucleation or segmental resection. Intraoperative US is useful to identify the location of the pancreatic duct for lesions in the head that are being enucleated. The insulinoma can be approached anteriorly or posteriorly depending on findings from palpation and intraoperative US. After an insulinoma is fully enucleated, it is essential to inspect the area for ductal leaks. Should a leak be identified, a suture repair should be attempted if feasible, and a suction drain should be left in place; postoperative management of the drain is identical to that for any pancreatic leak. The most common complication following resection for an insulinoma is a pancreatic leak. Rates of pancreatic fistula have been reported between 18% and 38% (Espana-Gomez et al, 2009; Nikfarjam et al, 2008). Fistulas are seen more commonly among patients treated with enucleation procedures than those undergoing formal resection.

Most insulinomas are solitary, but in patients with MEN-1, multifocal lesions are typical. In MEN-1 patients—in whom multiple, subcentimeter tumors often coalesce—segmental resection rather than enucleation is preferred (see Chapter 62A). The goal of surgery in MEN-1 patients is to remove only the tumors, preserving as much normal pancreas as possible. After preoperative imaging, if the tumor cannot be identified by operative exploration with complete mobilization of the pancreas—including kocherization to allow bimanual palpation of the entire gland—or intraoperative US, blind resection is not recommended. When the lesion is not found, a pancreatic biopsy specimen should be obtained to rule out adult nesidioblastosis, which generally can be treated successfully by subtotal pancreatectomy. The biopsy specimen is obtained by removing a small portion of the most distal tail.

Numerous studies have shown that laparoscopy is a safe and feasible approach for the treatment of pancreatic insulinomas (see Chapter 62B). Solitary lesions localized preoperatively are ideally suited for this approach. In the absence of bimanual palpation, laparoscopic US assists in tumor localization. Whereas preoperative localization has an accuracy rate of 45% for laparoscopic resection alone, when combined with laparoscopic US, the accuracy rises to 96% (Luo et al, 2009). Conversion rates to an open procedure range between 7% and 44% (Ayav et al, 2005; Jaroszewski et al, 2004; Luo et al, 2009), and the most common reason for conversion is failure to localize the tumor. Limited data suggest that fistula rates are lower among patients treated by laparoscopic compared to open approaches (Cunha et al, 2007).

The rarity of malignant insulinoma limits definitive statements about therapeutic strategies and outcome. In patients with metastatic disease, surgical resection of the tumor and metastatic lesions should be considered for palliation of symptoms of hypoglycemia. Because of the often indolent nature of malignant insulinomas, extended survival is possible. Multimodal therapy that includes surgical debulking, chemoembolization, radiofrequency thermoablation, and liver transplantation has been shown to prolong survival (Begu-Le Corroller et al, 2008). Median disease-free survival has been reported to be approximately 4 years in patients who underwent curative resection for malignant disease (Danforth et al, 1984; Hirshberg et al, 2005). Chemotherapy of malignant insulinomas consists of streptozotocin in combination with other agents, including 5-fluorouracil or doxorubicin. Reports regarding the success of these agents in clinical trials are understandably scarce given the rarity of this condition.

Gastrinoma (Zollinger-Ellison Syndrome)

Gastrinomas are the second most common functioning islet cell tumor of the pancreas. The overall incidence of gastrinomas is 0.5 to 3 per million population per year (Jensen et al, 2006). The peak age of onset is 50 years, and there is a slight male predominance. Despite their slow-growing nature, more than 60% of gastrinomas are malignant. Because of their indolent growth pattern, even in the presence of metastases, the 10-year survival approaches 90%. Approximately two thirds of gastrinomas are sporadic, with the remainder associated with familial MEN-1. Gastrinomas in MEN-1 patients tend to be multifocal, and as many as 50% of patients have lymph node, liver, or distant metastases at the time of presentation (Andersen, 1989).

