Mimics of inflammatory bowel disease - British Division of ...bdiap.org/wp-content/uploads/2017/04/Shepherd.pdf · summary as implying UC and treat as such ... Pathological mimics

Gloucestershire Cellular Pathology Laboratory

Mimics of inflammatory bowel disease

Professor Neil A Shepherd Gloucester & Cheltenham, UK

BDIAP Intestinal Pathology London, UK

29 November 2013

The three most important factors when assessing problematic inflammatory GI biopsies:

CONTEXT

CONTEXT

CONTEXT


Pathological mimics of inflammatory bowel disease • Infections viral bacterial – TB, yersinia, chronic enterocolitides mycotic protozoal helminthic • Drugs, enemas & suppositories • Endoscopic preparation • Immunopathology immunodeficiency syndromes GvHD granulomatous disease of childhood • Ischaemic enterocolitis • Radiation enterocolitis • Behcet’s syndrome

• Diversion proctocolitis • Diverticular/segmental colitis • Secondary colitis • Focal active colitis • Pouchitis and pre-pouch ileitis • Microscopic colitis (MC) lymphocytic colitis collagenous colitis granulomatous MC giant cell MC • Obstructive colitis • Pneumatosis cystoides intestinalis • Endometriosis • Malignant lymphoma and other tumours


Reporting biopsies for potential CIBD

• need full clinical and endoscopic information: get the endoscopic report with

request form

• exclude ‘mimics’ of IBD: clinical, endoscopic, microbiological and imaging information crucial

• call it CIBD, if all the data supports that diagnosis, and not ‘colitis’, ‘active colitis’, ‘proctitis’ unless the latter is in the context of known UC

• please don’t use unhelpful or potentially misleading terminology


Why not ‘colitis’? • ulcerative colitis • Crohn’s colitis • infective colitis • self-limiting colitis • pseudomembranous colitis • antibiotic-associated colitis • diversion colitis • diverticular colitis • segmental colitis • crescentic colitis • secondary colitis • obstructive colitis • minimal change colitis

• drug-induced colitis • eosinophilic colitis • microscopic colitis • lymphocytic colitis • collagenous colitis • phlegmonous colitis • focal active colitis • transient colitis • necrotising colitis • radiation colitis • ischaemic colitis • neutropaenic colitis • haemorrhagic colitis


Why not ‘colitis’, especially in the diagnostic summary?

• if it is CIBD, you’re in the clear

• if it isn’t and is just a mimic, clinicians may interpret the diagnostic

summary as implying UC and treat as such

• very damning consequences for the patient, especially if it is infective

• serious consequences for the Trust if major patient mishap occurs and the patient sues

The histopathological spectrum of CIBD


The pathological spectrum of Crohn’s disease

fibro-stricturing inflammatory +/- fistulae

Borley et al, 2000





Case report 37M. Clinical data available: “Blood and mucus

PR with urgency. Sigmoidoscopy showed patchy inflammation (sic) in sigmoid colon and rectum but thereafter normal. Patchy change and rectal aching (sic). ? Crohn's disease.”

Sigmoid colonic and rectal biopsies.


Case report


Case report


Case report: report at the time

Histological examination shows rectal mucosa with variable inflammation in the three submitted biopsies. One biopsy is intensely inflamed, with sloughing superficial ulceration and neutrophil exudation. The crypt pattern is quite regular, but goblet cells are almost entirely lost and there are intense regenerative changes. The lamina propria contains a dense mixed inflammatory infiltrate with multiple foci of neutrophils. A second biopsy shows more crypt irregularity but there is some retention of goblet cells and a less intense inflammatory infiltrate. The third biopsy shows variable goblet cell depletion and only limited inflammation, with no active cryptitis. Granulomatous lesions are not identified in any of these biopsies, but, although the appearances are not diagnostically specific, the features are certainly consistent with Crohn's disease. RECTAL MUCOSA - ACTIVE CHRONIC INFLAMMATION; FEATURES CONSISTENT WITH CROHN'S DISEASE


Case report

• treated with low dose mesalazine

• continuing symptoms

• six months later investigated for

continuing symptoms and PUO


Case report


Infection vs CIBD

• don’t ever forget amoebiasis

• steroids or other immunosuppressants for systemic amoebiasis = disaster with very high mortality

• always look for amoebae in index cases of ‘CIBD’

• ? routine PAS


Case report

32M. Abdominal pain and PR bleeding. Focal ulceration and induration in lower rectum and anal canal.

