REVIEW ARTICLE Neuroendocrine Proliferations of the Stomach: A Pragmatic Approach for the Perplexed...

Neuroendocrine Proliferations of the Stomach: A PragmaticApproach for the Perplexed Pathologist

Amber N. Cockburn, MD,* Christopher J. Morgan, DO,* and Robert M. Genta, MD, FACG*wz

Abstract: The classifications of neuroendocrine proliferations thatlead from enterochromaffin-like cell hyperplasia to neuroendocrinetumors in the stomach are complicated and relatively inaccessible tononspecialists. Consequently, these lesions tend to remain widelyunderdiagnosed until they progress to easily recognizable neuro-endocrine tumors. This review provides simple, yet rigorousguidelines on how to recognize, classify, and diagnose the neuro-endocrine proliferations found in the stomach, emphasizing themost common background in which they arise, atrophic gastritis.After a succinct outline of the types and distribution of the neu-roendocrine cells in the normal gastric mucosa we discuss the mostcommon situations in which the pathologist needs to think aboutgastric neuroendocrine cells. In general practice gastric biopsyspecimens are often numerically and topographically inadequatefor the evaluation of atrophic gastritis; therefore, we have includedan algorithm to address specifically the steps that should be takenwhen confronted with suboptimal sampling. Finally, we illustratethe suggested diagnostic process with 4 cases that are fairly rep-resentative of the type of situations encountered in everydaypractice. The pathologist who follows our simple steps will bebetter aware of this neglected area of gastric pathology and willlearn to suspect, recognize, and accurately diagnose the mostcommon abnormalities of the neuroendocrine system in thestomach.

Key Words: carcinoid, neuroendocrine tumor, atrophic gastritis,

ECL cells, neuroendocrine proliferations, neuroendocrine hyper-

plasia, neuroendocrine dysplasia

(Adv Anat Pathol 2013;20:148–157)

Since the first description of hormone-producing endocrinecells in the gastric mucosa of dogs by Heidenheim in 1870,

the field has evolved slowly for almost a century, occasionallyrevitalized by the discovery of new staining methods that betterallowed the visualization and categorization of the endocrinecells in the human gastrointestinal mucosa. In the last severaldecades the function of many of these cells has been eluci-dated, simple immunohistochemical methods for their identi-fication have become available, and disease associations haveemerged. However, except for the few with a special interest inthe neuroendocrine cells of the stomach, pathologists havegenerally renounced keeping up with the arcane classificationsof the proliferative lesions that lead from enterochromaffin-like(ECL) cell hyperplasia to neuroendocrine tumors (NET),formerly known as carcinoid tumors, and neuroendocrine

carcinomas. If we consider that most of these proliferationsoccur in a background of atrophic gastritis—an entity withcomplex and often unfamiliar diagnostic criteria, we canreadily understand why gastric neuroendocrine precursorlesions remain widely underdiagnosed until fully-formed easilyrecognizable NETs develop.

REVIEW OBJECTIVESThe aim of this review is to provide the general

pathologist with simple, yet rigorous guidelines on how torecognize, classify, and diagnose the neuroendocrine pro-liferations found in the stomach. We will first present asuccinct outline of the types and distribution of the neu-roendocrine cells in the normal gastric mucosa. We willthen discuss the most common situations in which thepathologist needs to think about gastric neuroendocrinecells. Finally, we will provide example cases and a series ofalgorithms that will guide through the specific diagnosticcriteria for each of the entities discussed. The pathologistwho follows our simple steps will be better aware of thisneglected area of gastric pathology and will learn to sus-pect, recognize, and accurately diagnose the most commonabnormalities of the neuroendocrine system in the stomach.

NEUROENDOCRINE COMPONENTS OF THENORMAL STOMACH

There is a wide array of endocrine cells scattered throughthe gastric epithelium. These include ECL cells, histamine-producing cells that constitute a majority of the neuro-endocrine cell population within the fundus, and 15% to35% of the total gastric neuroendocrine component; G cells(gastrin); D cells (somatostatin); A cells (glucagon); enter-ochromaffin cells (serotonin); and X cells, also referred to asA-like cells (ghrelin). In addition, there is a number of otherknown or presumptive endocrine-type cells that have beencharacterized mainly by histochemical and ultrastructuralmethods and whose products and function remain unknown.

