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Neuroendocrine Tumors of the Luminal Gastrointestinal Tract.

Neuroendocrine tumors (NETs) of the gastrointestinal (GI) tract were originally called carcinoid tumors (Karzinioide) by Oberndorfer. Though others had noted these small lesions (tumorlets) in the bowel wall, Obern-dorfer noted from his autopsy work that they were often multiple, had less gland formation than adenocarcinomas, and initially appeared to be harmless (reviewed in Kloppel et al (1)). As he collected more cases, the potential for malignant behavior became evident. The term carcinoid tumor, with the current term neuroendocrine tumor, encompasses a group of tumors with considerable variability in cell type, appearance, and behavior. We continue to struggle with these cases, as the incidence appears to be increasing, and despite evolution of grading schema, prediction of behavior remains weak.

EPIDEMIOLOGY

A 5-decade review of carcinoid tumors in National Cancer Institute (NCI) and Surveillance, Epidemiology and End Results (SEER) databases performed in 2003 (2) notes that NETs have increased in incidence for at least 30 to 50 years. Specifically, increases in gastric and rectal NETs were most prominent, while appendiceal NETs appeared to be decreasing, though this may have been due to "benign" appendiceal carcinoids not being properly registered in the SEER system. A review of all SEER-registered NET cases (including gut, pancreas, and lung) showed an incidence of 1.09 per 100 000 people in 1973 and 5.25 per 100 000 in 2004, a 5-fold increase. (3) An evaluation of Japanese pancreatic and gut NETs (4) identified an increase in NETs by a factor of 1.8 since 2005. This may represent a true elevation in NET incidence, but it may also be due to the increased identification of small, nonfunctioning incidental tumors by improved histologic/immunohistochemical and imaging methods, as well as increased screening endoscopies and specific diagnosis by endoscopic ultrasonography and fine-needle aspiration of lesions.

HISTOLOGY

Neuroendocrine tumors of the GI tract arise from the neuroendocrine cells of the GI mucosa, which arise from the fetal nervous system. While most of the epithelial neuroendocrine cells reside in endocrine organs, such as the thyroid and adrenal glands, a large number of them are present in, and have essential roles in the function of, the mucosa by the production and secretion of a variety of peptide hormones. The tumors that arise from these cells tend to have a characteristic histologic appearance regardless of the exact site of origin. Nuclear atypia is generally mild, and nuclei typically have the "salt and pepper" pattern of chromatin, with occasional small nucleoli. The cytoplasm is generally eosinophilic and slightly granular. Architecturally, they can present a number of patterns: solid/nested, trabecular, glandular, cystic, and papillary; these do not correlate with site, type, or functional status except in rare instances (ie, psammoma bodies in somatostatinomas of the duodenum). Diagnostic difficulties arise in the rare cases with unusual morphology--spindle, rhabdoid, clear cell, and oncocytic variants have been described. (5) Most NETs have common immunohistochemical staining patterns for proteins such as chromogranin A, synaptophysin, PGP 9.5, neuron-specific enolase, and CD56. A large variety of peptide hormones (somatostatin, pancreatic polypeptide, serotonin, gastrin, vasoactive intestinal peptide, and ghrelin, among others) can be identified by immunohistochemistry. Expression of all of these markers is dependent on the cell and site of origin but also on the degree of differentiation of the tumor. For example, high-grade tumors may have decreased or absent staining. They also should demonstrate epithelial differentiation by the expression of keratins, particularly low-molecular-weight keratins. Identification of the exact site of origin is difficult, but production of specific peptide hormones can give clues (see later sections). CDX-2 for intestinal origin versus TTF-1 (thyroid transcription factor 1) for lung/thyroid origin can be of use in metastatic lesions. (6) Xenin has been proposed to be specific for duodenal NET7 in the past but is not available or currently used in most laboratories. Both PAX8 and Islet 1 have been shown to stain NETs, particularly but not specifically, in rectal NET. (8)

Foregut NETs

Organs that arise from the fetal foregut include the esophagus, stomach, duodenum, and pancreas, as well as the lungs. Neuroendocrine tumors arising from the foregut can show considerable variability in protein expression depending on the specific site of origin.