Clinical Picture

Gastrinomas are so named because they produce excess levels of the gastrointestinal hormone gastrin. This results in acid hypersecretion and the subsequent development of intractable gastrointestinal ulcers. Zollinger-Ellison syndrome (ZES) is the name given to this condition, and it includes the presence of a gastrin-producing tumor in the presence of acid hypersecretion. With the advent of effective antisecretory medications, patients may or may not have intractable ulcer disease at the time of diagnosis. ZES patients come to medical attention with symptoms of abdominal pain, heartburn, nausea, and often weight loss. Diarrhea is a common problem in ZES, occuring in close to 80% of patients (Jensen et al, 2006), and 70% of patients being seen for evaluation of ZES have a confirmed history of peptic ulcer disease. Patients with ZES are also likely to exhibit sequelae of gastric acid hypersecretion, such as esophageal stricture or prominent gastric folds, documented by endoscopic gastroduodenoscopy (EGD). A suspicion of ZES is not appropriate for all patients who present with peptic ulcer disease (PUD). Approximately 0.2% of patients with PUD will have ZES, whereas 2% of patients with recurrent PUD will have ZES (Modlin et al, 1982). Other than recurrent ulcers, a higher suspicion of ZES should be held in patients who present with 1) PUD with diarrhea; 2) ulcers in unusual locations, including the distal duodenum and jejunum; 3) ulcers that are refractory to medical management or those associated with complications, such as bleeding and perforation; 4) disease at a young age; and 5) hyperparathyroidism, pituitary disorders, or a familial history of endocrinopathies. Given the nonspecific symptoms and relative rarity of this disorder, the mean time from the onset of symptoms to diagnosis is 5.9 years (Roy et al, 2000; Berna et al, 2006a). A high index of suspicion is necessary to diagnose these patients.

Diagnosis

The diagnosis of ZES is established by measuring a fasting serum gastrin (FSG) level and documenting the presence of acid hypersecretion (Table 61.4). Prior to testing, patients should be off all antisecretory medications at least 3 to 7 days. Proton pump inhibitors should be stopped for at least 1 week, and H2 receptor antagonists should be stopped for 2 days prior to testing. A fasting serum gastrin (FSG) level above 100 pg/mL or 10 times greater than the upper limit of normal (ULN) is highly suggestive of ZES. However, only one third of ZES patients have an FSG level 10 times higher than the ULN, and a number of conditions that are not associated with ZES can cause an elevated FSG level (Table 61.5). To help differentiate these conditions, the presence of gastric acid hypersecretion should be documented. Excess gastric acid production is demonstrated by having a gastric pH of less than 2.1 or a basal acid output level greater than 15 mEq/h.

Table 61.4 Diagnostic Criteria for Gastrinoma

Fasting gastrin level >100 pg/mL or >10 times higher than upper limit of normal
Basic acid output level >15 mEq/h
Secretin stimulation testing Increase of >200 pg/mL
Calcium infusion provocative testing Rise >395 pg/mL

Patients should be off antisecretory agents a minimum of 3 to 7 days.

Table 61.5 Differential Diagnosis of Hypergastrinemia

High Acid Output Normal Acid Production
Zollinger-Ellison syndrome Atrophic gastritis
G-cell hyperplasia Proton pump inhibitors
Retained gastric antrum Postvagotomy syndrome
Gastric outlet obstruction Renal failure

The magnitude of the increased FSG has been shown to correlate with certain tumor features (Berna et al, 2006a). Patients with pancreatic primary tumors are more likely than those with duodenal primary tumors to have an FSG level higher than 10 times the ULN (50% of pancreatic vs. 25% of duodenal primaries). FSG level also correlates with tumor size and extension. Patients with larger tumors (>3 cm) are more likely to have an FSG level greater than 10 times the ULN when compared with smaller tumors (40% vs. 23%, respectively). Fifty percent of patients with liver metastases will have an FSG level more than 10 times the ULN, compared with only a third of those who do not.

Two thirds of ZES patients will have equivocal FSG testing, and provocative testing should be performed. Three types of provocative tests are available for the diagnosis of ZES: 1) the secretin stimulation test, 2) the calcium infusion test, and 3) the standard meal test. The secretin stimulation test is performed by intravenously administering a 2 IU/kg bolus of secretin to the patient and serially measuring serum gastrin levels at specific time points. A serum gastrin rise of 200 pg/mL (range, >100 to 335 pg/mL) is consistent with ZES (Frucht et al, 1989b; McGuigan et al, 1980

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