PATHOLOGY OF GASTROINTESTINAL NEUROENDOCRINE TUMORS: AN UPDATE Roger K. Moreira, MD a , Kay Washington, MD, PhD b, * ABSTRACT G astrointestinal (GI) neuroendocrine tumors (NETs) are a heterogeneous group of rela- tively slow-growing neoplasms with marked site-specific differences in hormonal secretion and clinical behavior. Most are sporadic neoplasms, with only 5% to 10% arising in patients with hered- itary disorders, most commonly in multiple endo- crine neoplasia type 1. Although a uniform terminology is not universally accepted, use of the 4-category World Health Organization classifi- cation of these tumors is becoming more wide- spread, and recommendations for tumor grading and staging have been recently formulated. Most GI NETs are easily recognized on routine histologic examination; rarely, a limited panel of immunohis- tochemical markers may be useful in establishing the diagnosis. This article describes general and site-specific features of these tumors and outlines potential pitfalls in diagnosis. GASTROINTESTINAL NEUROENDOCRINE TUMORS OVERVIEW The term gastrointestinal neuroendocrine tumor (GI NET) refers to a low-grade neoplasm arising from the diffuse neuroendocrine system scattered throughout the mucosa of the gut. Such tumors have historically been called carcinoid tumors, terminology that is recognized as archaic and ambiguous but still widely used in clinical practice and in tumor registries. Although not in universal usage, the term neuroendocrine is preferred rather than the term endocrine because of shared anti- gens between neural elements and these cells of the diffuse endocrine system in the GI tract, such as neuron-specific enolase, chromogranins, syn- aptophysin, and protein gene product 9.5. 1 The neuroendocrine cells that give rise to GI NETs are epithelial cells derived from the same stem cells as other epithelial cell lineages in the GI tract, such as enterocytes, Paneth cells, and goblet cells; at least 15 morphologically and functionally distinct GI neuroendocrine cell types producing different hormones have been identified. 2 In general, the differentiation pattern of GI NETs reflects the profile of neuroendocrine cells nor- mally located in that part of the GI tract. GI NETS arise as a result of molecular events in progenitor cells that are neuroendocrine committed but not necessarily terminally differen- tiated. This concept helps explain why certain NETs are more homogeneous, with a dominant hormonal secretory pattern reflecting that of normal neuroendocrine cells in the location in Disclosures: This project was supported by grant number P50CA095103 from National Cancer Institute. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NCI or NIH. a Department of Pathology, Columbia University MedicalCenter, 630 West 168th Street, New York, NY 20032, USA b Department of Pathology, Vanderbilt University Medical Center, 1161 21st Avenue South, Nashville, TN 32732, USA * Corresponding author. E-mail address: [email protected]KEYWORDS Gastrointestinal Neuroendocrine Carcinoid Surgical Pathology 3 (2010) 327–347 doi:10.1016/j.path.2010.05.003 1875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All rights reserved. surgpath.theclinics.com
Transcript
PATHOLOGY OFGASTROINTESTINALNEUROENDOCRINETUMORS: AN UPDATE
Roger K. Moreira, MDa, Kay Washington, MD, PhDb,*
KEYWORDS
� Gastrointestinal � Neuroendocrine � Carcinoid
ABSTRACT
G astrointestinal (GI) neuroendocrine tumors(NETs) are a heterogeneous group of rela-tively slow-growing neoplasms with marked
site-specific differences in hormonal secretion andclinical behavior. Most are sporadic neoplasms,with only 5% to 10% arising in patients with hered-itary disorders, most commonly in multiple endo-crine neoplasia type 1. Although a uniformterminology is not universally accepted, use ofthe 4-category World Health Organization classifi-cation of these tumors is becoming more wide-spread, and recommendations for tumor gradingand staging have been recently formulated. MostGI NETs are easily recognized on routine histologicexamination; rarely, a limited panel of immunohis-tochemical markers may be useful in establishingthe diagnosis. This article describes general andsite-specific features of these tumors and outlinespotential pitfalls in diagnosis.
GASTROINTESTINAL NEUROENDOCRINE
TUMORS
OVERVIEW
The term gastrointestinal neuroendocrine tumor(GI NET) refers to a low-grade neoplasm arising
Disclosures: This project was supported by grant numbecontent is solely the responsibility of the authors andthe NCI or NIH.a Department of Pathology, Columbia University MedicaUSAb Department of Pathology, Vanderbilt University MeTN 32732, USA* Corresponding author.E-mail address: [email protected]
Surgical Pathology 3 (2010) 327–347doi:10.1016/j.path.2010.05.0031875-9181/10/$ – see front matter ª 2010 Elsevier Inc. All
from the diffuse neuroendocrine system scatteredthroughout the mucosa of the gut. Such tumorshave historically been called carcinoid tumors,terminology that is recognized as archaic andambiguous but still widely used in clinical practiceand in tumor registries. Although not in universalusage, the term neuroendocrine is preferred ratherthan the term endocrine because of shared anti-gens between neural elements and these cells ofthe diffuse endocrine system in the GI tract, suchas neuron-specific enolase, chromogranins, syn-aptophysin, and protein gene product 9.5.1 Theneuroendocrine cells that give rise to GI NETsare epithelial cells derived from the same stemcells as other epithelial cell lineages in the GI tract,such as enterocytes, Paneth cells, and gobletcells; at least 15 morphologically and functionallydistinct GI neuroendocrine cell types producingdifferent hormones have been identified.2 Ingeneral, the differentiation pattern of GI NETsreflects the profile of neuroendocrine cells nor-mally located in that part of the GI tract.