Esophagus

Endocrine cells in the esophagus are relatively rare; clusters in cardiac-type glands have been reported within the 2 cm of the esophagus proximal to the gastroesophageal junction but in hindsight, these may represent areas of Barrett esophagus. (9)

Neuroendocrine tumors of the esophagus are particularly uncommon, and reports are limited to individual cases and small case series. In the large series of Modlin and Sandor, (10) consisting of 8305 carcinoid tumors from the SEER database and 2 NCI archives, only 3 arose in the esophagus, which is 0.02% of all carcinomas in the esophagus and 0.05% of all GI NET cases. Of the 4 cases reported by Hoang et al, (11) 2 were associated with Barrett esophagus, which contained endocrine cell hyperplasia. One of these was associated with a separate adenocarcinoma. The remaining 2 arose as nodules in a background of normal squamous mucosa. They noted a rather minimal protein expression pattern, with the typical chromogranin and synaptophysin expression in all 4, serotonin expression in 2, and 1 case each expressing glucagon and pancreatic polypeptide. This correlates with the limited expression noted in gastric cardia-type mucosa in a previous study, (12) where only serotonin-producing cells were identified. These authors report no metastases from any of their cases. Though some of the previous 11 cases reviewed in the article were noted to be more aggressive, these were not graded according to current protocols and their grade cannot be determined.

Stomach

Gastric mucosa contains several varieties of neuroendocrine cells. The gastrin-producing G cells are the most common neuroendocrine cells. Most of these are in the antrum, where their activity is regulated by acid levels produced by the more proximal stomach. Enterochromaffin-like cells (ECL cells), producing histamine, reside predominantly in the body and fundus. The gastric mucosa also contains D cells (producing somatostatin), A cells (producing glucagon), and X/A-like cells (ghrelin-producing cells), as well as smaller numbers of less well-characterized endocrine cells.

Stomach NETs differ from the rest of the GI tract, in that the etiology of many of the cases is known. Gastric NETs are therefore divided into several subtypes, depending on the background in which they arose. Assessing the etiology can have important implications in prognosis and treatment of these tumors.

Type 1 gastric NETs arise in the fundus/body, in a background of atrophic gastritis with significantly elevated gastrin levels due to absent negative feedback of acid; high gastrin levels drive the hyperplasia of ECL cells in the body and fundus to the development of NETs. These are the most common gastric NETs, encompassing approximately 80% of the total cases. (13) This most often occurs in the setting of autoimmune gastritis, though persistent Helicobacter infection can also cause sufficient atrophy to induce the tumors. (14) Considering this, it is not surprising that most of these tumors arise in older females. Type 1 NETs are generally low-grade tumors with trabecular or solid architecture; immunohistochemistry demonstrates chromogranin A, synaptophysin, and usually serotonin and somatostatin positivity (Figure 1, A and B). (13) The tumors are frequently small and multiple; endoscopic resection in lesions smaller than 1 cm is generally sufficient as these very rarely act in a malignant manner. (13) Malignant behavior is linked to increased tumor size and grade (mitotic index). (15)

Type 2 gastric NETs are significantly less common (approximately 5% of cases). They occur in patients with multiple endocrine neoplasia (MEN) type 1 and in Zollinger-Ellison syndrome (ZES). Similar to type 1 NETs, these tumors occur in the fundus/body (though occasionally are in the antrum), in a setting of high gastrin levels due to a gastrinoma. In ZES, the background mucosa will show hypertrophic changes rather than inflammation and atrophy. Similar to the type 1 NETs, these are generally small and are considered to be of low to intermediate risk of malignant behavior. (16) The protein expression pattern is similar to type 1 NET. (17) As NETs in pure sporadic ZES are less common than in patients with ZES/MEN, loss of the menin tumor suppressor gene in MEN is thought to play a role. (18) Both MEN and ZES are uncommon disorders; it is not surprising that this is the least common type of gastric NET.