Only gastrin-producing (G cells) and ECL cells areeasily visualized by widely available immunohistochemicalmethods, and are relevant to the practice of gastric path-ology; therefore, we shall focus exclusively on these 2 celltypes and refer the interested reader to the detailed works ofSolcia’s group.1–3

Gastrin-producing CellsMost G cells are located in the neck region of the

mucus glands of the antrum, pylorus, and transitional zone,where they compose approximately 50% of the neuro-endocrine cell mass (Fig. 1A).4 In addition, scattered G cellsmay also be found in the mucosa of the corpus and fundusin approximately 10% of gastric biopsy specimens, irre-spective of the presence of atrophy (Fig. 1B).5,6 Gastrin isthe main regulator of acid secretion, a function it

From the *Miraca Life Sciences Research Institute, Miraca Life Sci-ences, Irving; Departments of wPathology and zMedicine, VeteransAffairs North Texas Health Care System, The University of TexasSouthwestern Medical Center, Dallas, TX.

The authors have no funding or conflicts of interest to disclose.Reprints: Robert M. Genta, MD, FACG, Miraca Life Sciences

Research Institute, Miraca Life Sciences, 6655 North MacArthurBlvd., Irving, TX 75039 (e-mail: [email protected]).

Copyright r 2013 by Lippincott Williams & Wilkins

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mailto:[email protected]

accomplishes by 2 mechanisms: direct and indirect. Thedirect mechanism acts on the parietal cell’s basolateralmembrane cholecystokinin B (CCKB) receptors. The indi-rect mechanism affects the ECL cell’s CCKB receptors thatrespond by releasing histamine, which in turn stimulatesparietal cell acid secretion by binding to the parietal cell’sbasolateral histamine2 receptor.

7

ECL CellsECL cells are small, irregularly shaped cells that are

heavily argyrophilic with the Grimelius’, Bodian, andSevier-Munger methods of staining.2,8–12 Although theseimmunochemical techniques have been crucial in the iden-tification and characterization of endocrine cells, the adventof immunohistochemical staining has made them largelyobsolete. In the stomach, synaptophysin, and chromogra-nin immunostains—although not completely specific, areperfectly adequate to visualize ECL cells and detect theirabnormal proliferations. ECL cells, typically found in thegastric corpus, are rare or absent in other compartmentsof the stomach. However, when measured by immuno-reactivity to the histamine-forming enzyme histidinedecarboxylase and to the CCKB receptor, ECL cells werealso identified in the transitional and pyloric region, and inpseudopyloric and intestinal metaplasia.6 In the oxynticglands, ECL cells are scattered in the deep and intermediateregions; few are observed in the neck area and none in thesurface epithelium (Fig. 2). ECL cells constitute the major,and only clinically relevant, endocrine cell population in themucosa of the gastric corpus.

WHEN NEUROENDOCRINE CELLSARE RELEVANT

There are 3 situations in which a good understandingof gastric neuroendocrine pathology is necessary. Thesimplest one is when an obvious NET (formerly carcinoid),described by the endoscopist as a nodule or polyp, isidentified. Although the histopathologic diagnosis of thislesion rarely poses a diagnostic dilemma, its detectionwarrants an investigation of the background mucosa thathas allowed its genesis. The second situation involves theevaluation of gastric atrophy, the milieu in which endocrinecell hyperplasia and dysplasia occur and progress. Finally,at a time when a third of the adults living in the indus-trialized world use proton pump inhibitors, iatrogenichypergastrinemia has reached endemic proportions.13

Clinicians occasionally suspect and inquire about ECL-cellhyperplasia; pathologists must be able to confidently statewhether the specimens are adequate to assess ECL-cellhyperplasia and—if present—whether it is significant.

The Unmistakable NETThe most evident situation in which a pathologist will

need to assess the endocrine cell population in the gastricmucosa is when a NET is found. Irrespective of its size, oneshould try to answer the question of whether it represents a:NET arising from an atrophic background (type I); NET(type II) associated with Zollinger-Ellison (ZE) syndrome,multiple endocrine neoplasia type I (MEN-I),14,15 orhyperparathyroidism16; or a sporadic type III NET(Table 1).

