importance of cryptolytic lesions pericryptal granulomas

4 JClin Pathol 1997;5O: 148-152

Importance of cryptolytic lesions and pericryptalgranulomas in inflammatory bowel disease

F D Lee, C Maguire, W Obeidat, R I Russell

AbstractAims-To explore the diagnostic im-portance of pericryptal granulomas asso-ciated with epithelial lysis in colorectalbiopsy specimens (cryptolytic colitis).Methods-A series of patients with sus-pected inflammatory bowel disease andcolorectal biopsy specimens showing ei-ther isolated pericryptal granulomas (14cases) or non-granulomatous pericryptalinflammation (eight cases) were followed.A diagnosis of Crohn's disease was estab-lished if subsequent biopsy specimens orintestinal resections showed unequivocalnon-crypt related granulomas, or if therewas evidence of significant small boweldisease.Results-Of the 14 patients with pericryp-tal granulomas and biopsy specimens, 10were subsequently found to have Crohn'sdisease; of the eight patients with peri-cryptal inflammation only, one developedCrohn's disease. The former group alsohad a much higher instance of morbidityand required surgical intervention moreoften.Conclusions-The presence of cryptolyticgranulomas in a colorectal biopsy speci-men otherwise showing only non-specificinflammatory changes should always raisesuspicion of Crohn's disease, especially ifsurgery or ileo-anal pouch formation iscontemplated.( Clin Pathol 1997;50:148-152)

Keywords: Crohn's disease; crypts of Lieberkuhn;granuloma.

Departments ofPathology andGastroenterology,Royal Infirmary,Glasgow G31 2ER

Correspondence to:Professor F D Lee,Department of Pathology,Glasgow Royal Infirmary,Glasgow G4 OSF.

Accepted for publication5 November 1996

The diagnosis of inflammatory bowel disease(IBD), and the distinction between Crohn'sdisease and ulcerative colitis relies heavily uponthe histopathological assessment of colorectalbiopsy specimens, to which immunocytochem-istry and molecular techniques have yet tomake a significant impact. In the great majorityof cases, a biopsy specimen of this kind consistsmainly of mucosa and lamina muscularismucosae, and seldom includes more than athin rim of superficial submucosa. Assessmenthas thus to be based on mucosal alterationswhich are often non-specific.

In patients with colitis undergoing totalcolectomy, it is of great importance to distin-guish between Crohn's disease and ulcerativecolitis preoperatively so that the appropriatesurgical procedure may be planned. For exam-

ple, in patients with Crohn's colitis, the opera-

tion of choice is a proctocolectomy andileostomy, or an ileorectal anastomosis if therectum is spared. However, in those patientswith ulcerative colitis, a pouch procedure maybe performed to retain faecal continence.

Histological changes regarded as character-istic of ulcerative colitis, such as goblet celldepletion, crypt abscess formation, crypt ir-regularity, and thickening of the lamina muscu-laris, may all be seen to a lesser or greaterdegree in Crohn's disease. Only the presence ofa discrete epithelioid granuloma in the laminapropria or in lymphoid aggregates can be reliedupon to distinguish clearly Crohn's diseasefrom ulcerative colitis, provided that no othercause of granulomatous disease is suspected(fig 1).' 2

In a large number of cases of putative IBD,discrete granulomas cannot be seen, but theremay be foci of pericryptal inflammation (fig 2).In some cases, this pericryptal inflammationmay be associated with distinct aggregates ofepithelioid histiocytes and frank granulomaformation (fig 3). These pericryptal granulo-mas may occur in the absence of the discrete,non-crypt related epithelioid granulomaswhich are characteristic of Crohn's disease.They invariably cause segmental disruption ofthe epithelial lining of crypts (figs 4A and 4B).In the most advanced stages, there may beextensive crypt ablation (fig 5). We have usedthe term cryptolytic colitis to describe theseappearances.The importance of these lesions is unknown.

They are usually considered to be a non-specific consequence of crypt damage. Theterm 'mucin granuloma' is sometimes appliedto them, implying that they result from phago-cytosis of mucin leaked from damaged crypts.

It is our experience that true pericryptalgranulomas are histologically distinct frommucin granulomas which are characterised bythe presence of giant cells with pale foamycytoplasm and an absence of epithelioid histio-cytes. We feel that pericryptal granulomas are acause rather than a consequence of crypt lysisand that they may be as important as discretegranulomas.The aim of this study was to investigate

whether patients with pericryptal granulomasoccurring in isolation have a high probability ofsubsequently developing Crohn's disease.