GI NETS arise as a result of molecular events inprogenitor cells that are neuroendocrinecommitted but not necessarily terminally differen-tiated. This concept helps explain why certainNETs are more homogeneous, with a dominanthormonal secretory pattern reflecting that ofnormal neuroendocrine cells in the location in
r P50CA095103 from National Cancer Institute. Thedoes not necessarily represent the official views of
l Center, 630 West 168th Street, New York, NY 20032,
1. The most common sites for GI NETs arestomach, appendix, and rectum.
2. Many NETs are asymptomatic and are discov-ered incidentally.
3. Clinical behavior of GI NETs varies withtumor site; NETs of the appendix and rectumare usually benign; ileal and colonic NETsbehave in a more aggressive fashion.
4. Histologic feature of low-grade GI NETs aresimilar in all sites, including various growthpatterns (insular, trabecular, or solid, oftenwith pseudorosette formation) and charac-teristic cytologic features (round, uniformnuclei, with salt-and-pepper type chromatinand small inconspicuous nucleoli). Poorlydifferentiated NETs may be more difficultto recognize as neuroendocrine and histo-logically resemble a poorly differentiatedadenocarcinoma or extrapulmonary smallcell adenocarcinoma.
5. Special types of NETs occur most often in theduodenum (periampullary somatostatino-ma: prominent glandular formation, intralu-minal mucin, psammoma bodies) andappendix (goblet cell carcinoids and tubularcarcinoids).
6. Ancillary tests are rarely indicated buta panel of immunohistochemical markers(most commonly synaptophysin and chro-mogranin) may be useful in select cases.
Moreira & Washington328
which they arise, and others secrete multiplehormones or lack apparent hormonal functionality.For instance, enterochromaffin-like (ECL) cellNETs arise almost exclusively in the stomach, par-alleling the normal distribution of ECL cells.Although GI NETs are derived from epithelialstem cells of the gut, investigations of theneoplastic progression for these tumors haveshown that they do not share the same molecularalterations as GI adenocarcinomas, and infre-quently show microsatellite instability or abnor-malities of Wnt signaling.3
MOLECULAR EVENTS
Although only 5% to 10% of GI NETs are linked tohereditary syndromes (generally autosomal domi-nantly inherited syndromes resulting from muta-tions in tumor suppressor genes, Table 1), suchcases have afforded important insights into
molecular pathways involved in neuroendocrineneoplasia. For instance, the MEN1 gene ismutated in up to 40% of sporadic GI and pancre-atic NETs.4 Molecular events seem to be differentin GI NETs arising in different sites, with foreguttumors often showing loss of 11q, the site ofMEN1, in contrast to hindgut tumors which oftenshow losses on 18q.5 Progress in understandingthe molecular pathways involved has beenhindered by the small number of cases studiedand the complex and heterogeneous pathobiologyof these tumors, but recent work suggests thatCpG island methylation is an important pathwayin sporadic GI NETs.6
EPIDEMIOLOGY
Analysis of more than 13,000 carcinoid tumors re-ported to the Surveillance, Epidemiology, and EndResults (SEER) database from 1950 to 1999suggests that the incidence of these tumors isincreasing in the US population7; however, it isnot clear if the marked increase in gastric andrectal carcinoids is related to changes in tumorregistry reporting, improvements in diagnosis, orto a true increase in these tumor types. Thesetumors are relatively rare, with the incidence forall GI NETs estimated as 2.0/100,000 for menand 2.4/100,000 for women.2 Average age fordiagnosis for all carcinoid tumors was 61 years inthe SEER data set. Rectal carcinoids are moreprevalent among black and Asian populations inthe United States. Five-year survival rates arebest for appendiceal and rectal NETs.
CLINICAL FEATURES
The clinical behavior of GI NETs varies with theirlocation in the GI tract. Small non–gastrin-secreting tumors are usually clinically silent andmay be discovered only at autopsy or resectionfor other indications. When symptoms are attribut-able to GI NETs, they are caused by local tumoreffects such as adhesions or abdominal fibrosisgiving rise to abdominal pain or small bowelobstruction, or to secretion of bioactivesubstances such as serotonin, histamine, orgastrin. The carcinoid syndrome (cutaneous flush-ing of upper chest, neck and face; gut hypermotil-ity with diarrhea) occurs in less than 10% ofpatients.5 Diagnostic strategies for patients sus-pected of having GI NETs include biochemicaltesting for urinary 5-hydroxyindoleacetic acid orserum testing for increased chromogranin A levels,followed by localization of the tumor by octreo-scan scintigraphy, positron emission tomography,or other radiographic imaging techniques.5
Table 1Hereditary syndromes associated with GI NETs
SyndromeInheritance andPrevalence Gene
Gene Product andFunction GI NETs Major Tumor Sites
Data from Toumpanakis CG, Caplin ME. Molecular genetics of gastroenteropancreatic neuroendocrine tumors. Am J Gastroenterol 2008;103(3):729–32.
