Primary Crohn's disease the colon and rectum' · Primary Crohn's disease of the colon and rectum'...

13
Gut, 1961, 2, 189 Primary Crohn's disease of the colon and rectum' J. S. CORNES AND METTE STECHER From the Department of Clinical Pathology, Westminster Medical School, London University, the Gordon Hospital, London, and the Research Department, St. Mark's Hospital, London SYNOPSIS Crohn's disease of the large bowel has been increasingly recognized and this paper presents a clinical and pathological study of 45 patients in whom the disorder was confined entirely to the large intestine. The clinical and pathological factors are contrasted with those of 86 patients with regional ileitis and of 200 patients with ulcerative colitis. Compared with regional ileitis the disease occurred in an older age group, had a different sex distribution, and a higher incidence of perianal and rectovaginal fistulae. A high incidence of recurrent disease following surgical treatment, found in the patients with regional ileitis, was not found in the patients with primary Crohn's disease of the large intestine. The incidence of the disease relative to ulcerative colitis was approximately 60%. The disease had the same sex distribution as ulcerative colitis but occurred in an older age group. The disease was usually of gradual onset and continuous course, and periods of freedom lasting a month or more were uncommon. The patients came to surgery much earlier than patients with ulcerative colitis. This study began with the examination of a small number of specimens of the large intestine showing many of the pathological features of regional ileitis described by Hadfield (1939), Warren and Sommers (1948). and Rappaport, Burgoyne, and Smetana (1951). The terminal ileum, however, was not in- volved in any of these cases and the usual pre- operative diagnosis was idiopathic ulcerative colitis. Although the first 13 cases of regional ileitis reported by Crohn, Ginzburg, and Oppenheimer in 1932 affected only the terminal ileum it was soon appreciated that the proximal ileum and jejunum could also be involved (Harris, Bell, and Brunn, 1933), and that the disease might be confined entirely to the jejunum (Brown, Bargen, and Weber, 1934). Involvement of the colon was first reported by Colp in 1934, and later by Donchess and Warren (1934), by Brown et al. (1934), by Crohn and Rosenak (1936), and by others. Recognition of the disease arising primarily in the large intestine has been retarded by a confusion in nomenclature, by the difficulty in clinical distinction from ulcerative colitis, and by the failure to base published series on adequately studied pathological material. Some pathologists do not distinguish between regional ileitis, regional colitis, and ulcera- 'Based on a lecture given in a series of talks on 'Current Pathology' at Westminster Medical School on 27 February 1961. tive colitis, regarding them all as variants of an essentially similar process manifesting itself in different areas of the bowel (Lumb, 1951; Gold- graber, Kirsner, and Palmer, 1959; Lumb and Protheroe, 1958). However, the pathological features of regional ileitis and ulcerative colitis are sufficiently dissimilar for a clear-cut distinction to be made between these two conditions in the vast majority of cases (Rappaport et al., 1951; Warren and Sommers, 1954; Lockhart-Mummery and Morson, 1960). The confusion in nomenclature has arisen from the use of the words 'regional' or 'segmental ' colitis to cover all cases of non-specific chronic inflamma- tion of the large intestine in which the rectum, recto- sigmoid, and terminal ileum are not primarily involved (Neuman, Bargen, and Judd, 1954). Defined in this way the term 'regional' colitis embraces at least three different types of disease, namely, ulcera- tive colitis, secondly a disease with pathological features similar to regional ileitis, and thirdly a disease which fails to show the characteristic patho- logical features of either regional ileitis or ulcerative colitis. This last type probabiy represents a group of unrecognized disorders. To overcome the difficulty of nomenclature Harris et al. used the term 'cicatrizing enteritis' to cover all cases with similar clinical and pathological features to the cases of regional ileitis described by Crohn et 189 on December 13, 2020 by guest. Protected by copyright. http://gut.bmj.com/ Gut: first published as 10.1136/gut.2.3.189 on 1 September 1961. Downloaded from

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Page 1: Primary Crohn's disease the colon and rectum' · Primary Crohn's disease of the colon and rectum' J. S. CORNESANDMETTESTECHER From the Department ofClinical Pathology, Westminster

Gut, 1961, 2, 189

Primary Crohn's disease of the colon and rectum'

J. S. CORNES AND METTE STECHER

From the Department of Clinical Pathology, Westminster Medical School, London University, the GordonHospital, London, and the Research Department, St. Mark's Hospital, London

SYNOPSIS Crohn's disease of the large bowel has been increasingly recognized and this paperpresents a clinical and pathological study of 45 patients in whom the disorder was confined entirelyto the large intestine. The clinical and pathological factors are contrasted with those of 86 patientswith regional ileitis and of 200 patients with ulcerative colitis. Compared with regional ileitis thedisease occurred in an older age group, had a different sex distribution, and a higher incidence ofperianal and rectovaginal fistulae. A high incidence of recurrent disease following surgical treatment,found in the patients with regional ileitis, was not found in the patients with primary Crohn's diseaseof the large intestine. The incidence of the disease relative to ulcerative colitis was approximately60%. The disease had the same sex distribution as ulcerative colitis but occurred in an older age

group. The disease was usually of gradual onset and continuous course, and periods of freedomlasting a month or more were uncommon. The patients came to surgery much earlier than patientswith ulcerative colitis.

This study began with the examination of a smallnumber of specimens of the large intestine showingmany of the pathological features of regional ileitisdescribed by Hadfield (1939), Warren and Sommers(1948). and Rappaport, Burgoyne, and Smetana(1951). The terminal ileum, however, was not in-volved in any of these cases and the usual pre-operative diagnosis was idiopathic ulcerative colitis.Although the first 13 cases of regional ileitis

reported by Crohn, Ginzburg, and Oppenheimer in1932 affected only the terminal ileum it was soonappreciated that the proximal ileum and jejunumcould also be involved (Harris, Bell, and Brunn,1933), and that the disease might be confined entirelyto the jejunum (Brown, Bargen, and Weber, 1934).Involvement of the colon was first reported by Colpin 1934, and later by Donchess and Warren (1934),by Brown et al. (1934), by Crohn and Rosenak (1936),and by others.