If the mucosa surrounding a small NET is atrophic,with loss of oxyntic glands, pseudopyloric and intestinalmetaplasia, and various degrees of chronic inflammation,then the tumor is likely a type I NET and a thoroughevaluation for atrophic gastritis is warranted. Atrophicgastritis is responsible for generating the most gastricNETs; consequently, type I NETs represent 70% to 80% ofall gastric NETs.17 Histologically, these tumors are com-posed of uniform cells with low proliferation index (grade1, G1), are confined to the oxyntic mucosa, and tend to bemultifocal (Fig. 3, G1). They arise in the setting of hyper-gastrinemia due to loss of negative inhibition caused byparietal cell atrophy.18,19

Type II gastric NETs are frequently detected as part ofthe work-up for MEN-1 syndrome or ZE syndrome.20 Inboth instances the tumors are usually small (<1 cm), have alow proliferation index, and show neither infiltrating norpleomorphic features (Fig. 3, G1). In patients with MEN-1syndrome the gastric mucosa is normal or mildly inflamedbut not atrophic. The fundic mucosa of patients with ZEsyndrome is often hypertrophic, with long densely packedoxyntic glands and no significant inflammation. This typeof NET is the most uncommon, representing 5% to 8% ofgastric NETs.17

Sporadic NETs occur in otherwise healthy gastricmucosa; the adjacent gastric mucosa may be normal orshow chronic gastritis, but it is not atrophic. These tumorsrepresent approximately 20% of all gastric NETs.17

Sporadic NETs are usually detected when they becomesymptomatic, either secondary to mucosal erosion andblood loss or metastasis. As these alerting events tend tooccur only after the tumors reach a certain size, thesetumors are usually larger than 1 cm, display infiltratinggrowth patterns with occasional areas of necrosis, andexhibit various degrees of pleomorphism (Fig. 3, G2). They

FIGURE 1. Immunohistochemical staining for gastrin. A, Antralmucosa: G cells, present in the neck region of virtually everyfoveola, form a distinctive band. B, In the corpus (whether nor-mal or atrophic, as in this photomicrograph) only rare scatteredG cells are seen, usually in the lower half of the mucosa.

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are more aggressive than nonsporadic NETs and, con-sequently, have a generally poor prognosis.21

The WHO Classification of Tumours of the DigestiveSystem (2010) gastrointestinal diseases emphasizes combiningthe proliferation index with the morphologic findings whengrading a NET.22 The accepted methods of determining theproliferation index include counting mitoses and/or obtainingthe Ki-67 index. Typically the NETs or the biopsies are toosmall to attain the requisite 50 high-power fields (HPF) neededfor a mitotic count. If the specimen is adequate, the mitoses aregraded as illustrated in Table 2. Because specimens are oftensmall, the Ki-67 index is preferentially used in our practice. It iscalculated by examining 500 to 2000 neoplastic cells anddetermining the percentage of Ki-67–positive neoplastic cells;counting should be performed in the areas of greatest labeling.Grade 1 (G1) tumors have a proliferation rate ofr2% (Fig. 3,G1). Grade 2 (G2) tumors’ proliferation index ranges from 3%to 20% (Fig. 3, G2) and neuroendocrine carcinomas (G3) havea proliferation index >20% (Fig. 3, G3). An important cav-eat: as lymphocytes will stain intensely with Ki-67, and areoften abundant within NETs, they must be identified andexcluded from the assessment, which must be limited to neo-plastic cells. Should the mitotic count and Ki-67 index differ,the higher grade is used.

GASTRIC MUCOSAL ATROPHY ANDATROPHIC GASTRITIS

Gastric mucosal atrophy is defined as the decrease of thestructures present in the normal stomach.23,24 When the van-ished structures (eg, oxyntic glands) are replaced by loose

connective tissue or fibrosis the atrophy is classified as non-metaplastic (Fig. 4A). Metaplastic atrophy is characterized bythe replacement of the native glands with either intestinal-typeepithelium (intestinal metaplasia, Fig. 4B) or pyloric-typeglands (pseudopyloric metaplasia, Fig. 4C). Mucosal atrophyis simply a histopathologic finding.25,26 In contrast, atrophicgastritis is a condition of the stomach characterized byextensive areas of atrophy, metaplastic or not, that may bepatchy and involve both the antrum and the corpus (multifocalatrophic gastritis, almost always a consequence of long-standing Helicobacter infection, Fig. 5A) or exclusively thecorpus (corpus-restricted atrophic gastritis, virtually synon-ymous with autoimmune atrophic gastritis, Fig. 5B).24,27,28

The diagnosis of atrophic gastritis requires that at least 2identifiable specimens from the antrum and 2 from the corpusbe available. As the separate submission of specimens as perthe Sydney System guidelines rarely occurs in clinical practiceand particularly difficult situations occur when a clinician onlysubmits multiple gastric biopsy fragments in a single formalincontainer, we have prepared a set of simple algorithms thatshould help decide how to approach most sets of suboptimallysampled gastric biopsy specimens (Fig. 6).