MethodsTwenty two patients with symptoms and signssuggestive of IBD and biopsy specimens withthe histological features of unspecified IBD

148

on October 7, 2021 by guest. P

rotected by copyright.http://jcp.bm

j.com/

J Clin P

athol: first published as 10.1136/jcp.50.2.148 on 1 February 1997. D

ownloaded from

http://jcp.bmj.com/

Importance of cryptolytic lesions and pericryptal granulomas in inflammatory bowel disease

IL

i~~~~~~~~~~i

s '' j j W ~ >,

or

X -. * w f -

* t b W 8, #8iS t t. * . .;.

*4;fie;LtfS **;?

*. §JO4' 1s;§1

r

Figure 1 Discrete granuloma with giant cellformation in the lamina propria(haematoxylin and eosin; original magnification xl 50).

V

Aft~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~8

Figure 2 Colonic biopsy specimen showing pericryptal inflammation without convincin,

granuloma formation (haematoxylin and eosin; original magnification x O).

*.5Stt ¢ * t j ^ . *,

s~~~~1*. s0j|s*t

4-

F ,p'As ; w r , ,.

e * "

Figure 3 Pericryptal granuloma in a colonic biopsy specimen with early erosion of the

crypt epithelium (haematoxylin and eosin; original magnification x280).

were studied. The biopsy specimens all show

unexplained chronic inflammatory reaction

the lamina propria, with or without cryptitis

crypt abscess formation, but lacked any oftfeatures which would enable a clear distincti

to be made between ulcerative colitis a:Crohn's disease. In particular, at the time

inclusion into the study discrete epithelioid cellgranulomas diagnostic of Crohn's disease werenot seen. The examining pathologist was una-ware of the subsequent definitive diagnosis.Patients were divided on the basis of histologyinto two groups.Group A was comprised of patients with

pericryptal granulomas identified on colorectalbiopsy specimens. A pericryptal granulomawas defined as an aggregate of five or more epi-thelioid cells with or without Langhans giantcell formation arising in the vicinity of a cryptand associated with disruption of the epitheliallining (figs 4A and 4B).Group B included patients with pericryptal

inflammation on colorectal biopsy specimens.Pericryptal inflammation was defined as a col-lection ofinflammatory cells without giant cellsand with few (less than five) or no epithelioidcells associated with a crypt. These lesions wereonly occasionally associated with cryptitis (fig2). This was in effect a control group to deter-mine whether or not lesions of this kind mightsimply be a non-specific consequence of cryptdamage and thus qualitatively similar to thelesions observed in group A.The patients were selected from collections

of colorectal biopsy specimens from the years1978-88. This was to allow an adequate lengthof time for follow up of the patients.

HISTOLOGYThe biopsy specimens were processed rou-tinely and 5 gm sections were taken at multiple

# levels, and stained with haemotoxylin andeosin. All slides were examined by an experi-

;. enced pathologist and the presence ofpericryp-tal granulomas was confirmed by using astandard immunohistochemical technique.

g The monoclonal antibodies directed againstCD68 (Dako, High Wycombe, UK) formacrophages and epithelioid cells using thestreptavidin-peroxidase method and broadspectrum cytokeratin (Dako) for epithelial cellsusing indirect immunoperoxidase methods

5 were especially useful in this regard. Alciang blue/PAS stains were also used to demonstrate

mucin and to help differentiate mucin granulo-* mas from pericryptal granulomas. In all cases,' the presence of intestinal pathogens was rigor-

ously excluded by standard cultural methods.* In addition, Ziehl-Neelsen stains were exam-

ined carefully but were negative for acid fastbacilli. All subsequent biopsy and resectionspecimens were also examined to detect thepresence of discrete non-crypt related epithe-

60-, lioid granulomas characteristic of Crohn's dis-ease, or features more suggestive of a diagnosis

t of ulcerative colitis.The progress of the patients was reviewed to

look for clinical or radiological evidence ofsmall bowel involvement. All operative inter-ventions, investigations, complications, and

red extraintestinal manifestations were recorded.in Information about the patients' current statusor was obtained from outpatient consultations. Ahe diagnosis of Crohn's disease was made in thoseLon patients with: (1) discrete non-crypt relatednd epithelioid granulomas on subsequent biopsyof or resection specimens; or (2) convincing

149



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Lee, Maguire, Obeidat, Russell

B..