Recognition of the disease arising primarily in thelarge intestine has been retarded by a confusion innomenclature, by the difficulty in clinical distinctionfrom ulcerative colitis, and by the failure to basepublished series on adequately studied pathologicalmaterial. Some pathologists do not distinguishbetween regional ileitis, regional colitis, and ulcera-'Based on a lecture given in a series of talks on 'Current Pathology'at Westminster Medical School on 27 February 1961.

tive colitis, regarding them all as variants of anessentially similar process manifesting itself indifferent areas of the bowel (Lumb, 1951; Gold-graber, Kirsner, and Palmer, 1959; Lumb andProtheroe, 1958). However, the pathological featuresof regional ileitis and ulcerative colitis are sufficientlydissimilar for a clear-cut distinction to be madebetween these two conditions in the vast majority ofcases (Rappaport et al., 1951; Warren and Sommers,1954; Lockhart-Mummery and Morson, 1960).The confusion in nomenclature has arisen from

the use of the words 'regional' or 'segmental ' colitisto cover all cases of non-specific chronic inflamma-tion of the large intestine in which the rectum, recto-sigmoid, and terminal ileum are not primarilyinvolved (Neuman, Bargen, and Judd, 1954). Definedin this way the term 'regional' colitis embraces atleast three different types of disease, namely, ulcera-tive colitis, secondly a disease with pathologicalfeatures similar to regional ileitis, and thirdly adisease which fails to show the characteristic patho-logical features of either regional ileitis or ulcerativecolitis. This last type probabiy represents a group ofunrecognized disorders.To overcome the difficulty of nomenclature Harris

et al. used the term 'cicatrizing enteritis' to cover allcases with similar clinical and pathological featuresto the cases of regional ileitis described by Crohn et

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J. S. Cornes and Mette Stecher

al. Crohn and his colleagues, however, use the term'granulomatous colitis' to describe cases of regionalileitis with colonic involvement in which the patho-logical features of the disease in the colon and ileumare identical (Crohn and Yarnis, 1958). Although'cicatrizing enteritis' and 'granulomatous colitis' areuseful terms they do not adequately describe theimportant and characteristic features of this disease.Cicatrizing enteritis can be found in a number ofchronic inflammatory disorders (Lumb, 1951), andgranulation tissue may be found in the superficialsubmucosa in the healing phase of ulcerative colitis(Dukes, 1954). Wells (1952), describing cases ofregional colitis characterized by fibrosis, non-caseat-ing tubercles, and multinucleated giant cells, calledthe condition 'Crohn's disease of the colon'. Becausethis eponymous title conveys a much fuller meaningthan any other term previously employed it hasbecome justly popular with British surgeons andpathologists, and is now an accepted part of ourterminology (Dukes and Lockhart-Mummery, 1957;Brooke, 1959; Watkinson, Thompson, and Goligher,1960; Lockhart-Mummery and Morson, 1960;Nevin, 1961).Although Crohn's disease of the colon associated

with regional ileitis is now a well recognized clinicaland pathological entity, very few cases of Crohn'sdisease arising primarily in the large intestine and inwhich the small intestine was apparently normal havebeen reported in the literature. In retrospect some ofthe cases reported by Moynihan (1907), Robson(1908), Braun (1909), Dalziel (1913), Lawen (1914),Tietze (1920), and Moschcowitz and Wilensky (1923)were probably examples of primary Crohn's diseaseof the large intestine. Well-documented case reportsof this type of disease have been published by James(1938) and by Castleman (1944). Brooke (1959)reported seven cases, in two of which the diseaserecurred in the small intestine after total proctoco-lectomy. Lockhart-Mummery and Morson (1960)have recently described 18 cases of primary Crohn'sdisease of the large intestine and seven cases ofregional ileitis with large intestinal involvement.

It is sometimes assumed that primary Crohn'sdisease of the large intestine occurs in the same typeof patient as regional ileitis, and that the clinicalbehaviour of the disease in the large intestine issimilar to that in the small. Goligher (1961) statesthat there is no reason to suppose Crohn's diseaseloses its notorious predilection to recurrence becauseit happens to have transferred its habitat from thesmall intestine to the large. Dukes (1959), however,believes that a careful distinction should be madebetween cases of primary Crohn's disease of thelarge intestine and cases of regional ileitis with orwithout colonic involvement. This study was under-

taken to see if this distinction was worth making, toassess the incidence of primary Crohn's disease ofthe large intestine relative to ulcerative colitis, and tocompare the clinical and pathological features ofthese cases with cases of regional ileitis and ulcerativecolitis.

CASES STUDIED

This study is based on 45 patients suffering fromprimary Crohn's disease of the large intestine treatedby surgical resection from whom parts or all of thelarge intestine were available for pathologicalexamination. Only patients in whom the small in-testine was shown to be free from disease by radio-logical examination, inspection at operation, andhistological examination of the resected portion ofthe terminal ileum when it was present in the opera-tion specimen, were included in this group. Therewas no evidence of active tuberculosis or sarcoidosis,and no acid-fast bacilli could be found in the stoolsor in sections from lesions in the large intestine andregional lymph nodes. Strict histological criteriawere used in the diagnosis of Crohn's disease, andonly those patients with a non-specific chronic in-flammatory reaction affecting the submucosa,muscle coats and subserosa, associated with fibrosisand the presence of non-caseating nodules ofepithelioid histiocytes in the wall of the largeintestine or regional lymph nodes, were included.For comparison a study was made of 86 patients

with regional ileitis who had been treated by surgicalresection and from whom operation specimens wereavailable for pathological examination.To assess the incidence of primary Crohn's disease

of the large intestine relative to ulcerative colitis astudy was made of 200 consecutive patients withproved ulcerative colitis treated by colectomy at theGordon Hospital, London, and the number ofpatients with primary Crohn's disease of the largeintestine treated by surgical resection at the samehospital over the same period of time was deter-mined. Only those patients with the characteristicpathological features of ulcerative colitis describedby Dukes (1954) and by Warren and Sommers (1954)were included in this group.The clinical records of all the patients included in

this study were analyzed, and follow-up studies weremade wherever possible.