When adequate sampling (2 separate and topo-graphically labeled specimens each from antrum and cor-pus) is available, foci of atrophy, metaplastic or not, in bothgastric compartments indicate multifocal atrophic gastritis,likely related to H. pylori infection. In these cases ECL-cellproliferations are exceedingly rare and, unless obviousneuroendocrine nests are seen on the hematoxylin andeosin–stained sections, there is no need to perform specialstains for neuroendocrine cells. If the antrum is either

FIGURE 2. ECL cells in normal corpus. A, Synaptophysin nonspecifically stains the zymogen granules in the chief cells with a resultingincreased background. In contrast, chromogranin (B) exclusively highlights endocrine cells.

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normal or shows reactive gastropathy with mild or mod-erate chronic inflammation only,25 and specimens from thecorpus show atrophy, particularly with intestinal andpseudopyloric metaplasia, then a diagnosis of autoimmuneatrophic gastritis is extremely likely. As autoimmune gas-tritis is often associated with ECL-cell proliferations andNETs, a work-up with immunohistochemical staining ofboth antrum and corpus is suggested.29–31

If only 1 sample from a stomach is available and it showsmucosal atrophy with or without metaplasia: if focal it shouldbe diagnosed as “gastric mucosal atrophy,” whereas if diffuseit may be called “chronic atrophic gastritis.” If the specimen islabeled antrum, and its histologic features corroborate itsantral origin, there is little that can be added regarding specificetiology, as it may be from the site of a healed ulcer, beassociated with reactive gastropathy, or be part of multifocalatrophic gastritis. In contrast, if the specimen is clearly ofcorpus origin (with residual oxyntic glands) or shows pseu-dopyloric metaplasia, the possibility of autoimmune atrophicgastritis should be mentioned and additional sampling sug-gested to the clinician.

THE PATIENT ON LONG-TERM PROTONPUMP INHIBITORS

The normal range of serum gastrin levels depends onthe method and laboratory, but is generally <150 pg/mL.Very high levels of gastrin (eg, >400 pg/mL) were pre-viously considered indicative of ZE syndrome or end-stageatrophic gastritis, where the gastric corpus has lost most orall the parietal cells and antral G cells secrete everincreasing quantities of gastrin in a futile attempt to stim-ulate acid secretion.13 In most subjects, chronic use of his-tamine2-receptor antagonists and proton pump inhibitors(PPI) is associated with a slight increase in serum gastrin.However, about 20% to 25% of chronic PPI users developmodest degrees of hypergastrinemia (200 to 400 pg/mL) andapproximately 1% per year, particularly patients withH. pylori infection, develop significant hypergastrinemia

(>400 pg/mL).32 Histologically, most chronic PPI usershave no significant changes in either G cells or ECL celldensity and distribution. However, some patients developECL cell hyperplasia (usually no greater than linear, rarelymicronodular). NETs may occur in PPI users, and someauthors have speculated that these NETs, and even neu-roendocrine carcinomas, are caused by the acid sup-pression.33,34 Given the billions of PPI prescriptions filled inthe last 25 years by millions of patients worldwide and thelack of a corresponding documented increase in the inci-dence of gastric NETs, it seems more likely that the fewreported cases represent the chance occurrence of 1 rare(NET) and 1 common (PPI use) event.

The density of G cells may increase, both in thestomach and the duodenum, as a consequence of acidsuppression.35 The changes, however, are essentiallyimpossible to detect without applying sophisticated count-ing techniques and an extensive bank of normal data col-lected with identical methods. Therefore, we suggest that nocomments be made on the numbers or density of G cells inresponse to clinicians’ requests to evaluate the effects ofPPIs on neuroendocrine cells.