Clinical and endoscopic diagnosis of Crohn’s disease.



Anorectal junction



Herida M et al. Rectal lymphogranuloma venereum surveillance in France 2002-2005. Euro Surveill 2006; 11: 146-8.


LGV proctocolitis

• current Western European mini-epidemic in HIV positive men

• clinical, endoscopic and histopathological mimic of Crohn’s disease

• clues: not that many: just have a high suspicion and know the clinical data

Campylobacter colitis mimicking CIBD


Campylobacter and ‘indeterminate colitis’






NSAIDs and CIBD: associations and masquerades

• NSAID colopathy may mimic CIBD, especially when used in suppositories Fenzy & Bogomoletz, 1987

• NSAIDs can cause CIBD?

• or trigger the first attack of CIBD

Bjarnason et al, 1987

• NSAIDs induce relapse of CIBD Rampton & Sladen, 1981


Other drugs associated with CIBD-like disease

• other drugs, including iron sulphate tablets, can induce a relapse of CIBD

• alpha methyl DOPA causes a CIBD-like condition Graham et al , 1981

immunosuppressive agents: • mycophenolate is used to treat CD and causes a CD-like syndrome in the

ileum and right colon Liapis et al, 2013


New kids on the block….. 60M. Diarrhoea. Past history of malignant melanoma.

Thanks to Prof Kieran Sheahan


Ipilimumab-associated colitis

• monoclonal antibody vs cytotoxic T-lymphocyte antigen 4 (CTLA4), a key negative regulator of CD4 regulatory T cells

• used in melanoma & rarely in ovarian, prostate & renal cell carcinoma

• colonic toxicity: 20% patients

• persistent bloody diarrhoea, fever, abdominal pain, rarely perforation

• resembles Crohn’s disease on endoscopy


New kids on the block

• imatinib causes an IBD-like colitis

Riddell, personal communication

• dasatinib causes an IBD-like haemorrhagic colitis Erkut et al, 2010

Sunami et al, 2011 Kmira et al, 2013





Author Year Patients UC-like UC later Treatment

Cawthorn 1983 3 3 0 variable

Sladen 1984 5 3 1 sulph, ster

Gore 1992 34 11 3 sulph, ster

Peppercorn 1992 8 8 0 sulph, ster

Polit 1993 1 1 0 sulph, ster

Rosendaal 1996 2 2 0 5ASA, abs

Makapugay 1996 23 23 3 sulph, ster

Pereira 1998 1 1 1 surgery

Imperiali 2000 20 20 0 variable

Evans 2002 4 2 0 surgery

Gupta 2003 7 7 0 surgery

Freeman 2008 24 24 0 surgery

Mulhall 2009 3 3 3 IBD-type

TOTAL 135 108 11


Diverticular colitis and ulcerative colitis

• mimicry of UC by diverticular colitis the rectum should always be biopsied!

• some cases progress from diverticular colitis to classical UC ? similar pathogenesis in some cases


Diverticulosis and Crohn’s disease

• granulomas

• focal active inflammation

• transmural inflammation in the form of lymphoid aggregates

• fissuring ulceration and fistulae

Makapugay & Dean, 1996; Burroughs et al, 1998; Gledhill & Dixon, 1998; Goldstein et al, 2000; Ludeman & Shepherd; 2002


Diverticular disease and Crohn’s disease • formerly believed that the two conditions coexisted much more often than would be expected

Meyers et al, 1978; Berman et al, 1979; McCue et al, 1989

• more recently it is clear that many, if not all, of the classical pathological hallmarks of CD can be mimicked by complicated DD

Study patient number and pathology

cases with CD elsewhere

cases with no CD

Burroughs et al, 1998 8: granulomatous pathology

0 8

Gledhill & Dixon, 1998 11: CD changes and diverticulitis

2 9

Goldstein et al, 2000 27: CD-like changes 4 (2 before; 2 after sigmoid resection)

23


Diverticular disease and Crohn’s disease

• a Crohn’s-like reaction can be a localised reaction to diverticulitis alone Gledhill and Dixon, 1998

• Crohn’s-like changes are an idiosyncratic inflammatory response to diverticulosis rather

than coexistent Crohn’s disease in the vast majority of patients Goldstein et al, 2000

• pathologists should be wary of making a diagnosis of sigmoid colonic Crohn’s disease in the context of diverticulosis

Goldstein et al, 2000

• whilst we do not deny that Crohn’s disease and diverticulosis can co-exist and that their coincidence may worsen the prognosis of either disease, we believe that extreme caution is required before making the diagnosis of coexistent disease, in the absence of collateral evidence to support a diagnosis of Crohn’s disease

Ludeman, Warren & Shepherd, 2002

• look elsewhere for evidence of Crohn’s disease!