RESULTS

AGE AND SEX INCIDENCE The age and sex incidenceof the patients in this study are shown in Table I.(The age given is the age at onset of symptoms.)Whilst regional ileitis occurred more commonly in

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Primary Crohn's disease of the colon and rectum

Regional Ileitis

Males Females Total

TABLE I

AGE AND SEX DISTRIBUTION

Ulcerative Colitis

Males Females Total

Primary Crohn's DiseaseofLarge Intestine

Males Females Total

4 4 3 729 8 18 2631 29 42 711 1 20 23 4310 17 20 371 2 8 100 4 2 60 0 0 0

86 84 116 200

males than in females, ulcerative colitis and primaryCrohn's disease of the large intestine occurred morecommonly in females than in males. Primary Crohn'sdisease of the large intestine was found in an olderage group than either regional ileitis or ulcerativecolitis.

FAMILIAL INCIDENCE Nine patients with ulcerativecolitis gave a history of the disease occurring in othermembers of their families. One woman with regionalileitis had a brother suffering from the same disease.One man with primary Crohn's disease of the largeintestine had a brother suffering from regionalileitis.

SYMPTOMS Although diarrhoea, melaena, abdominalpain, weight loss, and fatigue are symptoms commonto ulcerative colitis, primary Crohn's disease of thelarge intestine, and regional ileitis with colonicinvolvement, a detailed analysis of the data obtainedin this study draws attention to certain differences intheir symptoms.

Patients with primary Crohn's disease of the largeintestine were treated by surgical resection earlierthan patients with ulcerative colitis. The number ofpatients with this disorder undergoing surgical re-

section within five years of the onset of the diseasewas 77.8% compared with 48% in ulcerative colitis,and after 10 years was 8.9% compared with 26-5 %in ulcerative colitis.An acute onset was found more commonly in

patients with ulcerative colitis (29.5 %) than inpatients with primary Crohn's disease of the largeintestine (1i 1 %). Periods of freedom from diseaselasting a month or more, which were found in morethan half the patients with regional ileitis andulcerative colitis, were found in only six of the 45patients with primary Crohn's disease of the largeintestine.

All the patients with ulcerative colitis suffered fromdiarrhoea, although at the onset several of these

patients complained of constipation. Diarrhoeaoccurring in patients with regional ileitis or primaryCrohn's disease of the large intestine was usually lesssevere than that occurring in the patients with ulcera-tive colitis. Eighteen patients with regional ileitis andfour patients with primary Crohn's disease of thelarge intestine had no diarrhoea.

Despite the frequent finding of occult blood in thestools five patients with ulcerative colitis (25 %),eight patients with primary Crohn's disease of thelarge intestine (17.8 %), and 49 patients with regionalileitis (5699%) had not noticed any blood in theirstools.

EXAMINATION AND INVESTIGATIONS A strikingdifference was found in the incidence of perianal andrectovaginal fistulae in the three types of disease.These fistulae were found in nearly two-thirds of thepatients with primary Crohn's disease of the largeintestine, and nearly one-third of the patients withregional ileitis. Compared with ulcerative colitis thecharacteristic features of the fistulae in regionalileitis and primary Crohn's disease of the large in-testine were their indolent appearance, their multi-plicity, and their frequency of recurrence aftersurgical treatment.A pathological examination was made of the

tissues removed from just over half the operations onthese fistulae. Although multinucleated foreign bodytype giant cells were frequently seen in this material,non-caseating tubercles with Langhans type giantcells were found only in material from patients withregional ileitis or primary Crohn's disease of thelarge intestine.At sigmoidoscopy the rectal mucosa appeared

abnormal in 198 of the 200 patients with ulcerativecolitis, in 31 of the 45 patients with primary Crohn'sdisease of the large intestine, and in 24 of the 86patients with regional ileitis. Non-caseating tubercleswith giant cells were found in the rectal biopsies froma fifth of the patients with rectal disease due to

Age(years)

0-1011-2021-3031-4041-5051-6061-707 1-80Total

219179510053

210142500033

0435

32018

5204294

27

95555

1 14

45

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J. S. Cornes and Mette Stecher

...s _ _ V ,<~F , _ _ a;A.1

o..P X.. 't- 0 ''.fv 4 8.. - ' +Jb f O.. Iar '-r F

FIG. 1. Crohn's disease. Rectal biopsy showing tubercles and giant cells. x 120.

regional ileitis or primary Crohn's disease of thelarge intestine (Fig. 1).

Painful, swollen joints were found in seven of the45 patients with primary Crohn's disease of the largeintestine, in seven of the 86 patients with regionalileitis, and in 19 of the 200 patients with ulcerativecolitis. Ankylosing spondylitis was found in twopatients with regional ileitis and in two patients withulcerative colitis. Erythema nodosum was seen intwo patients with primary Crohn's disease of thelarge intestine, in five patients with regional ileitis,and in seven patients with ulcerative colitis.Normal haemoglobin levels, above 11-5 g. per

100 ml., were found in 43.2% of the patients withprimary Crohn's disease of the large intestine, in43.2% of the patients with regional ileitis, but inonly 26% of the patients with ulcerative colitis.Haemoglobin levels below 60% (Haldane) werefound in 9-1 % of the patients with primary Crohn'sdisease of the large intestine, in 9 5% of the patientswith regional ileitis, and in 21.6% of the patients

with ulcerative colitis. The erythrocyte sedimentationrate was found to be a useful indicator of the activityof all three diseases. We were unable to demonstrateany special association between the ABO and Rhanti-D blood groups and these three types of disease.

DISTRIBUTION OF LESIONS The distribution of thelesions in the small and large intestine in the patientswith regional ileitis, ulcerative colitis, and primaryCrohn's disease of the large intestine when surgicalresections were first performed are shown in Table II.

Skip lesions were found in 43-3 % of the patientswith regional ileitis involving the large intestine(Fig. 2), in 20% of the patients with primary Crohn'sdisease of the large intestine (Fig. 3), and in only 1 %of the patients with ulcerative colitis.

Involvement of the large intestine, found in 49 ofthe 86 patients with regional ileitis, was of two types.In the first type the lesions in the large intestine werein continuity with those in the terminal ileum andthey appeared to be spreading along the large

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Primary Crohn's disease of the colon and rectum

FIG. 2. Regional ileitis with skip lesion in descendingcolon.

FIG. 4. Regional ileitis with spread to caecum andascending colon, viewedfrom behind.

