thehistological diagnosis ofchronic gastritis fibreoptic ... · gastritis',...

J. clin. Path., 1972, 25, 1-11

The histological diagnosis of chronic gastritisin fibreoptic gastroscope biopsy specimensR. WHITEHEAD, S. C. TRUELOVE, AND M. W. L. GEAR1

From the Department ofMorbid Anatomy and the Nuffield Department of Clinical Medicine, TheRadcliffe Infirmary, Oxford

SYNOPSiS The advent of the fibreoptic gastroscope with biopsy facilities has provided the means ofobtaining biopsy specimens under direct vision from any part of the stomach. This creates newopportunities for the study of chronic gastritis, and, in particular, its evolution, topographicallocation, and causal relationships. On the basis of an experience with more than 2,500 biopsy speci-mens we have outlined a method for their systematic examination and have proposed a classificationof chronic gastritis. This classification includes the type of mucosa, the type and stage of activity ofthe gastritis, and the presence and type of metaplasia. The classification is sufficiently flexible to allowwithin it quantitative assessment of individual histological features.

Knowledge concerning the evolution of chronicgastritis and its topographical distribution in thestomach during life is scant. It was with some justifi-cation that MacDonald and Rubin (1967) wrote:'The definition and classification of chronic gastritisremains unsatisfactory.' Motteram (1951), forexample, subdivided chronic gastritis into superficialgastritis with minimal atrophy, atrophic gastritis withmoderate or severe atrophy, and gastric atrophy.Wood and Taft (1958) used the terms 'superficial,gastritis', 'atrophic' gastritis, and 'gastric atrophy'.The superficial gastritis of Williams, Edwards, Lewis,and Coghill (1957) was classified by others (Davidsonand Markson, 1955) as mild atrophic gastritis. Theseand other classifications were based on the appear-ances in body mucosa, whereas Schrager, Spink, andMitra (1967) used an entirely different classificationfor antral mucosa.These variations in classification are partly due to

inherent limitations in the methods of study whichwe have outlined in a separate paper (Gear, Truelove,and Whitehead, 1971). With the advent of fibreopticgastroscopes equipped with biopsy facilities theselimitations are largely overcome. It is now possibleto obtain free from autolysis or operative artefactmultiple, full-thickness biopsy specimens, ie, in-cluding muscularis mucosa, from all parts of thegastric mucosa at the same examination. The'Present address: Gloucestershire Royal Hospital, Southgate,Gloucester.Received for publication 28 June 1971.

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examination is easily performed and well tolerated,a combination lending itself admirably to the serialstudies necessary for proper investigation of theevolution of chronic gastritis and its relationship toother conditions.During an investigation of the relationship of

chronic gastritis to gastric ulcer (Gear et al, 1971)the absence of a classification of chronic gastritisapplicable to all areas of the gastric mucosa becameobvious. This paper describes such a classificationbased on our experience with over 2,500 biopsyspecimens, including material used in the study byGear et al (1971), and additional material frompatients with dyspepsia, duodenal ulcer, iron-deficiency anaemia, pernicious anaemia, malabsorp-tion syndromes, carcinoma of the stomach, andpatients without detectable gastric disease.

Methods

Great care is necessary in the technical handling ofthese small biopsy specimens. Trauma is avoided ifthe jaws of the biopsy instrument are immersed informol-saline contained in a shallow dish. The speci-men floats or is shaken free and then examined underthe dissecting microscope. If curled up it is gentlyuncurled with fine forceps and a dissecting needleand then transferred, mucosal surface uppermost,onto a strip of filter paper. Orientation is againchecked stereo-microscopically before it is transferred-still on the filter paper, to which it will adhere-

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R. Whitehead, S. C. Trielove, and M. W. L. Gear

into further fixative in a suitable container. Afterfixation, the biopsy specimen (still on its piece offilter paper) is wrapped in a further piece of filterpaper and processed in a perforated capsule. Beforeembedding, it is unwrapped, removed from theoriginal filter paper, and embedded in wax with themucosal surface uppermost. Four-micron sectionscut perpendicular to this surface are then easilyobtained, and several serial sections are mounted oneach slide.The following staining methods were employed:

haematoxylin and eosin (H and E), periodic acid-Schiff (PAS), Maxwell's method (1963), and areticulin method (James, 1967).