GI
Neu
roen
do
crine
Tum
ors
329
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GI NETs, most commonly ileal tumors, are asso-ciated with second primary tumors, usuallydiscovered synchronously, in about 17% ofpatients. The most common site for secondprimary tumors is the GI tract, followed by genito-urinary tract and lung. These synchronous tumorsare generally of higher grade than the GI NET,which may be discovered during staging workupof the associated second primary malignancy.8
TERMINOLOGY
There is no single unified terminology for GI NETS.Many pathologists in the United States still use theterm carcinoid to describe all low-grade NETs,regardless of tumor site, and some use the termatypical carcinoid to refer to GI NETs with focalnecrosis or increased mitotic activity. However, theatypical carcinoid has not been rigorously definedfor GI tumors and this nomenclature is not in wide-spreaduse. The termcarcinoidhas fallen outof favorbecause of its failure to encompass the full biologicspectrum and site-specific heterogeneity of thesetumors, as well as the narrow interpretation of thisterm to mean a serotonin-producing tumor associ-ated with carcinoid syndrome.9 The World HealthOrganization, although retaining the carcinoid termi-nology in the 2000 publication on classification oftumors of the digestive system,10 also outlines a 3-tier system11 classifying these neoplasms as well-differentiated NETs of benign or uncertain malignantpotential, well-differentiated neuroendocrine carci-noma, and poorly differentiated neuroendocrine
carcinoma. This system has gained more accep-tance among European pathologists and has theadvantage of being more biologically oriented thanthe umbrella term carcinoid, although this termi-nology can be cumbersome to apply to individualcases.
GROSS FEATURES
GI NETs grossly are firm tan to pale yellow noduleslocated just beneath the mucosal surface. Themuscularis propria may be thickened in the areaof tumor, perhaps as a result of secretion oftrophic factors by the tumor cells (Fig. 1). Densefibrotic stroma associated with the tumor cellsmay produce annular strictures, and mesentericfibrosis may be seen in small bowel NETs.Ischemic injury secondary to vascular sclerosismay also be seen in small bowel tumors(Fig. 2).12 Extensive lymphatic involvement bytumor is manifested as small yellow nodules onthe serosal surface. Multicentricity is commonand is site-related; gastric and jejunoileal tumors(33%) are more commonly multiple, whereasmultiplicity is rare with colonic or appendicealNETs. Molecular studies have shown that mostmultiple GI NETs are independent primaries.13
MICROSCOPIC FEATURES
Most GI NETs are readily recognizable as low-grade NETs. They are composed of solid nests,cords, trabeculae, and glands of relatively uniformcells with round to oval nuclei with finely granular
Fig. 1. Low-grade neuro-endocrine neoplasms ofthe GI tract grossly appearas yellow plaques; thick-ening of the bowel wallas a result of fibrosis andsmooth muscle hyper-plasia may be seen, as inthis example of an ilealtumor.
Fig. 2. Elastosis of mesen-teric vessels, visible as acel-lular thickening of vesselswalls (A) with duplicationof the internal elasticlamina and adventitialelastosis on elastin stain(B) may cause bowelischemia. These mesen-teric vascular changes areprimarily associated withileal NETs.
GI Neuroendocrine Tumors 331
chromatin and inconspicuous nucleoli (Fig. 3).Less commonly, cystic, tubular, or angiomatoidpatterns may be seen. The cytoplasm is generallypale, but in some cases fine red granules aredetectable (Fig. 4). Cytologic variants include clearcell NETs (generally found in the pancreas inpatients with von Hippel-Lindau disease), and on-cocytic and rhabdoid appearances. Large areas oftumor necrosis are uncommon and when presentsignify a higher-grade tumor, but punctate coagu-lative necrosis may be seen in larger low-gradetumors (Fig. 5). Perineural and lymphovascularinvasion are associated with more aggressivebehavior14 (see Fig. 5B, C) and are generally notseen in small low-grade tumors.
PRECURSOR LESIONS
Endocrine cell hyperplasia is most commonly seenin the GI tract in the stomach in the setting of hyper-gastrinemia and chronic atrophic gastritis.15
Duodenal gastrin-producing cells undergo a similarhyperplasia in patients with Zollinger-Ellisonsyndrome caused by multiple endocrine neoplasia(MEN) type 1. Hyperplastic lesions of the GI neuro-endocrine system have been divided for researchpurposes into diffuse, linear, and nodular patterns;the distinction between nodular hyperplasia anddysplasia is made by size, with dysplastic (preinva-sive) lesions measuring between 90 and 210 mm.Gastrin or somatostatin-producing lesions in the
Fig. 3. Low-grade GI NETsare composed of cords,trabeculae, and solid nestsof relatively uniform cellswith oval finely granularchromatin, typical ofneuroendocrinedifferentiation.
Differential DiagnosisOF GI NETS
� Gastric NETs
� Type 1 and 2 (ECL) NETs
� Sporadic (type 3)
� Type 4 (high-grade neuroendocrinecarcinoma)
� Duodenal and ampullary NETs
� Gastrinoma
� Somatostatinoma
� Nonfunctioning NETs
� Appendiceal NETs
� Goblet cell carcinoid
� Tubular carcinoid
� Adenocarcinoma
� Ileal NETs
� Colorectal NETs
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duodenum and measuring larger than 210 mm areclassified as GI NETs; microinvasion is recognizedby the identification of small clusters of neuroendo-crine cells localized in the lamina propria betweenglands and associated with stromal alterationssuch as thickened collagen.16 Although appendix,ileum, and rectum are common locations for GINETs, endocrine cell hyperplasia and dysplasticlesions are rarely encountered in these sites, andin general sporadic NETs lack identifiableprecursor lesions. Neuroendocrine cell hyperplasiaand multiple GI NETs have been reported in thesetting of ulcerative colitis17 and Crohn disease,and are associated with epithelial dysplasticchanges in some cases.18
DIFFERENTIAL DIAGNOSIS
Although most GI NETs do not present a diagnosticproblem, tumors with a glandular growth patternmay be erroneously diagnosed as adenocarci-noma. Low-grade GI NETS should not beconfused with high-grade neuroendocrine carci-noma or mixed high-grade adenocarcinoma/neuroendocrine carcinoma, both of which areassociated with poor prognosis. In the rectum,locally invasive prostatic adenocarcinoma maybe confused with an NET but knowledge of theclinical history and endoscopic appearance arehelpful in avoiding this pitfall.