Considering the moderate increase in gastrin levels in patients receiving long-term proton pump inhibitor medications, there has been concern about the possibility of induction of NET. Neuroendocrine cell hyperplasia and NET were identified in rodents in early studies of this drug class, (19) but they appear to be extremely rare in humans despite the widespread use of these medications. (20) One report (21) has suggested a relationship between proton pump inhibitors and duodenal gastrinomas.

The third type of gastric NET consists of sporadic tumors; these arise in mucosa which may or may not be inflamed, but does not show any evidence of atrophy or hyperplasia. They occur with greater frequency in the antrum. Compared to type 1 and type 2 NETs, type 3 NETs are more often large and higher-stage tumors, sometimes with a higher grade, and have a worse prognosis. Histologically, these lesions may have a more infiltrative pattern and can show significant necrosis and nuclear pleomorphism. (16) They more often express 5-hydroxytryptophan than serotonin. (13) In most cases, surgical rather than endoscopic treatment is required.

Type 4 neuroendocrine tumor has been suggested as the terminology for poorly differentiated NETs (carcinomas) of the stomach: the histologic appearance of these tumors is often similar to small cell carcinomas of other sites, and protein/hormone production is generally minimal. (22)

Neuroendocrine Cell Hyperplasia

In type 1 and type 2 NETs, neuroendocrine cell hyperplasia and dysplasia are generally identified in the background mucosa. The classification of these proliferations is based on that of Solcia et al. (23) Briefly, simple ECL hyperplasia is defined as clusters of fewer than 5 cells. This is rarely diagnosed, as it is very difficult to distinguish from normal levels of ECL cells. The definition of linear hyperplasia is the presence of at least 2 groups in which at least 5 adjacent ECL cells are present per millimeter or within 1 high-power field (HPF). Micronodular hyperplasia can be diagnosed when groups of more than 5 neuroendocrine cells are present within a gland structure, overall measuring less than 150 [micro]m, though usually present as multiple tiny nodules. Larger aggregates of neuroendocrine cells are termed adenomatoid hyperplasia, and dysplasia is diagnosed when larger nodules or aggregates of micro-nodules form outside of the gland basement membrane, or are larger than 150 [micro]m but still less than 500 [micro]m in diameter. Once the nodules are larger than 500 [micro]m, or if they invade the submucosa, they are considered to be micro-NETs. As these lesions are considered to be NET precursor lesions, identification in random biopsies is important to identify those patients predisposed to development of NET. (24)

Proximal Duodenum and Ampulla NETs

Similar to the stomach, the duodenum contains G, D, and enterochromaffin cells, though with a greater proportion of enterochromaffin cells. (25) Though NETs are common in the small bowel overall, those arising in the proximal portions of the duodenum and ampulla contribute little to this total. They are often clinically "silent" tumors but expression of many proteins can be identified by immunohistochemistry, leading to the usual subclassification of these tumors by the protein expression pattern. Duodenal gastrinomas are the most common NETs in this site; they can occur sporadically or in a background of MEN, where they are often associated with ZES (see above). Particularly in MEN-associated cases, hyperplasia of background G cells can be observed. (26) Even when small, these tumors can be aggressive, with lymph node metastases identified in a significant proportion. (27) Duodenal somatostatinomas are the next most common. (13) One clue to the diagnosis of these lesions is the presence of psammoma bodies--in other locations, these are not specific but this finding in the duodenum is nearly diagnostic (Figure 2, A through C). (28) The risk of developing these particular NETs is increased in patients with type 1 neurofibromatosis. (29) The third group of duodenal NETs contains those that are nonfunctional, but still may stain for calcitonin and serotonin, as well as a variety of other peptides/hormones: pancreatic polypeptide, vasoactive intestinal peptide, ghrelin, adrenocorticotropic hormone, and histamine. Duodenal/ampullary gangliocytic paragangliomas are also included as NETs. These are considered to be very rare neoplasms (192 reported cases in a meta-analysis (30) in 2011). Centers with an interest in endoscopic resection may see these somewhat more commonly--our center has identified 7 cases in the past 10 years. These NETs contain a mixture of spindle cells (which often stain for S100, chromogranin, and synaptophysin but less commonly for peptide products), epithelioid cells (staining for chromogranin and synaptophysin and a variety of peptides), and ganglion-type cells, which stain for neural markers such as Hu but also stain for many neuroendocrine markers (30) (Figure 3, A and B). Most of these tumors have a good prognosis but occasional metastases are identified.

