nature of the mucosal changes associated malignant neoplasms … · natureofthe mucosal changes...

Gut, 1966, 7, 361

Nature of the mucosal changes associated withmalignant neoplasms in the small intestine

F. D. LEE

From the University Department ofPathology, Western Infirmary,Glasgow

EDITORIAL COMMENT The author of this paper has again brought up the much discussed problem ofmalignant disease of the small bowel and its relation to idiopathic steatorrhoea. Whilst agreeingthat idiopathic steatorrhoea can be complicated by malignant disease he also feels that malignantdisease, and particularly small bowel lymphoma, can produce a mucosal abnormality similar tothat found in idiopathic steatorrhoea.

It has long been recognized that malabsorption maybe associated with lymphoid tumours in the smallintestine (Fairley and Mackie, 1937) but it is onlyrecently that it has been suggested that such tumoursmay arise as a complication of the primary mal-absorptive disorders' (Gough, Read, and Naish,1962). The evidence for this is almost entirely clinicalsince it has yet to be clearly demonstrated that themucosal abnormalities, which represent the onlydistinctive pathological feature of the primarymalabsorptive disorders, have been present for asignificant period before the onset of tumourgrowth, although they have been demonstrated inthe resected small bowel following operation(Spracklen, for Tonkin, 1963) and in intestinalbiopsies taken seven months before operation fortumour (Gough et al., 1962). It is possible that analteration in mucosal pattern in the small bowel maybe a response to the presence of a gross lesion, asituation comparable to the 'zonal gastritis' describedin relation to chronic peptic ulcer and carcinoma inthe stomach (Joske, Finckh, and Wood, 1955). If thiswere true, one might expect that mucosal abnor-malities would be found in association with anygross tumour of the small bowel regardless of itshistogenesis.The histopathology of the small intestine in a

series of resected malignant lymphoid tumours hasthus been compared with a closely matched series ofsmall-bowel adenocarcinomata. The marked diff-erence in the nature, severity, and extent of the muco-sal changes observed between the two groups would1 This term is applied to the three diseases, coeliac disease, idiopathicsteatorrhoea, and tropical sprue, as suggested by Girdwood, Delamore,and Williams (1961).

indicate that additional factors are operating inassociation with the lymphoid tumours to producemucosal abnormality. It is possible that a pre-existing malabsorptive disorder may have accountedfor the severe mucosal changes observed in onepatient who had a reticulosarcoma of the smallbowel resected following a seven-year history ofmal-absorption, and also in one patient with adeno-carcinoma of the jejunum. It is suggested, however,that in the majority of instances the lymphoidneoplasm is itself responsible for the mucosalabnormalities.

MATERIALS AND METHODS

A survey of all the surgically resected primary malignanttumours of the small intestine of lymphoid or adeno-carcinomatous type in the files of the Pathology Depart-ment of the Western Infirmary, Glasgow for the years1953-64 was undertaken. Those cases in which autolyticchange or inadequate material obviated adequate mucosalassessment were rejected, leaving nine cases available forstudy in each group. Where necessary blocks were re-cutand stained to provide satisfactory orientation of theintestinal mucosa and whenever possible extra blockswere taken to produce further information with regardto the extent of mucosal abnormality. Special stains wereonly employed to enable individual tumours to becorrectly classified within each group.The clinical records and operation notes were reviewed

in each case, particular attention being paid to anyfeature in the past history in any way suggestive ofintestinal malabsorption. The relevant clinical findingsin each group are recorded in the table, and aresummarized as follows:-

I MALIGNANT LYMPHOID NEOPLASM Of the nine patientsin this group, seven were males and two females, the

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F. D. Lee

average age at operation being 50 years with a range of32 to 70 years. The average duration of symptoms beforeoperation was six months with a range of one to 18months.

