Gastroenteropancreatic neuroendocrine tumors

Key points

Incidence and prevalence of GEP-NET is increasing.
Recently approved systemic targeted therapeutic agents and local therapies have rekindled interest in NET management.
Multidisciplinary centers employing a myriad of tumor therapies including strategies of image-guided techniques are poised to play a significant role in the management of these complex patients.

Introduction

The neuroendocrine system exists in two phenotypes, either as (1) discreet organoid aggregates (pituitary, adrenal, parathyroid) or as (2) disseminated, nonuniform distribution of cells, This latter group has been assigned the term diffuse neuroendocrine system (DNES; e.g., enterochromaffin cells in the gut mucosa, Merkel cells in the dermis). Collectively, the neuroendocrine system forms the largest group of hormone-producing cells in the body.

Neuroendocrine neoplasms/tumors (NET) once considered “rare” have been steadily increasing in incidence and prevalence over the past 3 decades. In fact, over the last 32 years (1973–2005), the incidence has increased 520% translating to an annual increase of 5.8%. ^, In 2011, it is estimated that approximately 18,000 cases and 8200 deaths will occur from NET in the United States alone (not just GEP-NET). Analysis of the SEER database encompassing the period 2003–2007 reveals that NET incidence and prevalence was 5.76/100,000 and 35/100,000, respectively, in 2004, These increases may represent a reflection of the increasing awareness and diagnostic capabilities over the same time period.

DNES NETs occur most frequently in the lung and gastro-entero-pancreatic (GEP) regions. NETs currently represent 2% of all cancers and GEP-NETs represent the second most prevalent gastrointestinal neoplasm after colorectal cancer. GEP-NETs are most common in the small intestine (30.8%), followed by rectum (26.3%), colon (17.6%), pancreas (12.1%), stomach (8.9%), and appendix (5.7%) ( Figure 15-1 ).

Figure 15-1, Neuroendocrine neoplasms, Surveillance Epidemiology and End Results (SEER) 1973–2007. GEP neuroendocrine neoplasms constitute 2% of all malignancies.

When compared to GE-NETs, pancreatic NETs (P-NETs) possess different patterns of underlying genetic defects that lead to malignant transformation. For GE-NETs, the cell of origin is believed to be the enterochromaffin cell, whereas for P-NETs it appears to be pluripotent cells in the pancreatic duct epithelium. This fundamental difference combined with differing natural histories, management, response to therapy(s), clinical course, and worse prognosis than GE-NETs leads many investigators to consider P-NETs as a distinct tumor entity. P-NETs account for less than 2% of all pancreatic cancers, with 50%–90% of these tumors being nonfunctional, meaning they are not associated with any hormone-related clinical syndrome, the so-called nonsyndromic. The prevalence of these occult NETs is corroborated by the higher incidence of P-NET at autopsy studies ranging from 0.8% to 10%. ^, The incidence of P-NET from the SEER database was 0.22/100,000.

The clinical manifestations of this relatively uncommon disease are protean and nonspecific, thereby leading to alternative diagnoses and the average lag between first symptoms and diagnosis of NET of about 7 years. It is therefore understandable that 60%–80% have metastases at presentation, with the liver being the most common distant metastatic site. An important consequence of metastases, the “carcinoid syndrome” (diarrhea, abdominal pain, sweating, flushing, bronchospasm, tachycardia, and fibrotic heart disease), develops in 7%–10% with GE-NET and 35%–50% of those with hepatic metastases ( Table 15-1 ). Pancreatic neuroendocrine tumors can also be associated with clinical syndromes associated with hormone release ( Table 15-2 ). There has been a gradual increase of the incidence or reporting of stomach and rectal NETs and a decrease in that of appendicular NETs. ^, The increasing burden of disease coupled with new therapies have increased the awareness of this disease and rekindled interest in exploring the benefits of intervention in GEP-NETs.

TABLE 15-2

Pancreatic NET Clinical Entities

	Tumor	Average Size cm	Typical Phenotype “Sporadic” Type Distribution	Clinical Caveats
α	Glucagonoma	3–7	Solitary Large/Tail	Uncommon. 60% Metachronous metastases. 5 yr Survival 50–60%. 8–13% Syndrome of “4D’s”
β	Insulinoma	0.5-2	Solitary 85% / Uniform	Commonest PNET. 4–7% Associated with MEN-1. 90% Benign, 5 yr Survival 97% Whipple’s Triad Pre-resection localization mandatory.
XXgw:math1XXdZZgw:math1ZZ	Somatostatinoma	Large	Solitary Large / Head	Rare; <5%. 70–92% Metachronous metastases. 5 yr Survival 60–75%. Non-specific Syndrome
G	Gastrinoma	2	Solitary / Head	2 ^nd most common PNET. 50% Metachronous metastases. Zollinger-Ellison Syndrome . 90% in “Gastrinoma Triangle” . Enucleation Rx
VIP	VIPoma	Large	Solitary Large / Tail	Rare; 3–8%. 5% Associated with MEN-1. Verner-Morrison Syndrome

1 – Diabetes, dermatitis, Deep Vein Thrombosis, Depression

2 – Triangle created by the 3 angles —1. Pancreas body/neck 2. 2nd/3rd portion of duodenum 3. Cystic & Common bile duct

3 – Profuse watery diarrhea. Water, sodium, chloride, potassium loss.

4 – Hypoglycemia symptoms. Low plasma glucose. Symptom resolution with glucose adminstration.