Results

NORMALThe pyloric glands occupy a roughly triangular areain the lower third of the stomach. On the greatercurve they occur only in the immediate pyloric regionbut on the lesser curve the upper limit-whilstusually in the region of the incisura angularis ismore variable and rarely extends to the oesophagus.The cardiac glands are found distal to the cardio-oesophageal junction for a distance of about 1 cmand the remaining mucosa is of body type. Thejunction between the three areas may be abrupt butis often occupied by a narrow transitional zone. Atthe pylorus-body junction in the lesser curve regionthe width of the transitional zone is variable andrarely the whole lesser curve shows a transitionalappearance.

Body mucosaThis is shown in Figure 1. Throughout the stomachthe superficial epithelium is a single layer of cellswith a basal nucleus below a typical cup-shapedcolumn of clear or faintly granular mucus. It dips toform shallowv gastric pits, into which open approxi-mately four gastric glands. These are simple straighttubules tightly packed together, roughly the samelength, which occupy three-quarters of the thicknessof the mucosa. The majority of cells lining the upperpart of the glands are parietal cells. These areeosinophilic and triangular with a central nucleus.Their longest side is applied to the basement mem-brane and sometimes intracellular canaliculi arevisible. At the junction of the glands with thepits, scattered amongst the parietal cells and some-times deeper, there are the mucous neck cells which,like the superficial epithelium, contain PAS-positiveand diastase-resistant mucus. The lower half of theglands contains the chief cells, which mingle withthe parietal cells in the region of the middle third.Chief cells have a basal nucleus and a cytoplasm

Fig. 1 Nornmal body mulcosa ( ",' 50 H and E).

filled with basophilic pepsinogen granules. Thedegree of basophilia of the granules varies frombiopsy to biopsy. Occasionally towards the basethere is an isolated argentaffin cell with its nucleusnear the lumen of the gland and a strongly eosino-philic cytoplasm due to granules just too small to beresolved with the light microscope.The lamina propria is most obvious between the

gastric pits where it contains a small number ofplasma cells, lymphocytes, eosinophils, and histio-cytes, together with a fine capillary plexus and non-myelinated nerves. At intervals along the mucosa themuscularis mucosa sends infrequent groups ofsmooth muscle fibres upwards between the glands.In reticulin preparations (Fig. 2) the basementmembrane of the surface epithelium, pits, and glandsappears as a single layer of fibres between which adelicate mesh of strands represents the supportingconnective tissues between and in relation to thecapillaries. The sharp division between the reticulinpattern of the lamina propria and the denser net-work around the fibres and vessels of the muscularismucosa is broken only by occasional tent-shapedskeins of fibres which surround the upward muscularprolongations.

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The histological diagnosis of chronic gastritis in fibreoptic gastroscope biopsy specimens

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Fig. 2 Normal body mucosa ( x 50 reticulin stain).

Pyloric mucosaFigure 3 shows the appearances. Here the gastricpits are deeper and sometimes branched, the glandsare shorter, less tightly packed than in the body,

ending at different levels and occupying a half or lessof the qnucosal thickness. They are simple orbranched coiled tubules, composed of mucus-secreting cells and occasional parietal cells (Fig. 4)especially near transitional zones. Argentaffin cellsare more frequent in this area than in the other areasof the gastric mucosa. The interdigitation of fibresfrom the muscularis mucosa is more marked andthere is more intertubular reticulin so that thepattern is quite distinctive (Fig. 5).

Cardiac mucosa (Fig. 6)This is essentially similar to the pyloric mucosa,except that the glands are even less tightly packedtogether. As a rule, parietal cells and argentaffin cellsare absent. A characteristic feature is the presence ofone or more dilated or cystic glands with a thinepithelial wall.

Transitional mucosa (Figs. 7 and 8)This is composed of both body and pyloric orcardiac type glands. Like pyloric and cardiacmucosa the pits occupy about one half of the mucosalthickness.

Recent electron microscopic and histiochemicalstudies have shown that in addition to argentaffincells several other endocrine polypeptide cells arepresent in the gastric mucosa. Pearse, Coulling,Weaver, and Friesen (1970) summarize presentknowledge of these specialized cells which are notconsidered in this present study.

Changes seen in chronic gastritisBecause the various grades of chronic gastritis areprobably different stages in one dynamic process, itseemed logical that the histological changes ingastritic mucosae should be considered together. In

Fig. 3 Normalpyloricmucosa (x 50 H and E).