Perforation was the mode of presentation in sevencases, this being a not uncommon feature ofthesetumours(Irvine and Johnstone, 1955). Intestinal obstruction waspresent in three cases, being associated with perforationin case 3 and with intussusception in case 8. Multipletumours were noted in cases 4, 5, and 9. The tumour wasfound in the ileum in four cases, in the jejunum in three,and in the 'upper small bowel' in case 9. The site oftumour was not stated in case 2.Only in case 9 was malabsorption demonstrated before

operation. This patient, a 51-year-old male, had twothickened and adherent segments of upper small bowelresected following perforation of the proximal segment.Both pathological specimens revealed multiple infiltratingtumours which had penetrated the bowel wall to becomeadherent to adjacent loops of bowel. The patient gavea two-month history of intermittent abdominal painlocated in the left iliac fossa. He also had a seven-yearhistory of weight loss and diarrhoea with pale, offensivestools; and five years before operation, frank malab-sorption with steatorrhoea and severe megaloblasticanaemia had been demonstrated. The anaemia wascontrolled with folic acid and vitamin B12, but a six-month trial period on a gluten-free diet failed to inducea remission of the malabsorptive defect. Intestinal biopsywas not carried out at the time of the initial investigation,but subtotal villous atrophy of the intestinal mucosais noted histologically throughout both resected segmentsof small bowel.

In case 5 a hypochromic anaemia refractory to oraliron therapy was observed five years before the onset ofsymptoms clearly attributable to tumour growth. Mal-absorption could not, however, be confirmed clinically inthis case, nor was there a history of malabsorption inany of the remaining seven cases.Although all the tumours in this group are considered

to be primary in the small bowel, it is of interest that incase 3 a polypoid lymphosarcoma had been removedfrom the posterior nares nine months before resectionof the intestinal neoplasm, which could thus have beenof metastatic origin. Since the patient is, however, aliveand well nine years after operation it is possible that theintestinal tumour was in fact an independent primarygrowth.

II ADENOCARCINOMA There were six males and threefemales in this group, and the average age at operationwas 57 years with a range of 29 to 74 years. The averageduration of symptoms was 10 months, varying from sixweeks to two years. Intestinal obstruction was the usualmode of presentation, being present in five cases; inthree cases diarrhoea, weight loss, anid hypochromicanaemia with or without frank melaena were the pre-senting symptoms, and in case 18 the patient gave afive-year history of post-prandial epigastric discomfort,although frankly obstructive features with vomiting andmarked duodenal dilatation were observed before oper-ation. The tumour was solitary in every case (although

FIG. 1. Lymphosarcoma of ileum (case 1). Crypt abscessformation in the mucosa close to the tumour. Haemalum-eosin x 396.

FIG. 2. Lymphosarcoma of jejunum (case 7). Pyloricmetaplasia in the intestinal mucosa overlying the tumour.Haemalum-eosin x 165.

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Nature of the mucosal changes associated with malignant neoplasms in the small intestine

associated with an independent primary carcinoma of thecolon in case 16). The tumour was found in the ileum infour cases and in the jejunum in four; the site was notrecorded in case 10. There was no evidence of malab-sorption in the past history in any of the cases.

THE ASSESSMENT OF MUCOSAL ABNORMALITY The mucosalchanges in any individual case were referred to as 'partial'or 'subtotal' villous atrophy if they could not be distin-guished histologically from those described in the primarymalabsorptive disorders (Shiner and Doniach, 1960);and if they could be demonstrated in all parts of theintestinal mucosa whether close to or distant from thetumour site. In the evaluation of these changes, particularattention was paid to the presence of abnormalities inthe surface epithelium, and to increased plasma-cellinfiltration in the lamina propria.The mucosa was designated as 'normal' in all cases in

which the mucosal pattern was within normal limits inany of the blocks taken, even if the mucosa close to thetumour exhibited abnormalities. The term 'non-specificzonal inflammation' has been applied to strictly localizedchanges which are characterized by intense mucosalleucocytic infiltration, in which lymphocytes predomi-nate, occasional crypt abscesses with or without frankulceration (Fig. 1) and metaplasia of pyloric type (Fig. 2).The mucosal villi vary in appearance from beingthickened and enlarged to presenting features resem-bling villous atrophy, although of strictly localized type.Conversely some of the features of this 'zonal' inflam-mation may be superimposed on a generalized villousatrophy close to the tumour site (Fig. 2).