5 – Diabetes, malabsorption, steatorrhea, cholelithiasis, anemia, achlorhydria

6 – Triad-peptic ulcer, gastric acid hypersecretion & non-β cell pancreas tumor

TABLE 15-1

Gastro-Enteric NET Clinical Entities

Location	Dominant Location	Syndrome	Clinical Caveats
Stomach	Fundus	No	80% Type 1-ECL cell origin. F>>M. Associated Chronic atrophic gastritis. Multifocal polyps <1cm. Benign.
	Fundus	Zollinger Ellison	6% Type 2 - ECL cell origin. Associated with MEN-1.
	Antrum	No	29% Type 3 - Poorly differentiated. Metachronous Gastric AdenoCA 5-10%. M>F, 5th decade, Metachronous metastases.
Duodenum & Proximal Jejunum	Proximal Duodenum	Zollinger Ellison	G Cell origin. 70% of all Gastrinomas occur in duodenum; 90% occur in 1st & 2nd portion A 50% of Duodenal Gastrinoma are associated with ZES A 20–30% of these are associated with MEN-1.
	Ampullary Periampullary	Somatostatinoma	D cell origin. 14–43% associated with NF1
	Periampullary	No	Triphasic lineage. Gangliocytic Paraganglioma. Rare
Distal Jejunum & Ileum	Ileocecal valve region	Seritonoma	EC cell origin. Multicentric NET 30%. Metachronous Colorectal Cancer 39%. Mesenteric fibrosis A Bowel or Venous Obstruction Carcinoid syndrome if 1) Liver metastases 2) Porto-systemic venous drainage
Appendix	Tip >> Base	Seritonoma	EC cell origin. Goblet cell type more aggressive.
Colorectal	Rectum>Ascending > Cecum> Sigmoid	Rare	L Cell origin. Higher incidence Synch/Metachronous Non-NET CA. Rectal NET 80%<0.6cm median. Rectum 50%, Ascending 22%, Cecum 11% , Sigmoid 10.5%.

Definition

Neuroendocrine tumors consist of a heterogeneous group of cells that have both phenotypical and biochemical characteristics of neural and endocrine cells and the potential for malignancy. These bicameral cells must satisfy three criteria to qualify as being of neuroendocrine origin: (1) absence of axons, (2) production of neurotransmitter/neuromodulator hormones, and (3) membrane-bound vesicles from which these hormones are released by a process of regulated exocytosis in response to external stimuli. The substances that can be considered to arise from neural tissue are chromogranins A, B, and C; neuron-specific enolase; and neural cell adhesion molecule CD56 ^, and biogenic amines.

Background

The recognition that single or clusters of hormone-producing chromium-staining cells were present in the intestine was described in 1868 by Heidenhain and later confirmed by Kulchitsky, The first case of intestinal NET was recorded by Langhans and also in an autopsy in two patients by Lubarsch. Ransom described a patient with ileal cancers with extensive metastases who experienced diarrhea and dyspnea after eating possibly was the first description of the carcinoid syndrome. The eponym of “karkinoide tumoren,” or “carcinoid,” was coined by Oberndorfer in 1907 after recognizing this as a discrete disease entity. Nicholls described the first pancreatic islet cell tumor in 1902. In the early 20th century, special silver stains were used by Masson and Gossett ^, to demonstrate the argentaffin and argyrophilic properties of these tumors that appeared to have a neural origin. They suggested that the cell of origin was the enterochromaffin cell, previously described by Kulchitshy in 1897, from the crypts of Leiberkuhn. ^, The concept that the DNES was composed of these argentaffin-positive and argyrophilic-clear cells was introduced by Feyrter in 1938. Many of these cells have the capacity for the uptake and decarboxylation of precursors of biogenic amines and were referred to as “APUD” (amine precursor uptake and decarboxylation) and were initially hypothesized to arise from the neural crest; this theory was subsequently disproved. In 1953, Lembeck described the production of serotonin in carcinoid tumors and in 1955 Page demonstrated the association of increased urinary 5-hydroxyindoleacetic acid (5-HIAA) in carcinoid syndrome. The malignant carcinoid syndrome was described originally by Cassidy in 1934, and one of the first detailed descriptions of the carcinoid syndrome was described in a patient who was dying from a clinical syndrome that included flushing, diarrhea, edema, wheezing, and right-sided heart failure. Pathology demonstrated the presence of fibrotic subendocardial plaques In 1953, enterochromaffin cell secretion of serotonin was confirmed.

Carcinoid syndrome

Carcinoid heart disease occurs in up to 50%–60% of patients with the carcinoid syndrome. This system complex represents the clinical manifestation of serotonin, and tachykinin release that occurs in 20% of G1/2 NETs of the jejunum and ileum. Specific signs and symptoms in descending order of frequency are dry flushing with or without palpitations (70%), diarrhea (50%), intermittent abdominal pain (40%), lacrimation, and rhinorrhea. Wheezing and pellagra are uncommon. More recent reports have suggested that the incidence of carcinoid heart disease has declined, perhaps because of the introduction of somatostatin analogs and other antitumor therapies designed to reduce the tumor load and the production of vasoactive products.

Carcinoid crisis

This GE-NET–associated entity has been characterized as profound flushing, bronchospasm, tachycardia, and rapidly fluctuating blood pressure, These paroxysms are usually precipitated by anaesthesia induction, handling of tumor, embolization, or radiofrequency ablation (RFA). To counterbalance these events, short-acting octreotide is used as a constant infusion of 50 µg/hour initiated 12 hours before and given 24–48 after intervention. Short-acting 100–500 µg octreotide administered intravenously (IV) is followed by continuous infusion. These events can occur in nonsyndromic patients also; therefore, prophylactic octreotide is recommended in these patients as well.

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