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R. Whitehead, S. C. Truelove, and M. W. L. Gear

Fig. 4 Normal pyloric mucosa, parietal cells (arrows)( x 400 H and E).

Fig. 6 Normal cardiac mucosa ( .< 50 H and E).

Fig. 5 Normal pyloricmucosa ( 30 reticulinstain).

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this way the criteria for classifying gastritis areestablished with a minimum ofpreconceived notions.

In turn, the different components of the mucosashould be assessed and variations from normalcarefully noted.

Superficial epitheliumThe superficial epithelium may show features suggest-ing both degenerative and regenerative processes.The cells may appear flattened or cuboidal withhyperchromatic nuclei, partial or complete loss of the

Fig. 7 Normal transitionalmucosa. Mixed body and pyloricglands with pits of 'pyloric' length(x 50HandE).

9 Fig. 8 Detail of Fig. 7. showing both pyloric (left)

* and body (right) glands(x 100 Hand E).

mucous column, and increased basophilia of thediminished cytoplasm. The cells may form a layerseveral cells in thickness, their limiting membranesbecoming blurred and indistinct so that bud-likesyncytial masses are formed. When degenerativechanges are most marked the epithelium may showinvasion by polymorphonuclear leucocytes and occa-sional lymphocytes sometimes appearing withinvacuolar spaces between the epithelial cells. Thisconstitutes a striking picture suggestive of an activeinflammatory destruction of the epithelium and may

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be associated with epithelial erosions. The super-ficial epithelium may also be the site of smallintestinal metaplasia (vide infra).

PitsThe above epithelial changes may also be seen in thegastric pits, which may also be elongated andtortuous so that they appear in transverse sectionmore frequently than normal. Polymorph invasionofthe crypt epithelium and collections ofpolymorphsin the dilated lumen (Fig. 9) mimic the appearanceof a crypt abscess in ulcerative colitis. The pits aresometimes separated by inflammatory oedema ofthe lamina propria and appear reduced in number,but a reduction may also result from shrinkage anddegenerative atrophy.

Gland tubulesThe gland tubules may remain normal despitesevere changes in the superficial epithelium andgastric pits. Frequently, however, groups of tubulesshrink or disappear completely. The number which

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Fig. 9 Gastric pits. Polymorph aggregates in lumen(x 400 Hand E).

Fig. 10 Body mucosal glands. Inflammatory infiltrationof lamina propria. Some gland tubules (arrow) areshrunken, others show invasion by inflammatory cells(arrowheads) and degenerative changes of componentcells (x 100 HandE).

disappear varies, and no normal tubules may remain.Sometimes an inflammatory destruction similar tothat seen in the superficial epithelium and gastricpits is observed (Fig. 10).

MetaplasiaPseudo-pyloric metaplasia is recognized only in bodyglands (Fig. 11), whereas intestinal metaplasiaaffects all types of glands, the superficial epithelium,and pits. The earliest stage of pseudo-pyloric meta-plasia consists of an increase in mucous neck cellswhich later replace the remaining specialized cellsin the rest of the tubule, so that the appearancemimics normal pyloric glands. This may reflectdeficient differentiation whereby the mucous neckcells descend into the gastric glands and becomepeptic and parietal cells. When there is intestinalmetaplasia epithelial cells of small-intestinal type,including absorptive cells in various stages ofmaturation, goblet cells, and Paneth cells, can berecognized. Argentaffin cells are also present inincreased numbers. Sometimes structures covered by

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Fig. 11 Body mucosa. Intestinal metaplasia of surfaceepithelium and pits. Pseudo-pyloric metaplasia ofglands(x SOHandE).

intestinal epithelium project from the surface thussimulating intestinal villi (Fig. 12).