..~~~~d#. w

~ ~ ~ .0

...,. .- .. .. .. .- .

r-, ,.~t%

-4

*:,bhSPiF §-*~ lb'1W# . : r

*iR;t n 4Je '

4.f.r

,Ii . _

If , :.

..

_.

Figure 4 (A) Colonic biopsy specimen with pericryptal granuloma, extensive erosion ojcrypt epithelium and early crypt abscess formation. (B) Crypt granuloma stained withCD68 using the immunoperoxidase technique (original magnification x150).

$t~ ~ ~.**;R t ^ y

is'^'" ~b'dUU.. *,t"". wv# o* ,f

* .;,' * ; rb. <*) .

40~.

%4~~~~~~~~~~~

b-,wV.Kt.a

Figure 5 Colonic biopsy specimen showing extensive crypt ablation associated with a

diffuse granulomatous process (haematoxylin and eosin; original magnification x130).

evidence of small bowel involvement; or b(1) and (2).

Fischer's exact test was used for statistianalysis.

ResultsOf the 22 patients studied, 14 were assignon the basis of histology, to group A, and eito group B.

DIAGNOSIS OF CROHN'S DISEASE

Following examination of all histology speci-mens and review of the patients' clinicalprogress, 10 of the 14 patients in group A were

subsequently diagnosed as having Crohn's dis-ease (table 1). Nine patients had discretegranulomas seen on subsequent biopsy (n = 5)or resection (n = 4) specimens. Of these ninepatients, four also had evidence of small bowelinvolvement. In one patient with Crohn'sdisease, discrete granulomas were not seen on

histology at any stage, although the patient hadrecurrent small bowel strictures requiringsurgery. Of the remaining four patients, twohad probable ulcerative colitis and two were

being treated for irritable bowel syndrome.In group B, one of eight patients had Crohn's

disease. This patient had a discrete granulomaseen on review of a rectal biopsy specimentaken at a previous presentation four years ear-

lier. At the time of inclusion in the study, thisbiopsy result was unavailable and the examin-ing pathologist was unaware of the diagnosis.Of the remaining seven patients, three were

thought to have ulcerative colitis. In twopatients, the initial presentation was presumedto be because of an infective episode; one hadbeen diagnosed as having irritable bowelsyndrome and another continued to have diar-rhoea secondary to alcohol abuse.The difference between groups A and B is

statistically significant (Fischer's exact testp < 0.05).

In most patients, the definitive diagnosis ofCrohn's disease was made after a relativelyshort follow up period. In eight of 10 patients,

f an unequivocal diagnosis of Crohn's diseasewas made within three years of findingpericryptal granulomas on the colorectalbiopsy specimen.

f.. SURGICAL INTERVENTIONSIn group A, six of 14 patients required surgical

* interventions. All of these patients had Crohn'sdisease. Colectomies or protocolectomies withileostomy formation were performed in fourpatients, two patients had eight hemicolecto-mies, and two had small bowel resections forstricture formation. None of the eight patientsin group B required surgery.

NUTRITIONAL PROBLEMSNutritional problems developed over thecourse of their illness in six patients withCrohn's disease in group A. These includedanaemia, hypoalbuminaemia and hypocalcae-mia. Two patients required intravenous nutri-tion and one had enteral feeding with an

elemental diet.In group B, only one patient had nutritional

problems. This was a man who was disabled as

oth a result of a childhood hemiplegia and who also

iral Table 1 Diagnosis of Crohn's Disease

Group A Group B

Total number 14 8Crohn's disease 10 1Discrete granulomas 9 1Small bowel involvement 5 0Both 4 0

150

,A. '.

t .1

dv 6

-1 ,



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Importance of cryptolytic lesions and pericryptal granulomas in inflammatory bowel disease

had probable ulcerative colitis. He had hy-poalbumimaemia and low folic acid concentra-tions and was treated with enteral feeding.

FOLLOW UPThe length of follow up in group A from thetime of inclusion into the study ranged fromthree to 17 years, with a mean follow up of 8.7years and a median follow up of nine years.

Four patients in group A died after follow up

periods of three, four, eight, and nine years,

respectively. Three of these patients hadCrohn's disease and one had probable ulcera-tive colitis.Length of follow up in group B ranged from

two to eight years, with a mean follow up of 6.6years and a median follow up of seven years.