DIAGNOSIS
Most GI NETs do not require use of special stainsor immunohistochemical studies for diagnosis.However, a panel of immunohistochemical
markers of neuroendocrine differentiation (Table 2)may be helpful in selected cases. Cytosolicmarkers such as neuron-specific enolase andCD56 are highly sensitive but relatively nonspecificfor neuroendocrine differentiation. Synaptophysin,
Fig. 4. Red cytoplasmicgranules are prominentin some GI NETs.
GI Neuroendocrine Tumors 333
a marker associated with small vesicles, has theadvantage of higher specificity, although retaininghigh sensitivity. The secretory granule markerchromogranin A is widely used and is highlyspecific for neuroendocrine differentiation(Fig. 6), but is not uniformly expressed amongthe different endocrine cell types, and is oftennegative in appendiceal and rectal NETs. Higher-grade NETs may be negative for chromogranin Aexpression, or display only focal positivity.
Immunohistochemical findings should be inter-preted in the context of the overall microscopicappearance of the lesion, and it is advisable touse a panel of markers rather than a single marker.In practice, the most widely used panel is synapto-physin and chromogranin A, although in someinstances low-grade NETs are negative for bothmarkers. The pathologist may also be asked todetermine likely sites of origin of NET metastaticto the liver; in such cases, octreoscan scintigraphyis superior to histopathologic assessment.However, expression of CDX2 has been reportedin up to 80% of GI NETs, more commonly intumors arising in the ileum and appendix, andseems to be a useful marker for NETs of GIorigin,19 although gastric NETs are frequentlynegative. Neuroendocrine secretory protein-55,a member of the chromogranin family of proteinsfound in dense core granules, has been reportedto be expressed by NETs of the pancreas andadrenal medulla but not NETs of GI and lungorigin.20
Cell-specific markers such as gastrin or somato-statin may be useful in subtyping GI NETs, butimmunohistochemical expression of suchhormones does not determine functional status
of the tumor, which is defined by clinical manifes-tations. However, subtle clinical signs of overpro-duction of such hormones may be overlooked inthe preoperative setting and only recognized retro-spectively on diagnosis of a GI NET.
STAGING AND PROGNOSTIC MARKERS
According to the 2000 WHO classification,11 GINETs are classified into 4 categories, based ona combination of gross, histologic, and immuno-histochemical features (Table 3):
1. Well-differentiated NET of probable benignbehavior
2. Well-differentiated NET of uncertain malignantbehavior
Recently, TNM classification systems for foregutand hindgut NETs have been proposed by theEuropean Neuroendocrine Tumor Society.21,22
For foregut and hindgut NETs, the T category isassigned based on tumor size, depth of penetra-tion into the bowel wall, and invasion of adjacentstructures, according to specific tumor site (seeRefs.20,21 for details). In situ carcinoma (Tis) isrecognized for gastric lesions less than 0.5 cm inthis classification system. N and M categoriesare assigned based on the presence or absenceof regional lymph node (N0–N1) or distant (M0–M1) metastases, respectively. A final stage is as-signed according to the combination of T, N, andM categories.
TheEuropeanNeuroendocrineTumor Society21,22
has also proposed a grading system (Table 4), in
Fig. 5. Focal areas ofcoagulative necrosis (A),perineural invasion (B),and lymphovascular inva-sion (C) are associatedwith more aggressivebehavior in GI NETs.
334 Moreira & Washington
GI Neuroendocrine Tumors 335
which GI NETs are classified in 3 different categoriesbased on mitotic counts and/or Ki-67 tumor labelingindex. G1 and G2 tumors usually correspond to well-differentiated NETs, whereas G3 indicates a poorlydifferentiated carcinoma.