ECL CELL PROLIFERATIONS IN ATROPHY—HYPERPLASIA, DYSPLASIA, AND

NEUROENDOCRINE TUMORSIn chronically hypergastrinemic states, gastrin stim-

ulates ECL cells to proliferate. The proliferations run thespectrum from simple hyperplasia to frank NET (pre-viously discussed) that is described by the Solcia classi-fication published in 1988.36

ECL-cell simple (or diffuse) hyperplasia is defined asECL-cell density >2 SDs of the normal density in matchedcontrols. The cells are hypertrophied and arranged singly or inclusters of fewer than 5 cells, usually in the lower third of thegastric pits. Because quantification is difficult, the causes arenumerous and a visual understanding of “normal” is notreadily available, we do not estimate or comment on simple

TABLE 1. Features of Type I, II, and III Neuroendocrine Tumors

Type I II III

Clinical association Autoimmune gastritis MEN1/ZES SporadicSex predilection Female (71%) None Male (74%)Mean age (y) 63 50 55Anatomic localization Body/fundus Body/fundus ThroughoutDistribution Multicentric Multicentric Single% of gastric NET’s 70%-80% 6%-10% 15%-20%Serum gastrin Elevated Elevated NormalECL cells Hyperplastic Hyperplastic NormalSize Small: 77% (<1 cm) to 97%

(<1.5 cm)Intermediate: usually1-2 cm

Large: mean diameter 3.2 cm

Lymph node metastasis 5%-10% 30% 55%Liver metastasis 2%-5% 10% 22%-75%Depth of invasion Muscularis propria or submucosa Muscularis propria or submucosa Muscularis propria or submucosaHistopathology Regular, monomorphic nuclei,

inconspicuous nucleoliRegular, monomorphic nuclei,inconspicuous nucleoli

Large vesicular nuclei, prominent nucleoli,irregular chromatin, smallerhyperchromatic nuclei, focal necrosis

Mitotic countProliferation index

<2/10HPF<2% Ki-67 index

<2/10HPF<2% Ki-67 index

2-20 /10HPF3%-20% Ki-67 index

WHO 2010 gradingclassification

G1 G1 G2

ECL indicates enterochromaffin-like; HPF, high-power field; MEN, multiple endocrine neoplasia type 1 syndrome; NET, neuroendocrine tumor; ZES,Zollinger-Ellison syndrome.



FIGURE 3. Neuroendocrine tumors/neuroendocrine carcinoma grading. (G1A) H&E of nested neuroendocrine cells that (G1B) staindiffusely positive for synaptophysin with (G1C) low (< 2%) Ki-67 proliferation index. Beware of intratumoral lymphocytes. (G2A) H&E,sheets and nests neuroendocrine cells that infiltrate the muscularis mucosae, (G2B) stain diffusely positive for synaptophysin and have(G2C) an intermediate (3% to 4%) Ki-67 proliferation index. (G3A) H&E, sheets of pleomorphic neuroendocrine cells with intermixednecrosis that (G3B) stain weakly positive for synaptophysin and have (G3C) a high (90%) Ki-67 proliferation index. H&E indicateshematoxylin and eosin.



hyperplasia. ECL-cell linear hyperplasia is defined as at least 2linear groups of 5 consecutive neuroendocrine cells lining agland per millimeter, or 2 linear groups in 1 HPF (Fig. 7A).This is typically found in the base or lower portions of the pits,but may be seen in the glandular neck region. Linear hyper-plasia is highlighted by neuroendocrine immunohistochemicalstains and should be mentioned in the pathology report. ECL-cell micronodular hyperplasia (Fig. 7B) consists of clusters of 5or more neuroendocrine cells, bounded by basement mem-brane, that do not exceed the diameter of a gastric gland(<150mm). The clusters may be grouped or scattered throughthe lamina propria and typically have a wide distribution in theoxyntic mucosa. When aggregates of 5 or more micronodulescluster it is termed adenomatoid hyperplasia (Fig. 7C). Ade-nomatoid hyperplasia typically forms in the lower third of themucosa. Several studies have concluded that linear, micro-nodular, and adenomatoid hyperplasia have low potential forprogression to NETs.10,37

Dysplasia occurs when the micronodules fuse with lossof the basement membrane or an individual nodule is>150mm. The dysplastic nodules may progress to becomemicroinvasive when newly formed stroma can be seen withinthe lamina propria (Fig. 7D). Measurement may be performedusing a calibrated micrometer eyepiece and calculating thesize for the specific objective or using a Vernier calibratedgauge. As these lesions have the potential to progress toNETs, they should be identified and mentioned in the path-ology report. Figure 8 shows an atrophic oxyntic mucosa inwhich all types of hyperplasia and dysplasia are present.

