Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

doi:10.1053/j.gastro.2008.05.047

Gastroenterology

Volume 135, Issue 5, November 2008, Pages 1469-1492

https://doi.org/10.1053/j.gastro.2008.05.047 Get rights and content

Pancreatic endocrine tumors (PETs) have long fascinated clinicians and investigators despite their relative rarity. Their clinical presentation varies depending on whether the tumor is functional or not, and also according to the specific hormonal syndrome produced. Tumors may be sporadic or inherited, but little is known about their molecular pathology, especially the sporadic forms. Chromogranin A appears to be the most useful serum marker for diagnosis, staging, and monitoring. Initially, therapy should be directed at the hormonal syndrome because this has the major initial impact on the patient's health. Most PETs are relatively indolent but ultimately malignant, except for insulinomas, which predominantly are benign. Surgery is the only modality that offers the possibility of cure, although it generally is noncurative in patients with Zollinger–Ellison syndrome or nonfunctional PETs with multiple endocrine neoplasia-type 1. Preoperative staging of disease extent is necessary to determine the likelihood of complete resection although debulking surgery often is believed to be useful in patients with unresectable tumors. Once metastatic, biotherapy is usually the first modality used because it generally is well tolerated. Systemic or regional therapies generally are reserved until symptoms occur or tumor growth is rapid. Recently, a number of newer agents, as well as receptor-directed radiotherapy, are being evaluated for patients with advanced disease. This review addresses a number of recent advances regarding the molecular pathology, diagnosis, localization, and management of PETs including discussion of peptide-receptor radionuclide therapy and other novel antitumor approaches. We conclude with a discussion of future directions and unsettled problems in the field.

Section snippets

Epidemiology

PETs occur in 0.5%–1.5% of autopsies but are functional or symptomatic in less than 1 in 1000, resulting in a clinical detection rate of 1:100,000 population, which comprises 1%–2% of pancreatic neoplasms.⁸ In older studies, nonfunctional PETs (NF-PETs), insulinomas, and gastrinomas had equal frequency;⁹ however, in recent studies NF-PETs were twice as frequent.10, 11 The relative frequency of PETs varies in surgical or medical series, but most studies suggest a relative order of: NF-PET >

Classification/Pathology

PETs are divided clinically into 2 groups: functional and NF-PETs. Functional PETs secrete biologically active peptides causing 1 of 9 well-established syndromes (Table 1). NF-PETs are not associated with a specific hormonal syndrome either because no peptide is secreted or the substance secreted does not cause specific symptoms. Most (>70%) NF-PETs are not truly nonfunctional because they secrete substances such as pancreatic polypeptide, other peptides (neurotensin, ghrelin, and so forth),

Molecular Pathogenesis

Little is known about the molecular pathogenesis of PETs.1, 2, 8 This has occurred in part because alterations in common oncogenes (fos, jun, myc, k-ras, and so forth) or common tumor-suppressor genes (p53, retinoblastoma, and so forth) are not generally implicated in their pathogenesis.1, 2, 8 Some of the most important insights have come from studies of inherited PET syndromes.1, 2, 8, 20 Altered genes causing these syndromes are important in some cases of sporadic PETs (ie, nonfamilial

Tumor Biology, Prognosis, and Tumor Markers

PETs differ in their malignant potential and location (Table 1). Some PETs (insulinomas, glucagonomas, and VIPomas in adults) are found almost entirely within the pancreas, whereas others, although still referred to as PETs, actually occur in extrapancreatic locations (duodenal gastrinomas [60%–80%],30, 31, 32 small intestinal somatostatinomas [40%–50%], and growth hormone-releasing factor secreting tumor (GRFomas) primarily in the lung [>70%]) (Table 1). Insulinomas are malignant in 5%–15%,

Gastrinoma: Clinical Features/Diagnosis

Gastrinomas secrete gastrin, which causes hyperchlorhydria, thereby producing the Zollinger–Ellison syndrome (ZES).31, 45, 59, 60 With a long mean delay (6.1 y) in presentation/diagnosis,45, 61, 62 patients generally present with acid-peptic conditions including complicated and uncomplicated ulcers and/or gastroesophageal reflux disease (Table 2,top). Occasionally other manifestations such as diarrhea, malabsorption, or, in MEN1/ZES patients, various other endocrine features predominate (Table 2

Tumor Localization/Staging

Imaging studies are essential for the management of patients with PETs. They are needed to localize the primary tumor as well as for staging to guide management, including surgical plans (curative resection, debulking, or medical management only), to monitor tumor growth, and for follow-up evaluation after therapy.6, 9, 103, 104, 105, 106, 107, 108

Gastrinoma: Medical Management

In ZES acid hypersecretion is the most important clinical effect.45, 62, 167, 168 Because of their potency and long duration of action, PPIs are the agents of choice for management.31, 45, 53, 167, 169, 170 Histamine H₂-receptor antagonists or SS analogues are effective, but the former drug class is limited by the need for frequent, high-dose administration,167, 169 whereas the latter class is limited by the need for parenteral therapy.