FIG. 3. Primary Crohn's disease of the large intestine withsmall intervening areas ofnormal mucosa.

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J. S. Cornes and Mette Stecher

TABLE

DISTRIBUTION OF LESIONS IN PRIILARGE INTESTINE, IN REGIO

ULCERATIVE C

Distribution

Rectum to and includingSigmoid colonDescending colonTransverse colonAscending colonCaecumCaecum to and includingAscending colonTransverse colonDescending colonSigmoid colonAscending and transverse colonTransverse to sigmoid colonCaecum, sigmoid, and rectumTransverse colonSigmoid colon

Ileum to and includingCaccumAscending colonTransverse colonDescending colonSigmoid colonRectumIleum with skip to sigmoid and rectumIleum and caecum, with skip tosigmoid and rectum

Rectum to and includingSigmoid colonDescending colonTransverse colonAscending colonCaecumTerminal ileumCaecum to descending colonTransverse colon

II by resection of the diseased terminal ileum, 65 by

dARY CROHN'S DISEASE OF removal of the terminal ileum with right hemi-ONAL ILEITIS, AND IN colectomy, and eight by removal of the terminalNAL ileum with total colectomy. One patient was treated

by the removal of a skip lesion in the sigmoid colon,No of Patients LNowesion the affected terminal ileum being left behind.

Most of the patients with ulcerative colitis were5 0 treated by total colectomy and ileo-rectal anasto-4 1 mosis, as described by Aylett (1960). Subtotal6 1 colectomy was performed in 11 cases, and palliative1 29 0 abdominoperineal excision of the rectum for13 29 2

advanced carcinoma in three cases.2

3

Total

115

5

337

Total

4101117

11541

71

232

45

3413

249

198

Total 200

0110102009

00203

13

221

000020002

intestine in a caudal direction (Fig. 4). In the secondtype lesions were found in the sigmoid colon andrectum which appeared to have been spread by a

surface contact between the terminal ileum and therectosigmoid. In several of these cases the surgeons

found the terminal ileum stuck to the sigmoid colonby fibrous adhesions.The incidence of segmental colitis varied with the

different types of disease. It was uncommon inulcerative colitis, but occurred in nearly one-third ofthe patients with primary Crohn's disease of the largeintestine and in more than half the patients withregional ileitis involving the large intestine.

TREATMENT Ten patients with primary Crohn'sdisease of the large intestine were treated by totalproctocolectomy, nine by subtotal proctocolectomy,nine by total colectomy, and 17 by subtotal colec-tomy. The disease was incompletely removed in 10cases.Twelve patients with regional ileitis were treated

MACROSCOPIC APPEARANCES There were no differ-ences in the macroscopic or microscopic appearancesof the large intestinal lesions in patients with regionalileitis and those of primary Crohn's disease of thelarge intestine.

Certain gross features helped to distinguishspecimens of primary Crohn's disease of the largeintestine from specimens of ulcerative colitis. A seg-mental distribution and the presence of skip lesionsoccurred much more frequently in Crohn's diseasethan in ulcerative colitis. The widespread, ragged,superficial ulceration seen in acute ulcerative colitis(Fig. 5) was not seen in the specimens of Crohn'sdisease, in which the ulcers were usually smaller,more elongated, and had a somewhat fissuredappearance. The ulcers of Crohn's disease extendedin a serpiginous fashion along the lumen of the bowel(Fig. 6), and occasionally branched or crossed eachother to give a reticular pattern (Fig. 7). The mucosabetween these ulcers was oedematous, the combina-tion of fissures with a swollen mucosa producing atypical 'cobblestone' appearance.

Mucosal tags projecting into the lumen of thelarge intestine were a characteristic feature of manyof the specimens of ulcerative colitis (Fig. 8). Theywere not found in the specimens from patients withprimary Crohn's disease of the large intestine.

Dilatation of the colon was found in 24 specimensfrom patients with acute ulcerative colitis. No dilata-tion was found in any of the specimens from patientswith Crohn's disease of the large intestine.

Serosal inflammation was a constant finding in thespecimens from patients with primary Crohn'sdisease of the large intestine, and tiny greyish-whitenodules, the size of a pin head, were seen on theserosal surface of six of these specimens. Theseserosal nodules were not found on the specimensfrom patients with ulcerative colitis. During opera-tions on patients with ulcerative colitis the surgeonsfrequently noticed congestion and apparent inflam-mation of the serosal surface of the colon, but by thetime most specimens reached the laboratory thesefeatures were no longer obvious. Specimens from

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Primary Crohn's disease of the colon and rectum

FIG. 5. Ulcerative colitis showing widespread raggedsuperficial ulceration.

FIG. 6. Primary Crohn's disease of the large intestine.

Close-up view ofulcers in the descending colon.

!"

7

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FI. 7... Prmr'rhnsdsaeoftesgoi.oo nretmsowin th.hr.trsi.oblsoeapaacofhentsia mucsa

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J. S. Cornes and Mette Stecher

FIG. 8. Ulcerative colitis with mucosal tags in the transverse colon.

patients with acute ulcerative colitis, however, invari-ably showed an acute inflammatory reaction of theserosal surface, and perforations were occasionallyseen.

Internal fistulae were found in two patients withprimary Crohn's disease of the large intestine and in16 patients with regional ileitis. No internal fistulawas found in the patients with ulcerative colitis.

Enlarged lymph nodes were found in 51 I 1 % of thespecimens of primary Crohn's disease of the largeintestine, 68.9% of the specimens of ulcerative colitis,and 82-7% of the specimens of regional ileitis. Thelargest nodes were found in specimens from patientswith ulcerative colitis and they frequently misled thesurgeons into suspecting the presence ofan associatedcarcinoma. Carcinomas were not found in any ofthese cases, however, and the large lymph nodessimply contained widely dilated sinusoids packedwith chronic inflammatory cells.

MICROSCOPIC APPEARANCES Sections from the speci-mens of primary Crohn's disease of the largeintestine showed a chronic inflammatory reactionaffecting the submucosa, muscle coats, and sub-serosa. Some damage to the muscle coats was invari-ably found, and fibrous tissue was seen throughoutthe submucosa, and often in the muscle coats andsubserosa as well. The muscle coats were usuallyconsiderably thickened, and the myenteric plexusand ganglion cells were prominent. Focal collectionsof lymphocytes were seen in the submucosa, musclecoats, and subserosa. Fissures extending into and

often penetrating the muscle coats were frequentlyfound, and were the basis for the formation ofinternal fistulae.