RESULTS

The incidence of mucosal abnormality observed inthe two forms of malignant tumour is recorded inthe Table. In the adenocarcinoma group, the mucosalpattern is considered to be essentially normal, withor without zonal inflammation, in seven cases. Theappearances in case 18 are, however, of considerableinterest in that subtotal villous atrophy of the mucosais observed both histologically (and with the dis-secting microscope) throughout the entire resected15-0 cm. segment of jejunum. In case 14, changes ofa generalized nature, corresponding to a mild partialvillous atrophy of the ileal mucosa, are seen.On the other hand, in only two cases in the lym-

phoid tumour group could the mucosa be considerednormal, and in one of these (case 3) it may bedoubted whether the tumour was primary in thesmall intestine. In the other six cases, generalizedvillous atrophy varying in severity from the partialvillous atrophy in case 7 (Fig. 3) to the frank sub-total villous atrophy in case 4 (Fig. 4) can be demon-strated. In case 9, as already indicated, the intestinalmucosa from two separate resections of the uppersmall bowel shows subtotal villous atrophythroughout.The irregular but widespread nature of the

'atrophic' process is revealed in case 5, in whichmultiple sections were taken from two separate

TABLEINCIDENCE OF MUCOSAL ABNORMALITY IN TWO TYPES OF MALIGNANT TUMOUR

Age Mode of Presentation Duration History ofof MalabsorptionSymptoms

Tumour Type Site of Small IntestinalTumour Mucosal Pattern

MFMM

32705155

PerforationPerforationPerforation and obstructionPerforation (multiple)

5 M 50 Perforation

FM

MM

49464651

PerforationIntestinal obstructionIntussusceptionPerforation

10 M 29 Diarrhoea, melaena, andweight loss

11 F 56 Intestinal obstruction12 M 74 Diarrhoea, hypochromic

anaemia, weight loss13 F 61 Intestinal obstruction14 M 65 Intestinal obstruction15 F 67 Intestinal obstruction16 M 37 Intestinal obstruction17 M 69 Diarrhoea, vomiting,

hypochromic anaemia18 M 53 Epigastric pain (intestinal

obstruction)'Marked plasma cell differentiation

21 wk.18 mth.20 wk.3 mth.

NoneNoneNoneNone

9 mth. Five-year historyof refractoryhypochromicanaemia

12 wk. None7 wk. None4 wk. None2 mth. Seven-year history

of steatorrhoeaand megaloblasticanaemia

2 yr. None

6 wk. None1 yr. None

6 wk. None7 wk. NoneUncertain None known6 mth. None2 yr. None

5 yr. None

Lymphosarcomal IleumReticulosarcoma Small bowelLymphosarcoma IleumReticulosarcoma Jejunum

(multiple)Lymphosarcoma Ileum

(multiple)

Reticulosarcoma JejunumLymphosarcoma JejunumLymphosarcomal IleumReticulosarcoma 'Upper small

bowel'

Subtotal villous atrophyPartial villous atrophyNormalSubtotal villous atrophy

Subtotal villous atrophy(irregular)

Partial villous atrophyPartial villous atrophyNormalSubtotal villous atrophy

Adenocarcinoma Small bowel Normal

Adenocarcinoma IleumAdenocarcinoma Jejunum

Adenocarcinoma JejunumAdenocarcinoma IleumAdenocarcinoma IleumAdenocarcinoma JejunumAdenocarcinoma Ileum

NormalNormal

NormalPartial villous atrophyNormalNormalNormal

Adenocarcinoma Jejunum Subtotal villous atrophy

Case SexNo.