Ampullary NETs, separated from duodenal NETs, appear to have a more aggressive phenotype, with generally higher-grade tumors with poor outcome reported. (31) This analysis, based on cases in the SEER database, indicated that ampullary NETs were less common than duodenal NETs and were more advanced at the time they were diagnosed.

Mixed adenoneuroendocrine carcinomas (MANECs) of the upper GI tract are rare, and when found in the small intestine are predominantly located in the ampullary region. These tumors contain a distinct population (> 30%) of mucin-producing adenocarcinoma (or rarely squamous cell carcinoma), which may be either intermixed or adjacent to a neuroendocrine component. In most cases the neuroendocrine component is low grade, but may occasionally be high grade. (32) Generally, MANECs behave as adenocarcinomas and should be staged as such.

Midgut NETs

Neuroendocrine tumors that arise in the mid to distal duodenum through the ileum, appendix, and proximal colon are derived from the serotonin-expressing entero-chromaffin cells of the midgut. As adenocarcinomas of the small bowel are rare, NETs are the most common smallbowel malignancies despite the fact that they are still uncommon. Most occur in the distal ileum. Although there is no known precursor lesion or hereditary syndrome associated with these NETs, those arising in the jejunum and ileum are often multiple lesions. (33) Midgut NETs are those most associated with the classic carcinoid syndrome of diarrhea, flushing, and right heart fibrosis/damage, most likely because even small tumors have a stronger tendency to metastasize to local lymph nodes and to the liver, compared to other GI NETs. Even with the presence of nodal or distant metastases, survival is often still several years, as these NETs are rather indolent, though they respond poorly to most chemotherapies. (34) While many of the other GI NETs are found incidentally on endoscopy, owing to their small size and lack of specific symptoms, small-bowel NETs can present with obstructive symptoms; tumors invading through the bowel wall cause a characteristic kinking of the bowel due to fibrosis (Figure 4). (33) Ischemia due to fibrosis of mesenteric vessels may also occur. Other than an increased tendency to express CDX-2, (6) small bowel and cecal NETs do not show any specific histologic or immunohistochemical patterns.

Appendiceal NETs

Small NETs of the appendix are notorious for their presence in appendices removed for other causes, most commonly acute appendicitis. Low-grade, typical appendiceal NETs have a better outcome than most GI NETs, though large lesions have a greater risk of metastases. Right hemicolectomy may be necessary in patients with higherstage/grade tumors. (35,36)

