J Clin Pathol 1980;33:801-810

Role of intestinal metaplasia in the histogenesis ofgastric carcinomaJR JASS

From the Department of Histopathology, Westminster Medical School, Horseferry Road, LondonSWIP 2AR, UK

SUMMARY Recent evidence suggests that intestinal metaplasia (IM) cannot be regarded as a singleentity. A simple classification of IM and its variants based on histological and mucin histochemicalcriteria was devised, and the incidence of IM subtypes in cancerous and benign gastrectomyspecimens was recorded. A particular subtype was associated with 'intestinal' cancers but not withtumours considered to arise in normal gastric epithelium (P < 0-01) or with benign lesions (P < 0 01).This subtype appeared to lack absorptive cells at light microscopic level and secreted both neutraland acid mucins, including marked amounts of sulphomucin but no O-acetyl sialomucin.

Intestinal metaplasia (IM) is usually a highly differ-entiated epithelium resembling small intestine asindicated by mucinl 2 and enzyme histochemistry3 4and ultrastructural studies.5 6 Variants of thisclassical form have been described, and severalauthors have suggested that these could play a specialrole in the development of gastric carcinoma.7-11The variants fall into two main groups: an incompletetype shows features of both gastric and smallintestinal epithelia,8 12 13 whereas a 'colonic' type hasacquired characteristics of large intestine includingenzymes14 and mucins.9-11 The present study wasdesigned to examine further the significance andinterrelationships of these variants.

Material and method

The stomachs examined were resected from patients

Received for publication 24 January 1980

attending Westminster Hospital. They included48 unselected gastric carcinomas and a selectedgroup of 25 benign specimens (gastric and duodenalulcers) showing extensive IM.The specimens were opened and pinned out on to

cork mats for preliminary fixation in 10% bufferedformol-saline. After further fixation serial blocks or

swiss-rolls were taken along the lesser curvature,greater curvature, anterior wall, and posterior wall.Additional blocks around any lesion were also taken.Six serial sections were cut from each block andstained by haematoxylin and eosin, diastase-periodic acid Schiff (D-PAS), Alcian blue (AB)pH 2-5/PAS, and high iron diamine/AB. Slides wereselected from 16 cases showing extensive IM forstaining by the periodate borohydride/KOH/PASmethod. Further details of these procedures aregiven in Table 1.An attempt was made to classify carcinomas into

two groups using the points system outlined in

Table 1 Special methods and their interpretation

Method Interpretation

Diastase-periodic acid Schiff (D-PAS)15 Magenta Neutral mucinsSome sialomucins

Negative SulphomucinsO-acetyl sialomucins

Periodate-borohydride (PB)/KOH/PAS'* Magenta O-acetyl sialomucinsNegative All other mucins

Alcian blue (AB) pH 2 5/PAS1s Blue SulphomucinsO-acetyl sialomucins

Purple PAS positive acid mucins or mixtures ofneutral and acid mucins

Magenta Neutral mucinsHigh iron diamine (HID)/AB pH 2-517 Brown Sulphomucins

Blue Sialomucins

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Table 2. Tumours scoring + 4 to + 8 were regardedas 'intestinal', and those scoring -9 to + 3 as'gastric'. The criteria for this scoring method werederived largely from the observations of LaurdnU8and Ming.19The extent of IM was graded in each section, as

shown in Table 3. Both morphological and histo-chemical criteria were used to classify IM and itsvariants. Complete IM was characterised by thepresence of goblet cells secreting acid mucins andabsorptive cells showing a well-developed brushborder (Fig. 1). This was designated type I IM.Incomplete IM again comprised goblet cells secret-ing acid mucins but apparently no mature absorptivecells, their place being taken by columnar mucouscells. When these cells secreted mostly neutralmucins, the epithelium (essentially a simple hybridof gastric and small intestinal mucous cells) wastermed type IIA (Fig. 2). When sulphomucins wereabundant in the columnar cells, the variant wasdesignated type IIB (Fig. 3). Cell heights of the IMsubtypes were measured in each case. Five readingswere taken at the mid portion of a typical crypt andthe average height was recorded. In the following theterm 'IM' without qualification refers to any type orcombination of types.