Once- or twice-daily oral PPIs (ie, omeprazole [40 mg],

Surgical Therapy for Cure

Surgery is the only treatment modality with the potential to cure patients with PETs. However, surgery is only likely to be effective in patients without diffuse metastatic disease who are able to tolerate the intervention and, in the case of ZES specifically, only in those with sporadic disease.13, 113, 197, 198, 199 Negative preoperative localization should not be considered a contraindication to surgery in patients with proven functional PETs because an experienced PET surgeon will very

General Treatment of Metastatic Disease

In recent studies the long-term outcome in patients with PETs is increasingly dependent on tumor growth. However, even with widespread liver metastases many patients remain relatively well with slow progression, especially early on in the disease process, such that many authorities advocate delaying the introduction of disease-modifying agents until there is clear development of enlarging tumor burden, or symptoms develop. Furthermore, standard antitumor therapies are not curative and

Liver-Directed Therapy (Embolization, Chemoembolization)

Most malignant PETs metastasize to the liver where they derive their blood supply from hepatic artery branches (75%–80%), in contrast to native liver tissue, which derives the majority of its blood supply from the portal vein.9, 248, 249 Recent studies have shown that liver metastases show rapid growth in less than 50% of patients and up to 30% show no growth on follow-up evaluation.33, 37, 250 Consequently, the usual approach to palliative therapy for liver metastases is to delay therapy until

Future Directions and Unsettled Problems

Even though there have been many advances in recent years in the diagnosis/management of PETs, it is not clear that survival in patients with advanced disease has improved. In fact, in a recent review²⁹⁴ of survival for all GI NETs (both carcinoids and PETs), no change in survival was reported over a 30-year period. Numerous factors contribute to this including their continued delay in diagnosis (mean, 4–6 y); the lack of general availability to most patients of the expertise and experience

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Insulinomas are functional pancreatic neuroendocrine tumors that can cause hypoglycemia. Congenital adrenal hyperplasia (CAH) is a disease that can have mutations in a variety of mutations that comprise cortisol synthesis and require certain patients to require cortisol supplementation to prevent hypoglycemia. We report a case presentation of a patient with CAH and migraines who develops an insulinoma with neuroglycopenic symptoms. His hypoglycemia was treated with stress dose steroids and fluid resuscitation before undergoing a 72-h fast to confirm the diagnosis of an insulinoma. The patient then underwent a robotic distal pancreatectomy with postoperative stress dose steroids and had no further hypoglycemic complications on his home regimen of hydrocortisone supplementation. As his neuroglycopenic symptoms were initially thought to be migraines exacerbating his CAH, this case illustrates the need to keep a broad differential for hypoglycemia in patients with CAH. Insulinomas should be in that differential and the appropriate biochemical testing and imaging should be performed.
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Using propensity score matching, 89 patients were allocated in each group (1:1), and were evenly distributed in terms of age, sex, Charlson comorbidity index, American Society of Anesthesiologists score, body mass index, distance between lesion and main pancreatic duct, lesion site, size, and grade. Adverse event (AE) rate was 18.0% and 61.8% after EUS-RFA and surgery, respectively (P < .001). No severe AEs were observed in the EUS-RFA group compared with 15.7% after surgery (P < .0001). Clinical efficacy was 100% after surgery and 95.5% after EUS-RFA (P = .160). However, the mean duration of follow-up time was shorter in the EUS-RFA group (median, 23 months; interquartile range, 14-31 months vs 37 months; interquartile range, 17.5-67 months in the surgical group; P < .0001). Hospital stay was significantly longer in the surgical group (11.1 ± 9.7 vs 3.0 ± 2.5 days in the EUS-RFA group; P < .0001). Fifteen lesions (16.9%) recurred after EUS-RFA and underwent a successful repeat EUS-RFA (11 patients) or surgical resection (4 patients).
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Established and novel circulating neuroendocrine tumor biomarkers for diagnostic, predictive and prognostic use
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The management of neuroendocrine tumors (NETs) represents a clinical challenge due to heterogeneity of their clinical behaviour, molecular biology and response to treatment. Over the years, several circulating biomarkers have been developed for the early diagnosis and follow-up of NETs. The specific secretory products of tumors associated with a secretory syndrome (functioning tumors) may be used as diagnostic and/or prognostic biomarkers while the most common non-specific circulating biomarkers, that may be increased in both functioning and non-functioning tumors, are chromogranin A and the neuron specific enolase. However, the diagnostic accuracy as well as the prognostic and predictive value of these biomarkers are limited and novel techniques of multianalyte analysis of regulators of tumor biology have been developed. The NETest has been most extensively studied and proved to be useful in NET diagnosis, early detection of post-operative recurrence and prediction of response to treatment but further investigation establishing higher level of evidence is required for implementation in clinical practice.
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: The authors disclose the following: this work is partially supported by the Intramural Program of the NIDDK, National Institutes of Health.