Foreign body type giant cells were seen in areasof ulceration and around abscesses in the wall of thelarge intestine. Non-caseating nodules of epithelioidhistiocytes containing small multinucleated giantcells were found typically only in areas free frommucosal ulceration. These nodules were seen in thesubmucosa, muscle coats, subserosa, and regionallymph nodes. They were rarely found in enlargedlymph nodes. Schaumann bodies were seen innodules of epithelioid cells in the large intestine ofone patient with primary Crohn's disease of the largeintestine and in the pericolic lymph nodes of twoother patients with this disorder.

Brunner-type glands were found in specimens ofterminal ileum from 29 patients with regional ileitis(Fig. 9). They were found only in areas of mucosalregeneration, and were often only partly stained bythe indulin-mucicarmine technique of Kawel andTesluk (1955). Despite an extensive search we wereunable to find these glands in the large intestine inany of the cases studied, or in the terminal ileumaffected by ulcerative colitis.

Severe ulceration with damage to the muscle coatsand an acute inflammatory reaction in the musclecoats and subserosa were seen in specimens frompatients with severe acute ulcerative colitis.

In chronic ulcerative colitis the inflammatoryreaction was limited to the mucosa and submucosa,and only tiny perineural and perivascular collections

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TABLE III

RELATIONSHIP BETWEEN LENGTH OF HISTORY ANDDEVELOPMENT OF CARCINOMA IN DISEASED INTESTINE

Length ofHistory(years)

Number of Cases

Regional Primary Crohn's Ulcerative ColitisIleitis' Disease of

Large Intestine' Total WithCarcinoma

0-5 42 286-10 21 10

11-15 11 416-20 7 121-25 3 126-30 0 030plus 2 1Total 86 45'No carcinoma was found in areas ofCrohn's disease of the large intestine.

FIG. 9. Brunner-type glands in the submucosa of theterminal ileum, from a patient with regional ileitis. x 60.

of lymphocytes were seen in the muscle coats andsubserosa. Mucosal tags and granulomatous polypiwere found in 97 of the 157 specimens from patientswith chronic ulcerative colitis. Crypt abscesses,mucosal ulceration, and some epithelial regenerationwere present in all the specimens from patients withchronic active disease. Damage to the muscle coatswas not seen and fibrosis, which was minimal, was

limited to the superficial submucosa. Thickening ofthe bowel wall and narrowing of the intestinal lumenwas invariably associated with a thickening of themuscle coats, and the myenteric plexus and ganglioncells were unusually prominent in these cases.

CARCINOMA Carcinomas were found in the speci-mens from 17 patients with ulcerative colitis. No

carcinoma was found in the specimens from patientswith primary Crohn's disease of the large intestine.Rectal carcinomas were found in specimens fromtwo patients with regional ileitis. In the first case therectal carcinoma was found five years after thesurgical resection of the diseased terminal ileum andat the second operation there was no evidence ofrecurrent disease in the small intestine or of regionalileitis involving the large intestine. In the secondcase the patient presented with a rectal carcinomaand regional ileitis and both were treated by surgicalresection. There was no evidence of regional ileitis2

49 270 332 122 717 35 15 0

200 17regional ileitis or primary

involving the rectum, and the remainder of the largeintestine appeared normal.The failure to demonstrate carcinoma in areas of

regional ileitis or primary Crohn's disease of thelarge intestine may be related to their shorter lengthof history (Table Ill). Whilst the total incidence ofcarcinoma in patients with ulcerative colitis treatedby all forms of surgery was 8.6%, the incidence inthose with ulcerative colitis of more than 10 years'duration was 14.8%, and of more than 15 years'duration was 22.4 %.

INCIDENCE OF PRIMARY CROHN'S DISEASE OF THE LARGE

INTESTINE From January 1949 until the end ofJanuary 1960 surgical resections of a part or all ofthe large intestine were performed at the GordonHospital, London, on 200 patients with ulcerativecolitis. In the same period and at the same hospitalsurgical resections of part or all of the large intestinewere performed on 13 patients with primary Crohn'sdisease of the large intestine. The surgical incidenceof primary Crohn's disease of the large intestinerelative to ulcerative colitis was therefore roughlyone in every 15 cases.

RECURRENCE AFTER SURGICAL RESECTION No recur-

rence was found in the small intestine after totalcolectomy for ulcerative colitis. Recurrence in thepreviously unaffected right side of the colon wasfound in two patients with ulcerative colitis treatedby left hemicolectomy.So far no recurrence has been found in the small

intestine following the surgical treatment of primaryCrohn's disease of the large intestine. Recurrence inpreviously unaffected segments of large intestinewithin a year of operation occurred in four patientstreated by subtotal colectomy. In two patients thedisease recurred in segments immediately proximal

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to the primary lesion, and in two patients in segmentsimmediately distal to the primary lesion.

Thirty-two of the 86 patients with regional ileitisdeveloped a recurrence in unaffected segments of thesmall or large intestine after surgical resection. Asecond resection was performed on 28 of thesepatients. In the four remaining patients recurrencewas indicated by a recurrence of symptoms andradiological evidence of disease. Recurrent diseaseaffected the ileum and jejunum in one case, the ileumin 23 cases, and the ileum and large intestine in eightcases. In 13 cases disease recurred within two years,in 22 cases within five years, in 31 cases within 10years, and in all the cases within 12 years.

DISCUSSION

Because these studies are based solely on surgicalmaterial they necessarily give a biased picture of thediseases investigated since they ignore all the patientswith the milder forms of these diseases who did notrequire any surgical treatment. This is particularlyimportant when complications such as fistulae orcarcinoma are considered, conditions which neces-sarily bring the patient to the surgical clinic. How-ever, the careful examination of resected specimensprovides the most reliable method so far available ofdistinguishing cases ofprimary Crohn's disease of thelarge intestine from that of ulcerative colitis.