Lamina propriaThe lamina propria may show an inflammatoryinfiltrate which includes plasma cells, lymphocytes,and eosinophil and neutrophil polymorphs. Neutro-phil polymorphs or a mixture of lymphocytes andplasma cells may predominate. The infiltrate may berestricted to a part or the whole of the area betweenthe gastric pits, and in addition may involve part orthe whole of the deeper parts. A polymorph-richinfiltrate is commonly associated with vasculardilatation and a sero-fibrinous oedemawithdestructiveinflammation ofthe related epithelium. When chronicinflammatory cells predominate plasma cells areseen in the upper layers and lymphocytes in thelower layers where follicular aggregates with orwithout germinal centres may form. In mucosa withonly minimal epithelial degenerative changes orwidespread atrophy and metaplasia, the inflamma-tory infiltrate is often very scanty and always of thetype in which plasma cells or lymphocytes pre-ponderate. Foci of fatty infiltration may appear inthe lamina propria and in any lymphoid folliclespresent which also appear atrophic (Fig. 13).The reticulin fibres may appear more widely

spaced than normal when there is inflammatoryoedema. A more frequent change is seen in associ-ation with atrophy (Figs. 14 and 15). Under thesuperficial epithelium and in the inter-pit and inter-

Fig. 12 Pyloric mucosa.Intestinal metaplasia andpseudo-villi ( x 50 H and E).

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Figs.14 andl15 Body andpyloric mucosa.Subepithelial and inter-tubularreticulin condensation anddeposition. Comnpare withFigs. 2 and S (x SO reticulinstain).

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gland areas a felt-like mesh results when the reticulinfibres collapse together as the tubules disappear andnew fibres are formed as part of the inflammatoryreaction. In severe atrophy the junction between themuscularis mucosa and lamina propria is less welldefined than normal and the whole of the normalreticulin pattern is obscured.

Classification of Chronic Gastritis

The classification proposed is based on establishingfour biopsy features: (1) the mucosal type; (2) thegrade of chronic gastritis; (3) the activity of gastritis;and (4) the presence and type of metaplasia.

MUCOSAL TYPEDifficulties in recognizing mucosal type arise whensevere gastritis is present and there is atrophy ormetaplasia. When only pseudo-pyloric or intestinalmetaplastic tubules remain, the mucosa cannot beclassified but if residual body glands remain, theirrecognition being facilitated in Maxwell preparations,then the mucosa must be of body or transitional type.If all the tubules remaining are of 'pyloric' type themucosa could have originated in any part of thestomach, because gastritis in pyloric or cardiacmucosa will be similar to gastritis with pseudo-pyloric metaplasia in body or transitional mucosa.The site of the biopsy specimen is fairly accuratelylocated, except in stomachs altered by previousoperations and in practice difficulty only arises inbiopsy specimens from the lesser curve area, whereeven in normal stomach the demarcation of oneregion from its neighbour is often poorly defined. Ahelpful point in the differentiation of normal pyloricglands from pseudo-pyloric glands is that whilst theformer may contain occasional parietal cells thelatter do not.

GRADE OF CHRONIC GASTRITISIn common with the majority of previous authors,two major subdivisions are advocated, namely,superficial gastritis and atrophic gastritis. In theformer the inflammatory and reactive changes al-ready outlined affect only the superficial epithelium,gastric pit region, and related lamina propria.Atrophic gastritis occurs if the changes affect thegland layer, and the difficult line of demarcation isbetween superficial gastritis and early atrophicgastritis, the later and more severe grades of atrophicgastritis being obvious. While deep extension of theinflammatory infiltrate around the tubules may behelpful, the only satisfactory criterion is recognitionof atrophy of the tubules. In this respect the prepar-

ations stained for reticulin are most valuable sinceloss of tubules, even in small numbers, is reflectedby the changes in reticulin pattern already outlined.Atrophic gastritis could be classified by accuratelyquantitating the number of glands which remain buta convenient subdivision is into mild, moderate, andsevere. If only one or two groups of tubules havedisappeared, the mucosa is classified as showingmild atrophy; if all normal tubules are lost or onlyone or two groups remain, then the designation issevere; and all appearances between these twoextremes are classed as moderate. It is important forthis scheme that only normal glands be consideredand those showing metaplasia be discounted.

In severe atrophic gastritis with widespread meta-plasia, a negligible inflammatory cell infiltrate,atrophic lymphoid aggregates, and fatty infiltrationof the lamina propria the appearances are oftenclassified as gastric mucosal atrophy (Figs. 16 and17).

ACTIVITY OF GASTRITISAs already outlined, some biopsy specimens exhibitan invasion of polymorphs into and degenerativechanges of the epithelial elements of the gastricmucosa. If this reflects an active stage of inflam-matory destruction as seems likely, then clearly itspresence should be brought into any scheme ofclassification. This activity could be recorded in asimple positive or negative fashion, a positivemeaning that 'activity' was seen in some part of thebiopsy specimens. A grading of activity could beachieved simply on the basis of whether it wasdiffuse throughout the mucosa or patchy in distribu-tion. In mucosa with minimal epithelial degenerativechanges and a slight chronic inflammatory infiltratethe appearance is recorded as quiescent. Thisquiescent phase is seen par excellence in mucosawith severe atrophy and metaplasia, ie, showingso-called gastric atrophy.