234

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ZonalInflam-mation

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FIG. 3 FIG. 4

FIG. 3. Lymphosarcoma ofjejunum (case 7). Partial villous atrophy of the mucosa. The average villous height is 290t,and the surface epithelium is markedly abnormal. Haemalum-eosin x 150.

FIG. 4. Reticulosarcoma ofjejunum (case 4). Subtotal villous atrophy of the mucosa. Haemalum-eosin x 99.

, v~~~~~~~NFG X:.v

FIG. 5

FIG. 5. Reticulosarcoma ofjejunum (case 6). Partial villous atrophy of the mucosa undergoing transition to subtotalatrophy. The average height is 2951. Haemalum-eosin x 126.

FIG. 6. Lymphosarcoma of jejunum (case 7). Degenerative changes in the surface epithelium overlying a lymphoidfollicle. Haemalum-eosin x 146.

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Nature of the mucosal changes associated with malignant neoplasms in the small intestine

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FIG. 7. Lymphosarcoma of ileum (case 3). Fibrousthickening of the mucosal villi with the formation ofbizarre shapes, associated with marked submucosaloedema. Haemalum-eosin x 80.

FIG. 8. Lymphosarcoma of ileum (case 1). Atypicalplasma-cell differentiation in the tumour. Haemalum-eosinx 396.

ileal resections. Variations in the mucosal patternfrom partial to subtotal villous atrophy are alsonoted in the jejunum in case 6 (Fig. 5), in whichnumerous sections were taken far removed fromthe tumour site. A curious feature, observed in twocases (6 and 7), is the presence of marked abnor-mality of the surface epithelium overlying lymphoidaggregates in areas quite separate from the maintumour mass (Fig. 6).

In cases 3 and 10 the intestinal mucosa shows apeculiar abnormality in which the villi exhibitbizarre shapes due to localized fibrous thickeningof the lamina propria (Fig. 7). In both instancesintense mucosal oedema, probably due to lymphaticocclusion by tumour growth, was considered to beresponsible for the villous abnormality, which isthus regarded as a variant of the zonal type ofinflammation.

Within the group of malignant lymphoid neo-plasms, the tumour is classified as reticulosarcomain four cases and lymphosarcoma in three cases.The remaining two cases are less readily classified.The tumour in case 8 is predominantly a lympho-sarcoma but shows marked plasma-cell differen-tiation; this feature is also prominent in case 1 inwhich the neoplasm is composed almost entirely ofplasma cells or their precursors (Fig. 8). In neithercase, however, was there evidence of generalizedmyelomatosis, nor could plasma-cell differentiationin a lymphoid neoplasm be correlated with thepresence of mucosal atrophy.

DISCUSSION

This comparison between the two major groups ofprimary malignant tumours in the small intestinewas undertaken initially to determine whether themucosal changes associated with such tumourscould be attributed solely to non-specific localfactors such as intestinal obstruction, stasis, oedema,and secondary infection of the bowel wall in thevicinity of the tumour. If this were the case thenature and extent of these changes would not berelated so much to the histogenesis of the tumour asto its mechanical effects, and one would expectthem to be more marked in the adenocarcinomagroup, in which intestinal obstruction was a moreprominent clinical feature. Whilst 'zonal' changes,no doubt due to mechanical factors, are observedin both groups, the high incidence of generalizedvillous atrophy in the group of lymphoid tumourscannot be explained readily on this basis. Suchwidespread mucosal abnormalities could, however,take origin either from a pre-existing malabsorptivedisorder such as idiopathic steatorrhoea or be