It may be argued that our histological criteria forthe diagnosis of primary Crohn's disease of the largeintestine are too strict, and that we have excludedcases which others might regard as examples of thiscondition. In our present state of knowledge webelieve this to be a wise procedure. Nothing is gainedand much may be lost by trying to classify doubtfulspecimens as atypical cases of ulcerative colitis oratypical cases of Crohn's disease of the largeintestine.

Despite these and other limitations the resultsshow that it is worth distinguishing between ulcera-tive colitis, primary Crohn's disease of the largeintestine, and regional ileitis with large intestinalinvolvement.

CLINICAL FEATURES In this study regional ileitis wasfound to be commoner in men than in women, andprimary Crohn's disease of the large intestine to becommoner in women than in men. Primary Crohn'sdisease of the large intestine occurred in an older agegroup than regional ileitis or ulcerative colitis, andapproximately one-quarter of the cases occurred inwomen over 60 years of age. In the series of 25 casesreported by Lockhart-Mummery and Morson theirseven cases of regional ileitis with large intestinalinvolvement all occurred in men, whose ages ranged

from 17 to 49 years with a mean of 27 years. Of their18 cases of primary Crohn's disease of the largeintestine, 10 occurred in men and eight in women,their ages ranging from 34 to 72 years with a meanof 54 years.

Patients with primary Crohn's disease of the largeintestine frequently present with segmental colitis.When only a short segment of the large intestine isaffected the lesion can mimic carcinoma (Moynihan,1907; Robson, 1908), and the frequent occurrence ofprimary Crohn's disease of the large intestine inpatients over 50 years of age adds to the difficulty inseparating the two diseases clinically. Similarly whenCrohn's disease is limited to the sigmoid colon andthe patient is over 50 years of age a diagnosis ofdiverticulitis may be made. This happened twice inour series and subtotal colectomies were performed.Examination of the operation specimens, however,showed Crohn's disease and no diverticulum couldbe found.A gradual onset and a continuous course were

common findings in patients with primary Crohn'sdisease of the large intestine and this probablyaccounts for their short clinical histories beforesurgical resections were undertaken. It is also pos-sible that the Crohn's disease might have been latentin the colon for several years before its presencebecame clinically manifest. Periods of complete free-dom from disease lasting a month or more, found inmore than half the patients with ulcerative colitis,were uncommon in patients with primary Crohn'sdisease of the large intestine. Diarrhoea and melaena,characteristic features of ulcerative colitis, occurredless frequently and were less severe in most of thepatients with primary Crohn's disease of the largeintestine. These clinical observations tied up with thelesser degree of mucosal ulceration and the morefrequent finding of normal haemoglobin levels inpatients with Crohn's disease of the large intestinethan in patients with ulcerative colitis.

FISTULAE Perianal and rectovaginal fistulae werefound more frequently in patients with primaryCrohn's disease of the large intestine than in patientswith regional ileitis or ulcerative colitis. Similar find-ings have been reported by Lockhart-Mummery andMorson. In their series anal fistulae were found in42-8% of the cases of regional ileitis with large in-testinal involvement, and in 77-8% of the cases ofprimary Crohn's disease of the large intestine. Thefinding of multiple fistulae, indolent anal lesions, andrecurrence after surgical treatment suggests a diag-nosis of Crohn's disease rather than ulcerative colitis.All material removed at operations on anal fistulaeshould be sent to the laboratory for examination.The finding of non-caseating tubercles with Langhans

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type giant cells in this material may then drawattention to a previously unsuspected case of regionalileitis or primary Crohn's disease of the largeintestine (Morson and Lockhart-Mummery, 1959).

RECTAL DISEASE Difficulty may be experienced inseparating the sigmoidoscopic appearances of ulcera-tive colitis and Crohn's disease. The finding ofgranular areas with intervening areas of normal orslightly oedematous mucosa suggests the diagnosisof Crohn's disease (Lockhart-Mummery and Mor-son, 1960). Rectal biopsy may help to establish thediagnosis of Crohn's disease when non-caseatingtubercles with Langhans type giant cells are found.The majority of biopsies, however, fail to show thesetubercles, and no great importance should beattached to a negative finding.

PATHOLOGY Although the combination of Crohn'sdisease and ulcerative colitis occurring in the samepatient has been frequently reported in the Americanliterature (Crohn and Yarnis, 1958; Colcock andVansant, 1960), we have not seen any example of thiscombination. The few supposed examples which wehave seen proved to be cases of ileostomy dys-function after total proctocolectomy for ulcerativecolitis (see Counsell, 1956), or cases of Crohn'sdisease of the large intestine in which few sectionshad been taken for histology and the presence ofnon-caseating tubercles in the intestinal wall orregional lymph nodes had been missed.

Finding Brunner-type glands in a tuberculousulcer of the large intestine was first reported byNicholson in 1923, and in 1951 Liber reported find-ing them in the terminal ileum of four patients withregional ileitis. We did not find these glands in thelarge intestine in any of the cases studied, and foundthem only in the terminal ileum affected by regionalileitis. Their partial staining reaction with indulinand mucicarmine and their occurrence only in areasof epithelial regeneration suggests a form of meta-plasia developing in the healing phase of regionalileitis. Kawel and Tesluk (1955), however, reporteda high incidence of recurrent disease after the surgicaltreatment of regional ileitis when these glands werepresent in the terminal ileum. In our series the recur-rence rate was the same whether these glands werepresent or not. Similar findings have been reportedby Antonius, Gump, Lattes, and Lepore (1960).

It is often stated that the histological appearancesof the non-caseating nodules of epithelioid histio-cytes found in patients with Crohn's disease aresimilar to those found in sarcoidosis. But a criticalcomparison of the lesions found in lymph nodes frompatients with these diseases reveals a number of dis-tinguishing features. In sarcoidosis, the lymph nodes

are usually considerably enlarged and many non-caseating nodules of epithelioid cells are found insidethem. In Crohn's disease, the nodules are found mostfrequently in normal-sized nodes and only a fewnodules can be seen. In sarcoid, the nodules show amonotonous uniformity of size, shape, and stage ofdevelopment. In Crohn's disease, the nodules varyconsiderably in size, shape, and degree of maturity,and are usually smaller than those seen in sarcoid.In sarcoid the nodules are cellular and compact. InCrohn's disease the epithelioid cells are more looselyarranged, and the cell margins are frequentlyseparated by oedema. The multinucleated giant cellsof sarcoidosis often contain more than 30 nuclei,whilst those in Crohn's disease seldom contain morethan 16 and appear to be formed by the fusion ofendothelial cells lining affected lymphatic capillaries.