Goblet Cell Carcinoids

Most typically found in the appendix, goblet cell carcinoids (GCCs) can also be found in other areas of the GI tract. (37) Rather than an origin in the ECL cells of the mucosa, these are thought to derive from a pluripotent stem cell. (38) These differentiate into cells that produce mucin (periodic acid-Schiff, mucicarmine, and Alcian blue positive) and histologically, they have the appearance of goblet cells, but also have a NET pattern with respect to nuclear appearance and infiltrative growth pattern of cell nests, cords, and glands (Figure 5, A and B). Goblet cell carcinoids express neuroendocrine markers: expression can be patchy and minimal but at least 1 marker should be present at least focally. (39) Paneth cells are commonly seen within the tumors, and extracellular mucin may be present. Atypia and mitotic activity tend to be low. Appendiceal GCCs have a worse prognosis than typical carcinoids/NETs of the appendix and tend to metastasize as signet ring carcinomas (adenocarcinoma ex GCC). This, and the fact that GCCs show similar immunohistochemical staining patterns with adenocarcinomas, has led to the suggestion of renaming GCC as "mucinproducing neuroendocrine tumor/carcinoma of the appendix." (38) The pattern of metastases differs from that of other GI NETs in that GCCs tend to spread via the peritoneum; ovarian metastases are common. (38) Right hemicolectomy is often performed when this diagnosis is made on appendectomy specimens.

The World Health Organization (WHO) also recognizes the category of "tubular carcinoid." These NETs form small glands, often with focal mucin present, with a typical NET infiltration pattern. They appear to originate from the base of the crypts. These are grouped with usual appendiceal NETs rather than with GCCs. (38,40,41)

Hindgut NETs

The distal colon and rectum are derived from the fetal hindgut. Outside of the cecum and proximal colon, which are midgut areas, most colonic NETs are found in the rectum. Rectal NETs are often found on screening colonoscopy as small, endoscopically resectable lesions. (42) The prognosis is good, with a low metastatic rate. (43) As per other sites, large size and increased histologic grade correlates with worse outcome. Occasionally, patients with inflammatory bowel disease can show evidence of neuroendocrine cell hyperplasia, and can develop NETs (reviewed in Kloppel et al (44)).

Mixed adenoneuroendocrine carcinomas may also rarely occur in the colon. These tumors contain morphologically distinct neuroendocrine and adenocarcinoma components.

This is distinct from morphologically typical adenocarcinomas demonstrating neuroendocrine differentiation by immunohistochemistry. Adenocarcinomas commonly express neuroendocrine markers, (45) and this should not lead to a diagnosis of MANEC. In most MANECs of the colon and rectum, the associated neuroendocrine component is high grade and the tumor behaves aggressively; MANECs should be considered carcinomas.

Grading and Staging of NETs

Other than the histologic appearance of poorly differentiated NETs, which are similar to small and large cell NETs of other sites, reliable grading of NETs into low-grade versus intermediate/uncertain behavior groups was historically difficult and unreliable. In recent years, a grading scheme based on mitotic activity, and particularly the mitotic index by Ki-67 immunohistochemical staining, has been developed primarily by the European NET Society (ENETS), and now adopted by the WHO and College of American Pathologists (CAP). (46) Low-grade (G1) tumors show a mitotic index less than 2%, or mitotic activity of fewer than 2 per 10 HPFs. Intermediate grade (G2) tumors have a mitotic index from 3% to 30% or mitotic activity of 2 to 20 per HPF (whichever one produces the higher grade), and grade 3 NETs have a mitotic index greater than 20% or mitotic rate greater than 20 per HPF. The mitotic index should be calculated by counting at least 500 and preferably 2000 cells; studies have noted that "eyeballing" and estimating the percentage is quite inaccurate, particularly at lower levels of activity, and therefore a strict count (either manual or by image analysis methods) is recommended. (47,48) There is general agreement that the count should be performed in the area of highest mitotic activity (hotspots). However, concern remains about what level of staining constitutes a true positive nuclear staining; Young et al (48) noted specifically that "cells were considered positive if they showed any evidence of taking up stain." While this appears logical, validation of this approach is not available. Mitotic activity should be counted in 50 HPFs, if available. Prognostication on the basis of greater or lesser than a 3% mitotic index feels quite arbitrary and indeed, Klimstra et al (49) note that clinical data to determine the best point of separation of low- and intermediate-grade NETs do not currently exist. It is probably best to report the specific mitotic index/rate in pathology reports, as these are likely to evolve as more data are collected and the raw data in the report will easily allow reclassification.