METAPLASIAIntestinal metaplasia nearly always occurs in amucosa which is the site of atrophic gastritis. Occa-sionally it is present in the superficial epitheliumand pits in superficial gastritis, and very occasionallyisolated islands are seen in otherwise normalmucosa. Pseudo-pyloric metaplasia, on the otherhand, occurs only in atrophic gastritis. There is someevidence that pseudo-pyloric metaplasia may bereversible (Harvey, 1907). Both types should berecorded separately, and the degree to which they arepresent can be graded.A full classification of chronic gastritis, therefore,

based on the above principles, would be as follows:

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Figs. 16 and 17 Bodymucosa. Gastric atrophy withpartial and completeintestinal metaplasia.Note absence of epithelialdegenerative changes andminimal cellular infiltrate oflamina propria ( x 50 Hand E).

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Mucosal Type Grade of Gastritis Metaplasia

Pyloric Superficial Quiescent Pseudo-pyloricBody ActiveMild rQuiescent

Cardiac Atrophic Moderate IntestinalL Severe LActive

TransitionalIndeternminate

Discussion

In previous studies on gastritis it has been assumedthat because two blind biopsy specimens revealsimilar features, they reflect the state of the gastricmucosa as a whole. Such a claim is unjustified andthe topographical location of chronic gastritis and

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its evolution in relation to possible aetiologicalfactors and other diseases have clearly not beenadequately studied. With the advent of the gastricfibrescope equipped with biopsy facilities this is nowpossible. Previous classifications of chronic gastritis,however, do not allow full use of all the informationavailable in multiple biopsy specimens from thedifferent areas of the stomach. The classificationpresented in this paper provides a means of allocatingeach biopsy specimen to one of the main types ofgastric mucosa. Atrophy, active and quiescentstages of gastritis, and the presence of both types ofmetaplasia are recorded and it is possible, within theclassification as a whole, to apply any form ofquantitative assessment to any of the individualfeatures. This classification is advocated for futurestudies dealing with the aetiology of chronic gastritisand its relationship to age, dyspepsia, anaemia,peptic ulcer, cancer, and autoimmune phenomena allof which need to be repeated using fibrescopicbiopsy specimens from several sites in the stomach.

This work was supported by a Medical ResearchCouncil grant to R.W.ReferencesDavidson, W. M. B., and Markson, J. L. (1955). The gastric mucosa in

iron deficiency anaemia. Lancet, 2. 639-643.Gear, M. W. L., Truelove, S. C., and Whitehead R. (1971). Gastric

ulcer and gastritis. Gut, 12, 639-645.Harvey, B. C. H. (1907). A study of the structure of the gastric

glands of the dog and of changes which they undergo aftergastroenterostomy and occlusion of the pylorus. Amer. J.Anat., 6, 207-243.

James, K. R. (1967). A simple silver method for the demonstration ofreticulin fibres. J. med. Lab. Technol., 24, 49 51.

MacDonald, W. C., and Rubin, C. E. (1967). Gastric biopsy-acritical evaluation. Gastroenterology, 53, 143-170.

Maxwell, A. (1963). The Alcian dyes applied to gastric mucosa.Stain Technol., 38, 286-287.

Motteram, R. (1951). A biopsy study of chronic gastritis and gastricatrophy. J. Path. Bact., 63, 389-394.

Pearse, A. G. E., Coulling, I., Weaver, B., and Friesen, S. (1970). Theendocrine polypeptide cells of the human stomach, duodenumand jejunum. Gut, 11, 649-658.

Schrager, J., Spink, R., and Mitra, S. (1967). The antrum in patientswith duodenal and gastric ulcers. Gut, 8, 497-508.

Williams, A. W., Edwards, F., Lewis, T. H. C., and Coghill, N. F.(1957). Investigation of non-ulcer dyspepsia by gastric biopsy.Brit. med. J., 1, 372-377.

Wood, I. J., and Taft, L. I. (1958). Diffuse Lesions of the Stomach,p. 86. Arnold, London.

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