One patient in group B died two years afterinclusion into the study and thus had a

relatively short follow up period. This patienthad probable ulcerative colitis and died of an

unrelated cause.

DiscussionWe have shown that isolated pericryptal granu-lomas when found on colorectal biopsy speci-mens are associated with a high probability ofthe subsequent development of Crohn's dis-ease. Ten of 14 patients in group A had an

unequivocal diagnosis of Crohn's diseasewhich was supported by the objective findingsof discrete non-crypt related epithelioid granu-lomas or small bowel complications, or both.Eight of 10 patients were diagnosed withinthree years of inclusion in the study.The large number of patients in group A who

required surgical interventions undoubtedlycontributed to the early diagnosis of Crohn'sdisease. In four cases, the definitive diagnosiswas reached following histological examinationof resection specimens.Many patients in group A also had nutri-

tional problems. This is not surprising consid-ering the high percentage of patients with smallbowel involvement and also the number of sur-

gical resections performed. Overall, group Ahad a much higher morbidity than group B.This reflects the larger number of patients withCrohn's disease in group A and also suggeststhat most patients had relatively severe disease.Ofthe four patients'in group A who were not

subsequently diagnosed as having Crohn's dis-ease, two had probable ulcerative colitis andtwo were being treated for irritable bowel syn-drome. Of the two thought to have ulcerativecolitis, both had distal colitis on endoscopicexamination and subsequent biopsy specimenshad shown no diagnostic features of Crohn'sdisease. Only one of these patients had hadsmall bowel radiology. One patient died of car-

diac problems after a follow up period of eightyears, and the other patient has gone abroad.Of the two patients with irritable bowel syn-

drome, one had had no subsequent rectalbiopsies, but had been a frequent attender at anoutpatient clinic for nine years. The otherpatient had a subsequent rectal biopsy per-formed which was normal, and has beenfollowed up for seven years so far. The reason

why these patients had pericryptal granulomas

on their initial rectal biopsy specimen isunclear. It is possible that both patients had anepisode of acute self-limiting colitis whichresolved and then subsequently developed irri-table bowel syndrome.

In our study, pericryptal inflammation wasassociated with a low probability of developingCrohn's disease: only one of eight patients ingroup B. All patients had a relatively longperiod of follow up, seven to eight years, exceptfor one who died two years after the date ofinclusion in the study. In group A, most ofpatients were diagnosed as having Crohn's dis-ease within three years. Therefore, it is unlikelythat further follow up of the group B patientswould result in many more having a diagnosisof Crohn's disease. There were no surgicalinterventions and few complications in groupB. This suggests that these patients hadrelatively benign and self-limiting disease, incontrast to the patients in group A.

Pericryptal inflammation was associatedwith a variety of different clinical outcomes.Three patients were thought to have ulcerativecolitis and of these, one had died of anunrelated cause after a follow up period of twoyears. Another had been treated with oralsulphasalazine and steroid enemas at the timeof initial presentation and had only had mildintermittent symptoms since then. The thirdpatient had distal colitis on endoscopy at pres-entation and had remained symptomatic; thispatient had never had small bowel radiology. Intwo patients, it is likely that the pericryptalinflammation resulted from an episode of acuteself-limiting colitis triggered by an entericinfection. Both patients had no recurrence oftheir symptoms for many years and remainedwell on no medication.

It seems that pericryptal inflammation is inmost cases a mild, transient and self-limitingphenomenon which as many different causes.It usually has a good prognosis and is not asso-ciated with progressive or debilitating disease.

SIGNIFICANCE OF PERICRYPTAL GRANULOMASGranulomatous lesions arising in the vicinity ofmucosal crypts have always presented difficul-ties in the interpretation of colorectal biopsyspecimens. In many studies, relatively littleemphasis has been given to such lesions. In arecent publication concerning the discrimina-tory values of 41 biopsy features in IBD, thereis no specific mention of pericryptalgranulomas.3 In a similar previous study, refer-ence is made to 'basal histiocytic cryptitis' as afeature of IBD and Crohn's disease in particu-lar, but it is not certain whether this lesion canbe equated with the pericryptal granuloma asdefined in the present study.4 Anotherpublication warns that granulomas restrictedto the edges of ruptured crypts are not specificfor Crohn's disease as they may be seen in otherinflammatory conditions, particularly ininfections.5 It is of course certainly true thattuberculosis, syphilis6 and chlamydial7 infec-tion can be associated with microgranulomaformation and that this might be pericryptal inlocation. It has also been shown recently thatpericryptal granulomas might be a feature of