Preliminary validation studies for this proposedstaging system23 using a data set of 202patients have demonstrated prognostic rele-vance of staging and grading of lesions for fore-gut and pancreatic tumors. A recently proposedstaging system using similar parameters (depthof tumor invasion, tumor size, lymph nodemetastases, and distant metastases) also seemsto provide useful overall survival estimates whenapplied to a set of 108 GI NETs from all GIsites.24
SITE-SPECIFIC FEATURES
Gastric NETs
Gastric NETs form a relatively heterogeneous groupof neoplasms because of the diverse population ofnative neuroendocrine cells in this organ. Tumorsmay arise from these cell types in a variety of clinicalsettings, and have been classified in 4 subtypes(Table 5). Types 1 and 2 tumors are ECL cellneoplasms that arise in the setting of hypergastrine-mia. Type 1 tumors, by far the most common, areseen in patients with body-predominant atrophicgastritis and hypergastrinemia secondary to hypo-chlorhydria. These patients develop ECL cell
Table 2Immunohistochemistry of GI NETs
Foregut Tumors
Site Stomach, proximalduodenum
Immunohistochemistry
Chromogranin A 86%–100% 1
Neuron-specific enolase 90%–100% 1
Synaptophysin 50% 1
Serotonin 33% 1
Other immunohistochemicalmarkers
Rarely, 1 for pancreatpolypeptide, histamgastrin, VIP, orcorticotropin
Carcinoid syndrome Rare
Abbreviation: VIP, vasoactive intestinal peptide.Data from Refs.55–61
hyperplasia (Fig. 7), which may progress to trueNETs, often multifocal (Fig. 8).25 The prognosis oftype 1 tumors is usually favorable, and they cansafely be resected endoscopically. In rare cases,more aggressive behavior and lymph node metas-tases are seen, usually associated with tumorslarger than 2 cm and with infiltration of the gastricwall.26 Type 2 tumors are seen in patients with hy-pergastrinemia caused by gastrin-producingtumors at other sites, such as the duodenum,pancreas, or porta hepatis region (gastrinomas),often in association with Zollinger-Ellison syndromeand MEN-1. Through similar mechanisms as fortype 1 tumors, these patients will develop ECL cellhyperplasia and neuroendocrine neoplasms. Liketype 1 tumors, type 2 neoplasms usually behave ina benign fashion. Metastatic disease occurs inapproximately 10% of cases, usually in tumorslarger than 2 cm and with invasion of the muscularispropria.26 Type 3 tumors are defined as sporadicECL cell neoplasms (ie, not associated with hyper-gastrinemia). As in types 1 and 2, type 3 tumorsoccur preferentially in the body and fundic regions,but tend to be solitary rather than multiple.25 Type3 tumors are frequently larger than 2 cm and carrya worse prognosis compared with types 1 and 2,especially if associated with muscularis propria infil-tration and vascular invasion, in which case metas-tases are likely to be present. Type 4 tumors arepoorly differentiated neuroendocrine carcinomas.These tumors are distributed throughout the
Midgut Tumors Hindgut Tumors
Jejunum, ileum,appendix, proximalcolon
Distal colon, rectum
82%–92% 1 40%–58% 1
95%–100% 1 80%–87% 1
95%–100% 1 94%–100% 1
86% 1 45%–83% 1
icine,
Prostatic acidphosphatase 1in 20%–40%
Prostatic acidphosphatase 1in 20%–82%
5%–39% Rare
Fig. 6. Most low-gradeGI NETs are strongly posi-tive for chromogranin A,a component of neurose-cretory granules, butroughly 50% of hindguttumors are negative forthis marker of neuroen-docrine differentiation.
Moreira & Washington336
stomach, are more commonly diagnosed at a moreadvanced stage (>4 cm), and often present withextensive metastases.2 The prognosis is, therefore,poor, with most patients dying within 1 year of diag-nosis.26 Like poorly differentiated neuroendocrinecarcinomas elsewhere, type 4 tumors are positive
Table 3WHO criteria for classification and assessment of the
Abbreviations: PD, poorly differentiated; WD, well differentiaa Exception: malignant duodenal gastrinomas are usually smb Exception: benign neuroendocrine tumors of the append
for synaptophysin but often negative for chromogra-nin A by immunohistochemistry.
NETs of the Duodenum and Upper Jejunum
The percentage of duodenal and upper jejunalNETs in relation to all GI NETs ranges from 3% in
biologic behavior of GI NETs
gicntiation
TumorSize (cm)
Angio-Invasion
Ki-67Index (%)
HormonalSyndrome
%1a � <2 �
%2 �/1 <2 �
>2 1 >2 1
Any 1 >30 �
ted.aller than 1 cm and confined to the submucosa.
ix usually invade the muscularis propria.
Table 4Grading of GI NETs
GradeMitotic Count(10 hpf) Ki-67 Index (%)
G1 <2 %2
G2 2–20 3–20
G3 >20 >20
Data from Rindi G, Kloppel G, Alhman H, et al. TNMstaging of foregut (neuro)endocrine tumors: a consensusproposal including a grading system. Virchows Arch2006;449:395–401; and Rindi G, Kloppel G, Couvelard A,et al. TNM staging of midgut and hindgut (neuro) endo-crine tumors: a consensus proposal including a gradingsystem. Virchows Arch 2007;451(4):757–62.
GI Neuroendocrine Tumors 337
studies that included old tumor databases7,27 to22% in recent series.28 These tumors show a slightmale predominance (1.5:1) and usually affectpatients in their fifth and sixth decade.26
Five distinct types of NETs are recognized in thislocation: gastrinomas, which account for approxi-mately two-thirds of all NETs, followed by soma-tostatinomas, nonfunctioning (nonsyndromic)serotonin- and calcitonin-producing tumors,
Data from Graeme-Cook F. Neuroendocrine tumors of the GI treditors. Surgical pathology of the GI tract, liver, biliary tract, anWilliams GT. Endocrine tumours of the gastrointestinal tract:
Gastrinomas can either occur sporadically (75%of cases) or in association with MEN-1 (25% ofcases).29 By definition, gastrinomas are associ-ated with increased serum levels of gastrin, andtwo-thirds of the patients present with Zollinger-Ellison syndrome. Although gastrinomas mayoccur in several different sites, they are usuallylocated in the so-called gastrinoma triangle, andapproximately 70% occur in the duodenum.Sporadic tumors are solitary and have no identifi-able precursor lesions, whereas tumors arising inthe setting of MEN-1 are usually multifocal andare believed to originate from an underlyingprecursor lesion (ie, G-cell hyperplasia).16
Duodenal gastrinomas are usually small lesions,usually measuring less than 1 cm in diameter andlocated in the first portion of the duodenum. Histo-logically, they show a mixture of histologic growthpatterns, often with a trabecular and pseudo-glandular architecture.26 In spite of their smallsize and lack of muscularis invasion, gastrinomasoften have an aggressive behavior, with earlyregional lymph node metastases. Therefore, gas-trinomas should be considered potentially malig-nant regardless of other features.