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related to the presence of tumour in some lessdirect way.Gough et al. (1962) reported three cases which

indicated that intestinal reticulosis may developas a complication of idiopathic steatorrhoea, andSpracklen, for Tonkin (1963), described a furthercasesupporting this conclusion. On the other hand,Eakins, Fulton, and Hadden (1964) drew attention tothe relatively short duration of clinically recognizedmalabsorption in many cases of intestinal reticulosisand considered that in some cases at least the tumouritself is responsible for malabsorption. The possibilitycannot be excluded therefore that, in those cases ofintestinal reticulosis in which malabsorption is due toa pre-existing primary malabsorptive disorder, theassociation is fortuitous. If this were true, it might beexpected that adenocarcinoma would also complicateidiopathic steatorrhoea on occasion, since lymphoidneoplasms comprise only 50% of primary malignanttumours in the small bowel (Skrimshire, 1955).This appears to be the case. Joske (1960) describeda case of jejunal adenocarcinoma associated with'atrophic jejunitis' and malabsorption and referredto a similar instance in the Case Records of theMassachusetts General Hospital (1958). Girdwoodet al. (1961) described the coexistence of subtotalvillous atrophy in a jejunal biopsy, malabsorption,and an anaplastic carcinoma 70 cm. below the duo-deno-jejunal junction; and Moertel and Hargraves(1961) have also reported a case in which jejunaladenocarcinoma complicated long-standing mal-absorption, and was associated with villous atrophyof the jejunal mucosa. It may well be that case 18in my series represents a fifth example of jejunaladenocarcinoma complicating idiopathic steator-rhoea in a clinicallyasymptomatic phase;the mucosalabnormalities in this case certainly form astriking contrast to the relatively normal mucosaobserved in the other cases of small-bowel carci-noma. It is also possible that in case 9, in whichreticulosarcoma of the small bowel was associatedwith a seven-year history of malabsorption andsubtotal villous atrophy of the intestinal mucosa, asimilar situation may pertain. Nevertheless, al-though it cannot be doubted that malignant tumoursmay complicate one or other of the primary mal-absorptive disorders, this association does not seemto provide a satisfactory explanation for the presenceof mucosal atrophy in six out of the eight other ran-dom selected cases of intestinal lymphoid tumour inthe present series. Although the absence of clinicallyrecognized malabsorption in these cases is of doubt-ful significance, it accords with general experience ofintestinal lymphoid neoplasms; malabsorption wasnot recorded either in the series of cases reported bySkrimshire (1955) or in the large series of cases

reviewed by Rosenberg, Diamond, Jaslowitz, andCraver (1961). It may be added that subtotal villousatrophy of the ileal mucosa, observed in cases 1 and 5in my series, would be an improbable finding inasymptomatic sprue, since even in active cases thelesions are said to be less severe in the ileum than inthe proximal small bowel (Rubin, 1960).The alternative possibility that an intestinal

tumour may in some indirect way bring aboutwidespread mucosal abnormality must thereforebe seriously considered. It is well recognized thattumours originating in lymphoid tissue may giverise to immunological disturbances, auto-immunehaemolytic anaemia being perhaps the most out-standing example (Dacie, 1962). Since a hyper-sensitivity mechanism may be of importance in thepathogenesis of coeliac disease and idiopathicsteatorrhoea (see Taylor, Thomson, Truelove, andWright, 1961), it is possible that an intestinal lym-phoid tumour (perhaps reflecting more widespreadabnormality of the intestinal lymphoid tissue)could by a similar mechanism bring about a com-parable mucosal abnormality. The development ofclinical malabsorption would then depend upon theextent or site of the mucosal damage. The relation-ship between epithelial abnormality and lymphoidaggregates observed in cases 6 and 7 might representthe morphological expression of the role oflymphoid tissue in bringing about mucosal damage.Although this hypothesis is largely speculative, itmay be capable of being subjected to clinical andexperimental investigation. The relationship betweenintestinal neoplasms and the malabsorption syn-drome, however, is likely to be complex and may befinally settled only by the long term follow-up ofpatients proven by intestinal biopsy to be sufferingfrom one or other of the primary malabsorptivedisorders; and by careful pathological study of theresected tumours and of the environment in whichthey arise.