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Reviews in Basic and Clinical GastroenterologyGastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors

Section snippets

Epidemiology

Classification/Pathology

Molecular Pathogenesis

Tumor Biology, Prognosis, and Tumor Markers

Gastrinoma: Clinical Features/Diagnosis

Tumor Localization/Staging

Gastrinoma: Medical Management

Surgical Therapy for Cure

General Treatment of Metastatic Disease

Liver-Directed Therapy (Embolization, Chemoembolization)

Future Directions and Unsettled Problems

Best Pract Res Clin Endocrinol Metab

Dig Liver Dis

Best Pract Res Clin Gastroenterol

Pancreatology

Best Pract Res Clin Endocrinol Metab

Best Pract Res Clin Gastroenterol

Best Pract Res Clin Gastroenterol

Best Pract Res Clin Gastroenterol

Gastroenterology

Best Pract Res Clin Endocrinol Metab

Am J Med

Gastroenterology

Best Pract Res Clin Gastroenterol

Endocr Pract

J Am Acad Dermatol

J Gastrointest Surg

Endocr Pract

Am J Gastroenterol

Endocrine tumors of the gastrointestinal tract: part 11

Best Practice Res Clin Gastroent

Endocrine tumors of the gastrointestinal tract: part 1

Best Practice Res Clin Gastroent

Neuroendocrine tumors

Best Pract Res Clin Endocrinol Metab

ENETS consensus guidelines for the management of patients with digestive neuroendocrine tumors part 1-stomach, duodenum and pancreas

Neuroendocrinology

Guidelines for the diagnosis and treatment of neuroendocrine gastrointestinal tumoursA consensus statement on behalf of the European Neuroendocrine Tumour Society (ENETS)

Neuroendocrinology

Endocrine neoplasms of the pancreas

Preliminary results of a Japanese nationwide survey of neuroendocrine gastrointestinal tumors

J Gastroenterol

Prognostic factors and survival in endocrine tumor patients: comparison between gastrointestinal and pancreatic localization

Endocr Relat Cancer

Inherited pancreatic endocrine tumor syndromes: advances in molecular pathogenesis, diagnosis, management and controversies

Cancer

Ectopic secretion of LH by an endocrine pancreatic tumor

J Endocrinol Invest

Paraneoplastic syndromes in cancer: case 1Polycythemia as a result of ectopic erythropoietin production in metastatic pancreatic carcinoid tumor

J Clin Oncol

Peptide YY producing strumal carcinoid of the ovary as the cause of severe constipation with contralateral epithelial ovarian cancer

J Obstet Gynaecol Res

TNM staging of foregut (neuro)endocrine tumors: a consensus proposal including a grading system

Virchows Arch

Positional cloning of the gene for multiple endocrine neoplasia—-type 1

Science

Multiple endocrine neoplasia type 1 (MEN1) as a cancer predisposition syndrome: clues into the mechanisms of MEN1-related carcinogenesis

Yale J Biol Med

Genotype/phenotype correlations of MEN1 gene mutations in sporadic gastrinoma

J Clin Endocrinol Metab

Allelic deletions on chromosome 11q13 in multiple endocrine neoplasia type-I-associated sporadic gastrinomas and pancreatic endocrine tumors

Cancer Res

Molecular genetics of gastroenteropancreatic endocrine tumors

Ann N Y Acad Sci

Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets

Endocr Relat Cancer

Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome

Mol Cancer

Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms

Clin Cancer Res

Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays

Clin Cancer Res

Gastrinoma (duodenal and pancreatic)

Neuroendocrinology

Location, incidence and malignant potential of duodenal gastrinomas

Surgery

Natural history of digestive endocrine tumors

Bone metastases in patients with gastrinomas: a prospective study of bone scanning, somatostatin receptor scanning, and MRI in their detection, their frequency, location and effect of their detection on management

Reviews in Basic and Clinical Gastroenterology
Gastrointestinal Neuroendocrine Tumors: Pancreatic Endocrine Tumors