Type 3 Type 4
10%–15% of cases Rare
Solitary Solitary
Variable; one-thirdlarger than 2 cm
Large
Any where in stomach Anywhere instomach
rinee 1,r-me
Sporadic Sporadic
e 71% of tumors >2 cmwith muscularispropria and vascularinvasion have lymphnode metastases
act and appendix. In: Odze RD, Goldblum JR, Crawford JM,d pancreas. Philadelphia: Saunders; 2004. p. 483–504; and
selected topics. Histopathology 2007;50(1):30–41.
Fig. 7. ECL cell hyper-plasia may be prominentin long-standing chronicatrophic gastritis associ-ated with hypergastrine-mia, and is best visualizedwith synaptophysin (shown)or chromogranin Aimmunohistochemistry.
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Duodenal somatostatinomas represent 15% to20% of duodenal NETs26,30 and about 1% of allgastroenteropancreatic NETs.31 They are predom-inantly located in the periampullary region, and areassociated with type 1 neurofibromatosis (vonRecklinhausen disease) in up to one-third of thecases, as well as with MEN-1.32 Originally namedglandular duodenal carcinoids, this tumor showscharacteristic histologic findings that includeprominent glandular architecture with intraluminalmucinous material, simulating an epithelial tumor,as well as the presence of psammoma bodies in
most cases (Fig. 9). The cytologic features ofa NET (ie, round, uniform nuclei, with salt-and-pepper chromatin, and abundant cytoplasm) aremorphologic clues on sections stained with hema-toxylin and eosin. Immunohistochemistry forsomatostatin is positive in almost all cases,although associated somatostatin syndrome (dia-betes, achlorhydria, cholelithiasis, and diarrhea)is rarely present. Muscularis propria invasionseems to be a poor prognostic feature, associatedwith lymph node metastasis. Duodenal/periampul-lary somatostatinomas do not seem to be related
Fig. 8. Type 1 gastricNETs arising in hypergas-trinemia are usually small(<1 cm) (A) and multiple.Note linear ECL cellhyperplasia highlightedby immunohistochemistryfor synaptophysin (B) inadjacent gastric mucosa.
339GI Neuroendocrine Tumors
to pancreatic somatostatinomas, which areusually well-differentiated NETs that do not showany of the distinctive histologic features of theirduodenal counterpart, and are sometimes associ-ated with somatostatin syndrome.9
Nonfunctioning duodenal NETs can usually beshown to be formed by serotonin-producing cellsor, less often, gastrin- and calcitonin-secretingcells. Hormonal syndromes, however, are notapparent. The prognosis of nonfunctioning NETsis significantly better than that of gastrinomas orsomatostatinomas. In general, metastatic diseaseis not seen unless the tumor displays other unfa-vorable features such as extension beyondsubmucosa.9
Poorly differentiated duodenal carcinomas arehormonally inactive tumors that typically arise inthe periampullary region of the duodenum.Histologically, they show an undifferentiatedmorphology, often with small cell features. Likepoorly differentiated neuroendocrine carcinomaselsewhere in the GI tract, these tumors mayshow strong synaptophysin positivity; chromogra-nin A immunohistochemistry is negative or onlyweakly positive. The prognosis in generally poor,with early lymph node and liver metastases.26
Duodenal gangliocytic paragangliomas are rareneoplasms that, likewise, usually occur in the peri-ampullary region. They have a polymorphoushistologic appearance, with areas reminiscent of
Fig. 9. Periampullary so-matostatinomas display aglandular growth patternwith psammoma bodiesand may be mistaken foradenocarcinoma.