Micro-NETs (microcarcinoids) are nodules of ECLcells with a diameter ranging from 500 mm (0.5mm) to0.5 cm that are not identified by endoscopy. They are oftenfound in biopsies labeled as “representative,” “random,” orequivalent generic designations. The identification of aNET in one of these should prompt further investigations,including a thorough evaluation of the adjacent mucosa.

Invasive NETs involve the mucosa and penetrate themuscularis mucosae to infiltrate the submucosa. However,gastric biopsies often include mucosa, limited muscularismucosae and minimal or no submucosa, essentially pre-cluding a diagnosis of invasive NET. The most useful andclinically relevant information we recommend including inall reports regarding NETs, regardless of the etiology,comprises: size, proliferation index, grade, and—whensufficient submucosa is available—invasion. We also statewhether the NET extends to the biopsy edge. Neuro-endocrine proliferations that are >500mm and endoscopi-cally identified are classified as NETs (see the Neuro-endocrine components of the normal stomach section).

Practical Suggestions for the Evaluation ofNeuroendocrine Proliferations

To work-up suspected proliferations, we recommendordering immunostains. A single neuroendocrine markerand gastrin are sufficient for working up ECL-cell hyper-plasia. In the evaluation of ECL-cell hyperplasia or dys-plasia it is not necessary to assess the proliferation index. Incontrast, the work-up of NETs includes ordering Ki-67 andchromogranin, synaptophysin, or CD56.

Illustrative Cases

Case 1Received 4 biopsies in 1 container labeled “antrum and

body.” No fragments have unequivocal oxyntic mucosa.Approach: We recommend ordering gastrin and at

least 1 neuroendocrine immunostain. Gastrin stain will helpdistinguish antrum from body. Synaptophysin or chro-mogranin will highlight endocrine cell hyperplasia. Thesestains will also highlight G cells and should be compared

TABLE 2. WHO 2010 Neuroendocrine Neoplasm GradingSystem

WHO 2010 grade Mitotic Count/10HPF Ki-67 Index (%)

NET G1 <2 r2NET G2 2-20 3-20NEC G3 >20 >20

NET indicates neuroendocrine tumor; NEC, neuroendocrine carcinoma.

FIGURE 4. Corpus mucosa with different types of atrophy. A, Nonmetaplastic moderately atrophic corpus mucosa. The foveolae arelonger than normal and oxyntic glands are separated by inflammatory or fibrous cells, but no metaplasia is present. B, Atrophy withintestinal metaplasia: no oxyntic cells remain, and the epithelium of lower portion of a foveola is replaced by intestinalized epithelium.C, Pseudopyloric metaplasia: the oxyntic mucosa has been replaced by antral-type foveolae and mucous glands.



FIGURE 5. Sydney system. A, Multifocal atrophic pangastritis: the red color represents the inflammation caused by Helicobacter pylori,diffuse throughout the stomach. Multiple foci of atrophy and intestinal metaplasia (represented in blue) are present throughout thestomach, with earlier development and greater intensity and extension in the antrum and along the lesser curvature. B, Corpus-restricted autoimmune atrophic gastritis: diffuse atrophy in the corpus with foci of intestinal and pyloric metaplasia (in blue). Theantrum is either normal or shows moderate reactive gastropathy.

FIGURE 6. Algorithm for frequently encountered suboptimal specimen scenarios. 1, The gastric biopsy is received with generic labeling such as“stomach” or “random,” and histologic examination reveals multiple fragments of gastric mucosa with at least 1 fragment showing evidence ofoxyntic mucosa with atrophy. No further work-up, including immunostains, is needed. 2 and 3, The gastric biopsy received is labeled “body/corpus” or “antrum and corpus,” and histologic examination shows only antral-type mucosa. Further work-up is needed. 4, The gastric biopsyreceived is labeled “polyp, site NOS” or “fundus/body/corpus polyp.” In addition to diagnosing the type of polyp, one should pay attention toany nonpolypoid background mucosa, in an attempt to detect evidence of oxyntic mucosa with atrophy. H&E indicates hematoxylin and eosin.



with the gastrin stain to avoid incorrectly diagnosing linearhyperplasia in biopsies from the antrum.

Suggested diagnosis: Chronic atrophic gastritis. Seecomment.