It is not generally appreciated that sarcoid-likelesions can be found in the wall of the intestine closeto carcinomas and villous papillomas (Dawson,1961), and that similar lesions may be found in theregional lymph nodes draining carcinomas frommany different parts of the body (Gresham andAckerley, 1958). It is possible that some of the so-called cases of carcinoma with regional ileitisreported in the literature are of this type.

DEVELOPMENT OF CARCINOMA So far no definitetendency to malignant change has been establishedin patients suffering from Crohn's disease (Nevin,1961). Carcinoma of the large intestine is, however, awell-recognized complication of ulcerative colitis,and its incidence appears to be related to the dura-tion of the colitis rather than to the age at onset ofthe disease (Counsell and Dukes, 1952; Dawson andPryse-Davies, 1959). The fact that no carcinomaoccurred in areas of regional ileitis or primaryCrohn's disease of the large intestine in the presentseries may be related to the finding that thesepatients came to surgery earlier than the patientswith ulcerative colitis. It may also be related to thedegree of mucosal ulceration, epithelial prolifera-tion, and polyp formation being less marked inregional ileitis and primary Crohn's disease of thelarge intestine than in ulcerative colitis.

PROGNOSIS It is not the purpose of this communica-tion to evaluate the different methods of treatmentemployed but we have noticed that several patientswith primary Crohn's disease of the large intestinewho had failed to obtain any adequate measure ofrelief by medical treatment were quickly restored tonormal health by surgical treatment and have con-tinued to enjoy a prolonged period of freedom fromdisease. Unnecessary delay in the surgical treatmentof segmental colitis can result in rectal involvement,

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the formation of perianal and rectovaginal fistulae,and the subsequent failure of ileorectal anastomosis.The high incidence of recurrent disease after surgicaltreatment found in patients with regional ileitis hasnot been found in patients with Crohn's diseasearising primarily in the large intestine. It is too soonto judge whether primary Crohn's disease of thelarge intestine has a better prognosis than regionalileitis but the results of surgical resection are so farmost encouraging.

SUMMARY

This study is based on 45 patients suffering from anon-specific chronic inflammatory disorder confinedentirely to the large intestine. The pre-operativeclinical diagnoses were idiopathic ulcerative colitis,diverticulitis, or carcinoma. Examination of thespecimens removed at operation showed many of thecharacteristic pathological features of regional ileitis.For the sake of convenience these cases have beencalled primary Crohn's disease of the large intestine.The clinical and pathological features of these 45cases are compared with 86 cases of regional ileitisand 200 cases of ulcerative colitis.Compared with regional ileitis the disease occurred

in an older age group, had a different sex distributionand a higher incidence of perianal and rectovaginalfistulae. A high incidence of recurrent disease follow-ing surgical treatment, found in the patients withregional ileitis, was not found in the patients withprimary Crohn's disease of the large intestine.The incidence of the disease relative to ulcerative

colitis was approximately 6%. The disease had thesame sex distribution as ulcerative colitis butoccurred in an older age group. The disease usuallyhad a gradual onset and continuous course, andperiods of freedom lasting a month or more wereuncommon. The patients came to surgery muchearlier than patients with ulcerative colitis. Diar-rhoea, melaena, and mucosal ulceration were lessmarked, and a normal pre-operative haemoglobinlevel was found in over 40% of the patients. Perianaland rectovaginal fistulae, found in two-thirds of thepatients, were frequently multiple, indolent, andtended to recur after surgical treatment. The in-cidence of skip lesions and segmental colitis wasmuch higher than that found in ulcerative colitis.The mucosal ulcers were usually elongated andfissured, and the intervening oedematous mucosahad a cobblestone appearance. The widespreadragged superficial ulceration, pseudo-polypi, dilatedbowel and perforations, found in some cases ofulcerative colitis, were not seen in primary Crohn'sdisease of the large intestine.

Carcinomas of the large intestine were found in

specimens from 17 patients with ulcerative colitis.No carcinoma was found in regional ileitis or pri-mary Crohn's disease of the large intestine. This maybe related to a shorter clinical history and a lesserdegree of mucosal ulceration, epithelial proliferation,and polyp formation.

Gratitude is expressed to Professor R. J. V. Pulvertaft forthe opportunity to undertake this work, for the provisionof research facilities, and for much encouragement in thepreparation of this paper. We are grateful to Dr. CuthbertDukes for suggesting the method of investigation used inthis study. Appreciation is expressed to Mr. StanleyAylett, Mr. Bryan Brooke, Dr. I. M. P. Dawson, Dr. C. E.Dukes, Mr. H. E. Lockhart-Mummery, and Dr. B. C.Morson for much helpful advice and criticism. We wishto thank Dr. 0. Bjamason, Mr. Bryan Brooke, Dr.I. M. P. Dawson, Professor C. V. Harrison, Dr. D. H.Mackenzie, Dr. A. D. Morgan, Dr. B. C. Morson, andMr. Gordon Ungley for the opportunity to studyspecimens of primary Crohn's disease of the large in-testine. We are grateful to Dr. Peter Hansell and Mr. E. V.Pittock for the photography, and to Miss Gloria Fisherfor technical assistance. The work was made possible byblock grants from the British Empire Cancer Campaignto the Westminster Medical School and the ResearchDepartment of St. Mark's Hospital, London.

REFERENCES

Antonius, J. I., Gump, F. E., Lattes, R., and Lepore, M. (1960). Astudy of certain microscopic features in regional enteritis, andtheir possible prognostic significance. Gastroenterology, 38,889-905.

Aylett, S. 0. (1960). Diffuse ulcerative colitis and its treatment byileo-rectal anastomosis. Ann. roy. Coil. Surg. Engl., 27, 260-284.

Braun, H. (1909). tber entzundliche Geschwulste am Darm. Dtsch.Z. Chir., 100, 1-12.

Brooke, B. N. (1959). Granulomatous diseases of the intestine. Lancet,2, 745-749.