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a paraganglioma, carcinoid-like regions, ganglioncells, as well as Schwannian spindle cell elements.Immunohistochemical studies demonstrate thepresence of somatostatin, serotonin, and pancre-atic polypeptide in the endocrine cells, ganglioncells stain positively for neuron-specific enolase(NSE), and Schwann cells express S-100 andneurofilament.33,34
NETs of the Distal Jejunum and Ileum
Tumors in this location account for approximately25% of all GI NETs, making this region the singlemost common site for NETs. Men and women areequally affected, with a peak incidence in thesixth decade.7,30 The terminal ileum is the mostcommon location. Histologically, tumors in theterminal ileum have a solid, nested, or trabeculararchitecture and are usually composed of cyto-logically bland cells. A background of denselyfibrotic stroma is characteristic of ileal NETs.NETs of the ileum often present with small bowelstenosis, and are commonly associated withfibrosis of peritumoral tissues, peritoneal cavity,and retroperitoneum.35 There is recent evidencethat tumor-associated fibrosis may be causedby fibrogenic mediators such as tumor growthfactor b and connective tissue growth factor(CTGF), via activation of intestinal stellate cells.These same mediators have been postulated toplay a role in fibrotic processes in distant organs,such as heart and lungs, in the setting of carci-noid syndrome.36 Immunohistochemically, thesetumors may produce serotonin, substance P,and catecholamines.9
Ileal NETs generally pursue an aggressive clin-ical course, with frequent metastases to regionallymph nodes at the time of clinical presentation.Approximately 20% of patients present with livermetastases. Because serotonin is metabolizedby the liver, only patients with metastatic disease(to liver or to other distant organs) are at risk ofdeveloping carcinoid syndrome, characterized byflushing, diarrhea, bronchospasm, and endocar-dial fibrosis.9
NETs of the Appendix
Appendiceal NETs are among the most commonin the GI tract and account for most appendicealneoplasms. They are found in 0.32% to 0.6% ofall surgically resected appendices, and occurprimarily in the tip of the organ.37 Most of thesetumors are found incidentally, although somepatients may present with appendicitis or recur-rent abdominal pain. The peak incidence is duringthe fourth and fifth decades and women areaffected more often than men.9
Most appendiceal NETs are believed to beenterochromaffin cell neoplasms, although rareexamples of L-cell tumors occur. Histologically,appendiceal NETs usually demonstrate an insular,or, less commonly, a trabecular growth pattern.The cells are bland, with uniform, round nuclei,inconspicuous nucleoli, and abundant, pale,eosinophilic cytoplasm. Rare tumors demonstrateclear cell cytoplasm. These tumors have beencalled balloon cell carcinoids and are believed tobe a variant of classic carcinoid tumors. Theymust be distinguished from goblet cell carcinoids,which contain true cytoplasmic mucin.38 A fibrous
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background can also be seen in some cases,similar to that observed in ileal NETs. Immunohis-tochemically, appendiceal NETs are positive forsynaptophysin, chromogranin A, and NSE, andmay also express serotonin and substance P. S-100-positive sustentacular cells are typicallypresent.39
Characteristically, these tumors infiltrate themuscularis propria and often extend into the
Fig. 10. Goblet cell carci-noid of the appendixconsists of an admixtureof goblet cells and ofteninconspicuous neuroen-docrine cells (A). Muci-carmine stain highlightsthe mucin-containinggoblet cells (B).
periappendiceal fat. Although these featureswould predict an aggressive behavior in NETselsewhere in the GI tract, appendiceal tumorshave a much more favorable prognosis and lymphnode metastases are uncommon. The frequencyof metastatic disease, however, varies accordingto tumor size, being 0% for tumors less than 1cm, 3% to 6.7% for 1- to 2-cm tumors, and 21%to 30% for tumors larger than 2 cm.40,41 Many
Fig. 10. Immunohisto-chemistry for synaptophy-sin (C) reveals scatteredneuroendocrine cells.
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other histologic parameters such as depth of inva-sion within the wall, location of the tumor within thelength of the appendix, perineural invasion,lymphatic invasion, and presence of serosal tumorhave been evaluated and found to be of noprognostic significance in several studies.41–43
Conflicting results have been reported on theprognostic value of tumor invasion of themesoappendix.42,44,45
Although most NETs of the appendix displayclassic carcinoid morphology, unusual subtypesin this location include goblet cell carcinoid, mixedcarcinoid-adenocarcinoma, and tubular carcinoid.
Goblet cell carcinoids are unusual tumors that,like conventional carcinoids, tend to occur at thedistal end of the appendix. However, they presentgrossly as diffuse areas of thickening of the appen-diceal wall rather than as discrete masses. Theyoccur most often during the fifth decade of life,and have an equal gender distribution. Althoughthese tumors may be found incidentally, patientsfrequently present with appendicitis.
Histologically, goblet cell carcinoids are formedby small clusters of mucinous cells with a gobletcell–like appearance (Fig. 10), often admixedwith a variable amount of endocrine and Panethcells. In a minority of cases, small central luminaare present, giving the infiltrating glands an intes-tinal crypt appearance. Extensive invasion of theappendiceal wall by discrete and often inconspic-uous nests of tumor cells is characteristic. Stromalreaction against infiltrating tumor is usually absent.Perineural and lymphatic invasion may be present
and presence of pools of extracellular mucin-containing tumor cells are not uncommon.46 Cyto-logically, tumor cells are bland with cytoplasmicmucin staining positive with periodic acid-Schiffand Alcian blue. Immunohistochemically, gobletcell carcinoids are positive for keratin and carci-noembryonic antigen.46,47 Synaptophysin andchromogranin highlight a variable number ofneuroendocrine cells within the tumor nests.
Goblet cell carcinoid is considered by some torepresent a form of low-grade adenocarcinoma,37
partly because of the scarcity of neuroendocrinecells within the tumor. However, these neoplasmsdo not contain mutations commonly present inadenocarcinomas, such as K-ras, b-catenin orDPC-4, and certain chromosome losses (such as11q, 16q, 18q) found in ileal carcinoids havebeen detected.48 Electron microscopy studiesdemonstrated features of adenocarcinomas andcarcinoid tumors, with the presence of cyto-plasmic mucin and electron dense granules.47
Although epithelial abnormalities such as disarrayand nuclear enlargement of goblet cells and anassociation with mucinous neoplasms and appen-dicial carcinomas have been reported, a definiteprecursor lesion for goblet cell carcinoid has notbeen identified.