Table 2 Points system for classifying gastriccarcinoma

Extensive IM around tumour +3Little or no IM -3Other patterns of IM 0Expanding growth +2Infiltrating growth -2Expanding and infiltrating 0Tubular differentiation + 2Little tubular differentiation -2Acid m icins predominate + IAbsence of mucus secretions + INeutral mucins predominate -Mucins mainly confined to signet ring cells -

+4 to +8 'intestinal'.-9 to + 3 'gastric'.

Table 3 Grading of intestinal metaplasia

Little or none +/0 (<5,%)Moderate + + (5-20%)Extensive + + + (20-100%)

Results

Using the points system indicated in Table 2, it waspossible to divide the 48 carcinomas into 23'intestinal' and 25 'gastric' types. This was an attemptat a histogenetic classification, the terms 'intestinal'and 'gastric' implying the likely precursor epi-thelium. All 23 'intestinal' cancers were associated

Jass

with extensive IM, but this was found in only sevenof the 'gastric' cases.Complete or type I IM (Fig. 1) usually resembled

small intestine though villi were rarely well developedand the ratio of goblet cells to absorptive cells wasvariable. Sometimes goblet cells were numerous inthe lower half of crypts, conferring a likeness tocolonic mucosa. However, the mucin histochemistrymostly resembled small intestine with N-acetylsialomucins predominating. In the majority of casesthe occasional crypt contained a mixed population ofgoblet cells, some secreting 0- and some N-acetylsialomucins (Table 4). In one case (an 'intestinal'cancer scoring + 4), the secretion of O-acylatedsialomucins was marked (Fig. 4). Sulphomucinswere detected only patchily in type I IM.Type TTA IM (Fig. 2) comprised intestinal goblet

cells and columnar shaped mucous cells. The gobletcells secreted N-acetyl sialomucins and occasionallya sulphomucin, but, unlike type 1, no 0-acetylsialomucins (Table 4). The bordering columnar cellssecreted mainly neutral mucins. The secretarymaterial was either limited to the cell apex oroccupied the whole cell. Sometimes small amountsof N-acetyl sialomucin were also present, butsulphomucins were encountered as a trace if at all.Cells at the base of the crypts secreted droplets ofsulphomucin at times but appeared to lose thiscapacity as they matured. Paneth cells were rarelyobserved.Type TIB IM resembled TTA in showing incom-

plete differentiation. Thus goblet cells were againbordered by columnar mucous cells instead ofabsorptive cells. However, the columnar cellssecreted marked amounts of sulphomucin. Thesecells were often distended with mucus and only withspecial stains distinguished easily from adjacentintestinal goblet cells which usually produced asialomucin (Fig. 3). With haematoxylin and eosinthis epithelium frequently resembled hyperplasticcolonic mucosa. This feature, together with thesulphomucin secretion and rarely observed Panethcells, invited the term 'colonic metaplasia'. However,unlike normal colonic mucosa, there was nosecretion of O-acylated sialomucin (Table 4) (Fig. 5).The mucin histochemistry of IM and its variants issummarised in Figure 6. There were also structuralfeatures distinguishing types TTA and TTB IM. Theoverall architecture of TIB mucosa tended to bemore irregular. The crypts were elongated, tortuous,and branched, and papillary formations werenumerous. The cells lining TIB crypts were tallerthan those of TTA (see below).

Increased sulphomucin secretion was noted inother sites. Branched glands lined by a low columnarepithelium and arising at the base of intestinalised

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Role of intestinal metaplasia in the histogenesis ofgastric carcinoma

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(b)Fig. 1 (a) H and E. (b) HID/A B. Complete or type I intestinal metaplasia. The crypts are lined byabsorptive cells and goblet cells. The latter secrete sialomucins only. A well-developed brush border is shown(x 450).

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Role of intestinal metaplasia in the histogenesis of gastric carcinoma

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Fig. 3 (a) H and E. (b) HID/AB. Type JIB intestinal metaplasia. The presence of two types of mucous cell isnot obvious with H and E. With HID/AB the larger goblet cells secrete sialomucins and the intervening lessdistended cells secrete sulphomucins. There is no well-developed brush border ( x 450).