SUMMARY

A high incidence of partial or subtotal villousatrophy of the intestinal mucosa has been demon-strated in a series of resected primary malignantlymphoid tumours of the small bowel. These mucosalchanges are much less common in a closely-matchedseries of small-intestinal adenocarcinomata, andcannot readily be attributed to local mechanicalfactors. In two patients, one with jejunal adeno-carcinoma and one with reticulosarcoma of thesmall bowel, the mucosal changes may have beendue to a pre-existing primary malabsorptive disorder.In the majority of cases, however, it is postulatedthat the mucosal abnormalities are brought about

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Nature of the mucosal changes associated with malignant neoplasms in the small intestine 367

by the malignant lymphoid tumour, possibly as aresult of immunological disturbances.

I wish to thank Mr. D. B. Brown, Professor A. W. Kay,and Mr. A. B. Kerr for permission to study their patients.My thanks are also due to Mr. N. Russell for his technicalassistance, and to Mr. G. Kerr for taking the photo-micrographs.

REFERENCES

Case records of the Massachusetts General Hospital (1958). Case44362. New Engl. J. Med., 259, 491-495.

Dacie, J. V. (1962). The Haemolytic Anaemias, Congenital and Ac-quired, part 2-The Auto-Immune Haemolytic Anaemias,2nd ed. Churchill, London.

Eakins, D., Fulton, T., and Hadden, D. R. (1964). Reticulum cellsarcoma of the small bowel and steatorrhoea. Gut, 5, 315-323.

Fairley, N. H., and Mackie, F. P. (1937). The clinical and biochemicalsyndrome in lymphadenoma and allied diseases involving themesenteric lymph glands. Brit. med. J., 1, 375-380.

Girdwood, R. H., Delamore, I. W., and Williams, A. W. (1961).Jejunal biopsy in malabsorptive disorders of the adult. Ibid.,1, 319-323.

Gough, K. R., Read, A. E., and Naish, J. M. (1962). Intestinal reti-culosis as a complication of idiopathic steatorrhoea. Gut, 3,232-239.

Irvine, W. T., and Johnstone, J. M. (1955). Lymphosarcoma of thesmall intestine, with special reference to perforating tumours.Brit J. Surg., 42, 611-618.

Joske, R. A. (1960). Primary carcinoma of the jejunum with atrophicjejunitis and intestinal malabsorption. Gastroenterology,38, 811-816.

-, Finckh, E. S., and Wood, I. J. (1955). Gastric biopsy. A studyof 1,000 consecutive successful gastric biopsies. Quart. J. Med.,24, 269-294.

Moertel, C. G., and Hargraves, M. M. (1961). Coexistence of adeno-carcinoma ofthe jejunum and nontropical sprue. J. Amer. med.Ass., 176, 612-614.

Rosenberg, S. A., Diamond, H. D., Jaslowitz, B., and Craver, L. F.,(1961). Lymphosarcoma: a review of 1,269 cases. Medicine(Baltimore), 40, 31-84.

Rubin, C. E. (1960). Celiac disease and idiopathic sprue. Somereflections on reversibility, gluten, and the intestine. Gastro-enterology, 39, 260-261.

Shiner, M., and Doniach, I. (1960). Histopathologic studies in stea-torrhoea. Ibid., 38, 419-440.

Skrimshire, J. F. P. (1955). Lymphoma of the stomach and intestine.Quart. J. Med., 24, 203-214.

Spracklen, F., for Tonkin, R. D. (1963). Reticulosis of the smallbowel as a late complication of idiopathic steatorrhoea. Proc.roy. Soc. Med., 56, 167-168.

Taylor, K. B., Thomson, D. L., Truelove, S. C., and Wright, R. (1961).An immunological study of coeliac disease and idiopathicsteatorrhoea: serological reactions to gluten and milk proteins.Brit. med. J., 2, 1727-1731.

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