Comment: Sections show body-type mucosa (con-firmed by gastrin stain) with loss of oxyntic glands, pyloricgland metaplasia, and intestinal metaplasia. Synaptophysinand chromogranin stains highlight linear and micronodularhyperplasia. The antral mucosa shows no significant his-topathologic abnormalities. This pattern of atrophy likelyrepresents autoimmune atrophic gastritis. Correlation withclinical and serologic findings, including antiparietal andanti-intrinsic factor antibodies, is recommended.

Case 2Received biopsies labeled “gastric nodules.” The

endoscopy report does not quantify the number of nodulesseen and the gastroenterologist is unavailable. Multiplesections show nodular neuroendocrine proliferations>500 mm. No biopsies are available to assess the back-ground mucosa.

Approach: Order gastrin, synaptophysin, chromogra-nin, and Ki-67. Determine proliferation index.

Suggested Diagnosis: NET, G1 (carcinoids). Seecomment.

Comment: Sections show 3 fragments of body-typemucosa (confirmed by gastrin stain) with NET(s) ranging in

size from <1 to 2mm. Each tumor extends to the biopsyedge. The Ki-67 proliferation index is <2%, confirminggrade 1. No muscularis mucosae is available for assessmentof invasion. These biopsies may represent multiple NET orfragments of a single mass. Multiple NET may arise in thesetting of autoimmune chronic atrophic gastritis, ZE syn-drome, or MEN-1 syndrome. Clinical and endoscopiccorrelation and topographically defined biopsy sampling ofboth antrum and corpus mucosa are recommended.

Case 3Received biopsies from a single gastric nodule with

accompanying, separately submitted mucosal biopsies.Sections show fragments of NET with uniform nuclei andcells arranged in nests. There is no obvious invasion,however the muscularis mucosae is limited. The separatelysubmitted mucosa shows unremarkable oxyntic mucosa.

Approach: Order synaptophysin, chromogranin, and Ki-67 (if fewer than 50 HPF available for assessment of pro-liferation index). Ki-67 proliferation index is 3% to 20%.

Suggested Diagnosis: NET. See comment.Comment: Sections show neuroendocrine cells, high-

lighted by synaptophysin and chromogranin stains, withsmall, uniform nuclei arranged in a nested pattern. Noinvasion is identified; however the specimen is limited byscant muscularis mucosae. The tumor extends to the biopsyedges. The Ki-67 proliferation index is 5%, qualifying this

FIGURE 7. ECL cell proliferations. A, Linear hyperplasia. B, Nodular hyperplasia. C, Adenomatoid hyperplasia. D, Dysplasia.



tumor as grade 2. Grade 2 tumors are considered low-grademalignant tumors, despite the histologic differentiation.Patient work-up should include ruling out local metastases.

Case 4Received biopsies from an ulcerated mass in the fundus.

Sections show a diffuse infiltrate of single cells with largenuclei, stippled chromatin, prominent nucleoli, and a moderateamount of cytoplasm. No definite adenocarcinoma is identi-fied. No background mucosa is available for assessment.

Approach: Order synaptophysin, chromogranin, andKi-67. Depending on results, pancytokeratin, CD-56, andmelanoma markers (S100, MART-1) may be helpful.

Suggested diagnosis: Neuroendocrine carcinoma. SeeComment.

Comment: Sections show a diffuse infiltrate of singlecells with large nuclei, stippled chromatin, prominentnucleoli, and a moderate amount of cytoplasm. No ade-nocarcinoma is identified. The neoplastic cells are immu-noreactive for synaptophysin and chromogranin. The Ki-67proliferation index is 80%. Overall, these findings areconsistent with a neuroendocrine carcinoma. No angioin-vasion is identified.

CONCLUSIONSNeuroendocrine proliferations may be daunting and

the terminology is often confusing, especially with the newclassification. It is important to approach gastric specimenssystematically. To do so, one must remain alert for themucosal milieu in which ECL-cell hyperplasia will mostlikely occur. Robertson Davies wrote “the eye sees onlywhat the mind is prepared to comprehend.”38 This review

should aid in the understanding of ECL cell proliferationsso that the pathologist may recognize and appreciate theimportance of ECL cell proliferations.

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FIGURE 8. In this synaptophysin-stained section from an atro-phic gastric corpus the entire spectrum of enterochromaffin-likecell proliferation is present, from simple hyperplasia to dysplasia.



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REVIEW ARTICLE Neuroendocrine Proliferations of the Stomach: A Pragmatic Approach for the Perplexed...

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