Table 4 Incidence ofPB/KOH/PAS positive staining invariants ofIM

IM type Incidence of type in 16 cases PB/KOH/PAS positiveshowing extensive IM goblet cells

I 14 1211A 4 0IIB 4 0

crypts (IIA or IIB usually) sometimes secretedsulphated material. Sulphomucins (and sialomucins)were also seen in sites not showing obvious IM asjudged histologically, such as in dilated acini or inthe lower half of antral crypts (possibly representingincipient IM). Very occasionally apparently normalsurface epithelium bordering gastric cancer showedsulphomucin secretion. Finally, sulphomucins were

frequently observed in dysplastic and carcinomatousepithelia. In cancers this was usually encounteredas an extracellular secretion, either glycocalyceal,

intraluminal, or in pools. O-acylated sialomucinswere not observed in any of these sites.The cells comprising type IIB IM were taller than

those of type IIA, which were in turn taller thanthose of type I. The mean cell heights of IIB, IIA,and I were 39 1km, 30 ,4m, and 23 /im. The differencebetween the mean cell height of type IIB and type IIAwas significant, as was the difference between IIAand I (P < 0-02 and < 0001, respectively). Cellheight was also more variable in IIB than in IIAor I, as indicated by the respective standard deviations(13 ,pm, 7 ,um, and 4 ,pm). The incidence of IM andits variants in specimens showing extensive IM isgiven in Table 5. Type I IM was found in the majorityof cases, but two cancers showed IIB only and twogastric ulcers IIA only. The association of type IIBIM with 'intestinal' cancers appeared to be significantwhen compared with either 'gastric' cancers(P < 0 01) or benign specimens (P < 0 01). More-over, type IIB IM was always most marked in theepithelium immediately bordering cancers. None of

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Fig. 4 (a) PAS. (b) PB/KOH/PAS. Type I intestinal metaplasia (left) and normal gastric mucosa (right).The goblet cells are more numerous than the example shown in Fig. 1, but absorptive cells with awell-developed brush border are present. Only the goblet cells are stained by the PB/KOH/PAS method,indicating secretion of O-acylated sialomucins ( x 115).

Jass

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(b)Fig. 5 (a) PAS. (b) PB/KOH/PAS. Type IIB itutestinal ietaplasia. Thier-e is no secr'etiotn of O-acylatedsialomlcinis (x 115).

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TYPE I-0

TYPE lHa

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TYPE fb 0

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Fig. 6 Diagram summarising the mucin histochemistryof intestinal metaplasia and its variants. neutralmucins; CD sialomucins; C, O-acetyl sialomucins;* sulphomucins.

Table 5 Incidence ofIM subtypes in cases showingextensive IM

IM type 'Intestinal' 'Gastric' Benigncancers cancers lesions

Extensive 23 7 25I 21 7 23IA 6 1 13IIB 17 0 2

the other variants showed any significant associationwith the cancerous specimens. The high incidence oftype IIA IM in benign cases appeared significantwhen compared to the incidence in malignant casestaken as a whole (P < 0-05). The association of

O-acylated sialomucins with type I IM but not withIIA and IIB also appeared to be significant (P < 0 01).

Discussion

Morphological,20 21 epidemiological,22 and prospec-tive studies23 24 suggest that intestinal metaplasia(IM) may be a premalignant lesion. It is generallyaccepted that only a proportion of gastric cancersarise from IM. These apparently form a well-defined group showing tubular differentiation and anexpanding as opposed to a diffuse pattern ofgrowth.'8 19 25 However, several authors havepointed out that 'intestinal' differentiation in atumour need not always indicate an origin from anintestinalised mucosa.3 4 13 26 27 An attempt at ahistogenetic classification was made in the presentstudy in which importance was attached to thepresence of IM around tumours (Table 2). Thuscarcinomas showing 'intestinal' differentiation butlittle or no IM in the adjoining mucosa were notincluded in the 'intestinal' group.While it is acknowledged that some gastric