Brown, P. W., Bargen, J. A., and Weber, H. M. (1934). Chronicinflammatory lesions of the small intestine (regional enteritis).Amer. J. dig. Dis., 1, 426-431.

Castleman, B. (1944). Case records of the Massachusetts GeneralHospital. Case 30172. New Engl. J. Med., 230,S26-529.

Colcock, B. P., and Vansant, J. H. (1960). Surgical treatment ofregional enteritis. New Engl. J. Med., 262, 435-439.

Colp, R. (1934). A case of nonspecific granuloma of the terminal ileumand the cecum. Surg. Clin. N. Amer., 14, 443-449.

Counsell, B. (1956). Lesions of the ileum associated with ulcerativecolitis. Brit. J. Surg., 44, 276-290.

, and Dukes, C. E. (1952). The association of chronic ulcerativecolitis and carcinoma ofthe rectum and colon. Ibid., 39,485-495.

Crohn, B. B., Ginzburg, L., and Oppenheimer, G. D. (1932). Regionalileitis. A pathologic and clinical entity. J. Amer. med. Ass., 99,1323-1329.

*, and Rosenak, B. D. (1936). A combined form of ileitis andcolitis. Ibid., 106, 1-7.

-, and Yarnis, H. (1958). Regional Ileitis, 2nd ed. Grune andStratton, New York and London.

Dalziel, T. K. (1913). Chronic interstitial enteritis. Brit. med. J., 2,1068-1070.

Dawson, I. M. P. (1961). Villous papilloma of the rectum with giantcell systems. Proc. roy. Soc. Med., 54, 723.

, and Pryse-Davies, J. (1959). The development of carcinoma ofthe large intestine in ulcerative colitis. Brit. J. Surg., 47, 113-128.

Donchess, J. C., and Warren, S. (1934). Chronic cicatrizing enteritiswith involvement of the cecum and the colon. Arch. Path.(Chicago), 18, 22-29.

on Decem

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Primary Crohn's disease of the colon and rectum 201

Dukes, C. E. (1954). The surgical pathology of ulcerative colitis. Ann.roy. Coil. Surg. Engi., 14, 389-400.

-(1959). Personal communication.and Lockhart-Mummery, H. E. (1957). Practical points in thepathology and surgical treatment of ulcerative colitis. Brit. J.Surg., 45, 25-36.

Goldgraber, M. B., Kirsner, J. B., and Palmer, W. L. (1959). Thehistopathology of chronic ulcerative colitis and its pathogenicimplications. Proceedings of the World Congress of Gastro-enterology, Washington, D.C., 1958. Vol. 2, pp. 935-943.Williams and Wilkins, Baltimore.

Goligher, J. C. (1961). Surgical treatment of ulcerative colitis. Brit.med. J., 1, 151-154.

Gresham, G. A., and Ackerley, A. G. (1958). Giant cell granu-lomata in regional lymph nodes of carcinoma. J. clin. Path., 11,244-250.

Hadfield, G. (1939). The primary histological lesion of regional ileitis.Lancet, 2, 773-775.

Harris, F. I., Bell, G. H., and Brunn, H. (1933). Chronic cicatrizingenteritis; regional ileitis (Crohn). A new surgical entity. Surg.Gynec. Obstet., 57, 637-645.

James, T. G. I. (1938). Chronic regional colitis. Brit. J. Surg., 25,511-516.

Kawel, C. A., Jr., and Tesluk, H. (1955). Brunner-type glands inregional enteritis. Gastroenterology, 28, 810-820.

Lawen, A. (1914). Ober Appendicitis fibroplastica. Dtsch. Z. Chir.,129, 221-241.

Liber, A. F. (1951). Aberrant pyloric glands in regional enteritis.A.M.A. Arch Path., 51, 205-212.

Lockhart-Mummery, H. E., and Morson, B. C. (1960). Crohn'sdisease (regional enteritis) of the large intestine and its distinc-tion from ulcerative colitis. Gut, 1, 87-105.

Lumb, G. (1951). Cicatrizing enterocolitis. Brit. J. Surg., 39, 233-243., and Protheroe, R. H. B. (1958). Ulcerative colitis. A pathologic

study of 152 surgical specimens. Gastroenterology, 34, 381-407.Morson, B. C., and Lockhart-Mummery, H. E. (1959). Anal lesions

in Crohn's disease. Lancet, 2, 1122-1123.Moschcowitz, E., and Wilensky, A. 0. (1923). Non-specific granulo-

mata of the intestine. Amer. J. med. Sci., 166, 48-66.Moynihan, B. G. A. (1907). The mimicry of malignant disease in the

large intestine. Edinb. med. J., n.s. 21, 228-236.Neuman, H. W., Bargen, J. A., and Judd, E. S. (1954). A clinical study

of two hundred and one cases of regional (segmental) colitis.Surg. Gynec. Obstet., 99, 563-571.

Nevin, R. W. (1961). A review of granulomata of the large intestine.Proc. roy. Soc. Med., 54, 137-142.

Nicholson, G. W. (1923). Heteromorphoses (metaplasia) of thealimentary tract. J. Path. Bact., 26, 399-417.

Rappaport, H., Burgoyne, F. H., and Smetana, H. F. (1951). Thepathology of regional enteritis. Milit. Surg., 109, 463-502.

Robson, A. W. M. (1908). An address on some abdominal tumourssimulating malignant disease, and their treatment. Brit. med.J., 1, 425-428.

Tietze, A. (1920). U0ber entzundliche Dickdarmgeschwulste. Ergebn.Chir. Orthop., 12, 211-273.

Warren, S., and Sommers, S. C. (1948). Cicatrizing enteritis (regionalileitis) as pathologic entity: analysis of 120 cases. Amer. J. Path.,24, 475-501.

-, (1954). Pathology of regional ileitis and ulcerative colitis.J. Amer. med. Ass., 154, 189-193.

Watkinson, G., Thompson, H., and Goligher, J. C. (1960). Right-sided or segmental ulcerative colitis. Brit. J. Surg., 47, 337-351.

Wells, C. (1952). Ulcerative colitis and Crohn's disease. Ann. roy.Coll. Surg. Engl., 11, 105-120.

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