151



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

Lee, Maguire, Obeidat, Russell

diverticular colitis.8 In a recent study by Sura-wicz et al, pericryptal granulomas were referredto as 'granulomatous crypt abscesses' and wereequated with mucin granulomas, implying thatthey may be a result of mucin leakage fromdamaged crypts and that the aetiology and sig-nificance is different from that of a discretegranuloma.9 However, there are earlier refer-ences to granulomas within crypts having asimilar significance as granulomas elsewhere inthe mucosa.10

In our study, special stains have, for the mostpart, failed to demonstrate mucin in pericryp-tal granulomas, and in any case it is unlikelythat the presence of epithelioid histocytescould be explained solely on the basis of mucinleakage. The analysis ofmultiple sections ofthecolorectal biopsy specimens included in thisstudy strongly suggests that crypts are beingdamaged or eroded as a consequence of granu-loma formation in the lamina propria, and thatthis process may lead to widespread crypt abla-tion. This phenomenon is well recognised byhistopathologists in other contexts. Tubercu-lous granulomas arising in the endometriumfrequently erode glands, and provoke neu-trophil migration into gland lamina." A similarphenomenon may also be observed in relationto renal tubules. It is possible that this may alsotake place in the colonic mucosa in Crohn'sdisease.The results of our study thus suggest that

the presence of pericryptal granulomas in acolorectal biopsy specimen should initiate anintensive search for unequivocal granulomaselsewhere in the gastrointestinal tract. We

would also recommend that the patient hasclose follow up, be screened for nutritionaldeficiencies and have small bowel radiologyand other investigations as necessary. Finally,as these patients are very likely to developCrohn's disease in the near future, the presenceof pericryptal granulomas should signal awarning to surgeons that ileoanal pouchconstruction might have unwelcome conse-quences.

1 Rotterdam H, Korelitz BI, Sommers SC. Microgranulomasin grossly normal rectal mucosa in Crohn's disease. Am JClin Pathol 1977;67:550-4.

2 Cook MG, Dixon MF. Analysis of reliability of detectionand diagnostic value of various pathological features inCrohn's disease and ulcerative colitis. Gut 1973;14:255-62.

3 Theodossi A, Spiegelhalter DJ, Jass J, Firth J, Dixon M,Leader M, et al. Observer variation and discriminatoryvalue of biopsy features in inflammatory bowel disease. Gut1994;35:961-8.

4 Seldenrijk CA, Morson BC, Meuwissen SGH, SchipperNW, Lindeman J, Meijer CJLM. Histopathological evalua-tion of colonic mucosal biopsy specimens in chronicinflammatory bowel disease: diagnostic implications. Gut1991;32:1514-20.

5 Goldman H, Antonioli DA. Mucosal biopsy of the rectum,colon and distal ileum. Hum Pathol 1982;13:981-1012.

6 McMillan A, Lee FD. Sigmoidoscopic and microscopicappearance of the rectal mucosa in homosexual men. Gut1984;23:1035-41.

7 Quinn TC, Goodell SE, Mkrtichian E, Schuffler MD, WangS, Stamm WE, et al. Chlamydia trachomatis proctitis. NEnglJMed 1981;305:195-200.

8 Makapugay LM, Dean PJ. Diverticular disease-associatedchronic colitis. Am Jf Surg Pathol 1996;20:94-102

9 Surawicz CM, Haggitt RC, Husseman M, McFarland LV.Mucosal biopsy diagnosis of colitis: Acute self limited coli-tis and idiopathic inflammatory bowel disease. Gastroenter-ology 1994;107:755-63.

10 Surawicz CM, Meisel JL, Ylvisaker T, Saunders DR, RubinCE. Rectal biopsy in the diagnosis of Crohn's disease: valueof multiple biopsies and serial sectioning. Gastroenterology1981;80:66-71.

11 Govan ADT. Tuberculous endometritis. J Pathol Bacteriol1962;83:363-72.

152



j.com/

J Clin P


ownloaded from

http://jcp.bmj.com/

importance of cryptolytic lesions pericryptal granulomas

Documents