cancers may arise from IM, there are certain objec-tions to calling IM premalignant. Firstly, it is a highlydifferentiated mucosa resembling small intestinemorphologically 6 and histochemically.1-4 Secondly,it is an extremely common finding.20 28 An answer toboth these objections may be provided by the recentdemonstration of incomplete variants of IM. Inthese, absorptive cells either show incompletedifferentiation8 13 or are apparently absent at lightmicroscopic level, their place being taken by simplemucous cells.8 10 13 Small intestinal enzymes, suchas alkaline phosphatase and aminopeptidase (nor-mally present along the brush border of absorptivecells), are reduced in amount or absent." 14 29 Inaddition to these negative findings, some variantsappear to have acquired colonic characteristics,including enzymes'4 and mucins.9-Y1 Several authorshave indicated that IM variants could play a specialrole in the histogenesis of gastric cancer.7-11 30Complete or type I IM was not entirely uniform

in its differentiation since 'colonic' mucins, includingsulphomucins and O-acetyl sialomucins,31 werefrequently demonstrated, though in small amounts.In one case, however, O-acetyl sialomucin wasmarked (Fig. 4). This variant of type I IM isprobably synonymous with one description of'colonic' metaplasia occurring as scattered foci incases of 'intestinal' cancer.9 While such anomalousdifferentiation may be associated with 'intestinal'cancers, the results of the present study do notsupport a direct histogenetic link between thisvariant and cancer. Type IIA IM, a simple hybridof gastric and small intestinal epithelia, is syn-

Ja~s.

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Role of intestinal metaplasia in the histogenesis ofgastric carcinoma 809

onymous with the well-documented partial orincomplete IM.6 813 There was no associationbetween this type and cancer. Type IIB is probablyat least in part synonymous with 'enterocolic'metaplasiall and was associated with 'intestinal'cancers but not with 'gastric' cancers or benignspecimens showing extensive IM.

It is not certain whether enzyme studies candifferentiate between types IIA and IIB. Absorptivecells may be present in IIA but show incompletedifferentiation with only a partially developedbrush border.813 Intestinal enzymes may then bepresent, though perhaps reduced in amount. Anincomplete variant lacking small intestinal enzymesbut producing cytoplasmic 'colonic' enzymes hasbeen described.14 It remains to be shown whether thisis synonymous with type IIB IM.Apart from its association with gastric cancer,

what evidence is there to suggest that type IIB IMmay be premalignant ? It is unlikely to be a secondaryreactive phenomenon to tumour growth because ofits association with 'intestinal' cancers but not'gastric' cancers. Furthermore, gastric adenomatouspolyps and dysplastic change appear to arise intype hIB IM.30 Also of relevance is a strikinghistological and histochemical similarity betweentype IIB IM and the columnar epithelium of Barrett'soesophagus.32 On the other hand, while type IIBIM may be described as hyperplastic (being com-posed of crowded elongated cells) and showingincomplete differentiation, it is not obviouslydysplastic. Interestingly, hyperplasia has beendescribed as an early change in various sites ofexperimental carcinogenesis, such as colon33 andsmall intestine34 35 as well as stomach.36 37 Moreover,in the rat stomach, hyperplasia is accompanied byaltered patterns of mucin secretion, with increasedproduction of acid mucins including sulphomucins.37Also of relevance is the description of tumourantigens in 'normal' mucosa bordering gastriccancer. These include alpha fetoprotein,38 carcino-embryonic antigen,39 40 and goblet cell antigen4'all found within IM. It is not clear whether a fourthtumour marker, termed fetal sulphoglycoproteinantigen, also occurs in a metaplastic epithelium.42However, it has been suggested that this could berelated to the sulphomucin of type hIB IM.30 Thusthere are grounds for regarding type IIB IM as apremalignant change, and a prospective study is nowin progress to confirm or refute this.

This work was supported by a grant from theWestminster Joint Research Committee. I thankDr MI Filipe for her help and guidance, the lab-oratory staff for preparing the numerous sections,and Mrs A Leaver for typing the manuscript.

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Requests for reprints to: Dr JR Jass, Department ofHistopathology, Westminster Medical School, HorseferryRoad, London SW]P 2AR, UK.

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