Traditionally, goblet cell carcinoids have beenregarded as being more aggressive than conven-tional appendiceal carcinoids, but less aggressivethan appendiceal adenocarcinomas.49,50 Histo-logic features that have been found to have prog-nostic significance in these tumors include
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extension beyond the appendix, atypical histo-logic patterns, and more than 2 mitoses/10 highpower fields.50,51 Size is difficult to assessbecause of the infiltrative nature of these tumorsand therefore is not a useful prognostic indicator.Perineural and lymphatic invasion do not seem tocorrelate with a worse outcome.50 An importantprognostic consideration in goblet cell carcinoidsis the assessment of their growth pattern. Burkeand colleagues46 described atypical histologicfeatures in goblet cell carcinoids that includedfused/cribriform glands, solid growth, single filingof cells, diffusely infiltrating signet ring cells,compressed small glandular nests, as well asextracellular mucin pools containing fused glandslacking lumina, features collectively called carci-nomatous growth patterns. Tumors containinggreater than 50% carcinomatous growth patternwere likely to behave in an aggressive fashion.Conversely, tumors lacking a significant carcino-matous growth pattern were classified as gobletcell carcinoids and had a favorable prognosis.38
More recently, Tang and colleagues52 studied 63appendiceal tumors with features of goblet cellcarcinoids. The tumors were classified as typicalgoblet cell carcinoids or adenocarcinoma exgoblet cell carcinoids (based on the presence ofatypical features such as large clusters of cells,signet ring cells, cellular atypia, areas of poordifferentiated tumor, destructive growth withinthe appendiceal wall, among others). Irrespectiveof tumor stage, tumors classified as typical gobletcell carcinoids were associated with a 100% 5-year disease-specific survival, in contrast to 36%
Fig. 11. Tubular carci-noid of appendix growsin infiltrative cords ina background fibroticstroma. These tumorsare composed of L cellsand may be negative forchromogranin A.
and 0% survival for the subgroups showing atyp-ical features. Therefore, if strict diagnostic criteriaare used in the diagnosis of goblet cell carcinoids,these tumors almost invariably have a favorableprognosis, although atypical features indicatea much more aggressive behavior.
Tubular carcinoids are tumors composed ofdiscrete small glandular structures lined by bland,cuboidal epithelium, which contain a small amountof luminal mucin.39 The glandular structures showan infiltrative growth pattern in a backgroundfibrotic stroma (Fig. 11). These neoplasms usuallyoccur in the appendiceal tip and are almost alwaysan incidental finding. Tubular carcinoids arederived from L cells and express enterogluca-gon.39 Chromogranin and synaptophysin stainingis variable. These tumors in general behave ina benign fashion.
NETs of the Colon and Rectum
NETs of the colon are uncommon.53 When theyoccur, these tend to be poorly differentiatedtumors with aggressive behavior, usually associ-ated with metastatic disease at the time of diag-nosis. Chromogranin A is negative or only weaklypositive because of the high-grade nature of thetumors.
NETs occur much more frequently in the rectumthan in the colon, representing more than 27% ofall GI NETs in large tumor registry databases.7
Tumors in this location, as opposed to the colon,are generally small (<1 cm) well-differentiatedneoplasms that present endoscopically asmovable submucosal nodules. The prognosis is
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favorable in most cases. High-risk features predic-tive of aggressive behavior include size greaterthan 2 cm, invasion into muscularis propria ordeeper, lymphovascular invasion, and 2 or moremitoses per 50 high power fields.54 Immunohisto-chemically, rectal NETs can be positive forglucagon and pancreatic polypeptide, and mayexpress prostatic acid phosphatase; chromogra-nin A may be only weakly expressed (Fig. 12),leading to confusion with locally advanced pros-tate carcinoma. Poorly differentiated NETs in therectum are uncommon, but when they occur,have a poor prognosis as in other GI sites.
In summary, GI NETs are relatively uncommonneoplasms in the GI tract compared with adeno-carcinomas. They represent a morphologicallyand biologically heterogeneous group of tumorsand are associated with genetic syndromes(most commonly MEN type 1) in approximately5% to 10% of cases. Although no classificationguidelines are universally accepted, the 4-cate-gory WHO scheme has gained increasing accep-tance worldwide. TNM staging systems for GINETs have also recently been proposed and arecurrently being evaluated. The existing guidelinesemphasize that GI NETs should be assessed
Fig. 12. Rectal NETs areoften immunoreactivefor prostatic acid phos-phatase (A) and onlyweakly positive for chro-mogranin A (B), leadingto diagnostic confusionwith locally advancedprostate carcinoma.
PitfallsIN GI NETS
! Multifocal small NETs in the gastric body (type1 gastric NETs) are commonly found in hyper-gastrinemic states and in chronic atrophicgastritis, and are generally clinically benign.Surgical resection is rarely indicated, andsuch lesions must be distinguished from soli-tary sporadic gastric NETs, which behave ina more aggressive fashion.
! GI NETS with a glandular growth pattern,most often seen in duodenal or ampullarysomatostatin-producing NETs, may beconfused with low-grade adenocarcinoma.Identification of psammoma bodies ina low-grade glandular neoplasm at this siteshould prompt consideration ofsomatostatinoma.
! Ileal NETs may be associated with extensivefibrosis and present clinically as localizedareas of stenosis (mimicking Crohn disease).Mesenteric and retroperitoneal fibrosis mayalso be present.
! Strict criteria should be applied to diagnosetypical goblet cell carcinoids of the appendix.Goblet cell carcinoids with atypical featuresusually behave aggressively.
! GI NETs, especially those arising in theappendix or rectum, may be negative forchromogranin A expression.
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according to their location and site-specificmorphologic features, reflecting their heteroge-neous nature. Special types of GI NETs such ashypergastrinemia-associated gastric NETs,duodenal somatostatinomas, and gangliocyticparagangliomas, and appendiceal goblet cellcarcinoids and tubular carcinoids should berecognized because of their particular biologiccharacteristics and clinical implications.
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