Staging.--For years, all GI NETs were grouped together in staging systems. However, ENETS has proposed site-specific staging systems for GI NETs. (46,50) Despite the fact that jejunal NETs are all technically midgut tumors, this system groups proximal jejunal NETs with duodenal NETs, and distal jejunal NETs with ileal lesions, (51) which may be justified by their behavior patterns. The Union for International Cancer Control (UICC)/American Joint Committee on Cancer (AJCC) have also developed a TNM (tumor, nodes, metastases) staging system dependent on site, which does not exactly correlate with the ENETS version. (52,53) There are differences in several of the sites, most notably in appendiceal NET staging, where there are considerable size differences in what is considered to be T2 versus T3 disease as well as in extent of invasion into adjacent tissues. (53) The CAP uses the AJCC version in the synoptic checklist. As with grading, a specific statement in the report as to tumor size and extent of invasion would be helpful for later review of the case, as it seems likely that these staging systems will continue to evolve.

GENETICS OF NETs

Neuroendocrine tumors of the GI tract have lagged behind other tumors in detailed genetic analysis, but there are now a few recent studies. Banck et al (54) evaluated well-differentiated small intestinal tumors, identifying potential mechanisms for tumorigenesis (ie, DNA damage, apoptosis, RAS signaling) as well as potential treatment targets (ie, SMAD/transforming growth factor-[beta], SRC/mammalian target of ropamycin (mTOR), epidermal growth factor receptor (EGFR), plateletderived growth factor receptor (PDGFRA). Francis et al (55) noted specific mutations in CDKN1B in 7 of 50 small intestinal NETs, suggesting p27 as a tumor suppressor gene in these NETs.

CONCLUSION

Gastrointestinal NETs are a relatively homogenous group by histology but show considerable differences of protein expression by immunohistochemistry. Recent changes in staging and grading have aided in determining the prognosis of these often indolent tumors, but evolution of the ways we assess these tumors is to be expected.

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Andrea Grin, MD; Catherine J. Streutker, MD, MSc

Accepted for publication May 2, 2014.

From the Department of Laboratory Medicine and the Li Ka Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

The authors have no relevant financial interest in the products or companies described in this article

Reprints: Catherine J. Streutker, MD, MSc, Department of Laboratory Medicine, Division of Pathology, St. Michael's Hospital, 30 Bond St, 2-099 CC, Toronto, ON M5B 1W8, Canada (e-mail: streutkerc@smh.ca).

Caption: Figure 1. Gastric neuroendocrine tumor arising in a background of autoimmune gastritis (type 1). A, Hematoxylin-eosin. B, Chromogranin (original magnification X200 [A and B]).

Caption: Figure 2. Somatostatinoma of the duodenum with psammoma bodies (arrows in [A] point to psammomatous calcifications). The tumor is positive for chromogranin (B) and somatostatin (C) (hematoxylin-eosin, original magnification X400 [A]; original magnification X400 [B and C]).

Caption: Figure 3. Gangliocytic paraganglioma of the duodenum composed of spindled, epithelioid, and ganglion cells (arrow in [B] points to ganglion cells) (hematoxylin-eosin, original magnifications X50 [A] and X400 [B]).

Caption: Figure 4. Small intestinal neuroendocrine tumor with characteristic serosal fibrosis causing kinking of the bowel wall (hematoxylin-eosin, original magnification X1; scanned slide).

Caption: Figure 5. Appendiceal goblet cell carcinoid. A, Hematoxylin-eosin. B, Chromogranin (original magnification X630 [A]; original magnification X200 [B]).

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Author:Grin, Andrea; Streutker, Catherine J.
Publication:Archives of Pathology & Laboratory Medicine
Date:Jun 1, 2015
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