Focal active colitis (FAC)

term used to describe isolated finding of neutrophilic crypt injury

single/multiple foci of cryptitis single discrete crypt abscess multiple crypt abscesses no significant chronic inflammation

histological features:

Greenson et al, 1997


Focal active colitis

follow-up (1-74 months, mean = 25 maths)

no patient developed CIBD

acute self-limited infectious colitis (45%) incidental finding (25%) irritable bowel syndrome (14%) ischaemia (10%) antibiotic associated colitis (5%)

45% patients immunosuppressed, 40% taking NSAIDs




infective/ self-limited

drugs

IBS

incidental

CIBD


USA 42 cases

adults

45% 14% (NSAIDS and Abs)

14% 26% 0

Volk et al, 1998

USA 31 cases

adults

48% ? 10% ischaemic

colitis

29% 13% all CD

Xin et al, 2003

USA 31 cases children

31% 0% 0% 27.6% 31% 8 CD; 1 UC


Shetty et al, 2011 • prospective, unselected series from routine practice of one specialist gastrointestinal

pathologist (NAS) in a single large general hospital (GRH, UK)

• prospective patient accrual initiated in 1994 and terminated in 2004

• approved by the Glos Research Ethics Committee (ref 05/Q2005/70)

• full written consent & questionnaire, specifically designed, in which gastrointestinal symptoms, drug history and full medical history were documented

• only those consenting & fully completing questionnaires included

• hospital records & study questionnaires analysed independently for:

patient symptoms, drug history, microbiological findings endoscopic findings (including preparation) follow up, especially subsequent endoscopic & histopathological analysis for

potential inflammatory bowel disease (IBD), & final outcome

Basal focal active colitis

• 10 cases of ‘basal FAC’

• diffuse basal involvement of crypts by

neutrophils with enhanced apoptosis • strongly associated with drugs,

especially NSAIDs

• ? relatively specific abnormality, more likely associated with drug therapy than FAC in general

• similar to ‘apoptotic colopathy’ McKenna et al, 1999


Results

infective/ self-limited

drugs

IBS

incidental

CIBD

Shetty et al, 2011

UK 90 cases

adults

19% 24% NSAIDS and

Abs

33% 8% 16% 10 CD, 2 UC,

2 IBDU

14 patients with CIBD 10: Crohn’s disease (5 colorectum only; 3 ileum and colorectum; two colorectum and anus; one colon and duodenum) 2: IBDU 2: ulcerative colitis with characteristic endoscopic & histological findings affecting at least the rectum time between FAC diagnosis & subsequent CIBD diagnosis: 18m to 6 years no clinical or histopathological feature predicted ultimate diagnosis of CIBD type


infective/

self-limited

drugs

IBS

incidental

CIBD


USA 42 cases

adults


14% 26% 0

Volk et al, 1998

USA 31 cases

adults

48% ? 10% ischaemic

colitis

29% 13% all CD

Xin et al, 2003

USA 31 cases children

31% 0% 0% 27.6% 31% 8 CD; 1 UC

Shetty et al, 2011

UK 90 cases

adults


33% 8% 16% 10 CD; 2 UC;



• FAC is not an uncommon diagnosis in pathological practice

• about 15 cases per year diagnosed in this single busy gastro-intestinal pathological practice

• FAC will be diagnosed about 50 times per year in the average ‘general hospital’ practice

• diagnosis more often in women, especially those eventually with CIBD

• female predominance not seen in two studies but, in Greenson’s original study, 63% of the patients were female



• ? associated chronic inflammatory change in addition to FAC

• may be difficult: ? normal round cell infiltrate of the lamina propria

• our study and those of Greenson: the changes represent ‘pure’ FAC

• Volk study: eosinophils in 39% of cases and infiltrates of plasma cells in 35%

• apples and pears ?


FAC becoming Crohn’s disease: a recent case

23F. Initial diarrhoea. Normal colonoscopy including TI.

Six months later: worse symptoms with endoscopic TI disease


A touch of reality ?

“my approach to all GI biopsies is to ignore small inflammatory things, since they are not specific diseases and they mean nothing to clinicians, unless the report is accompanied by a long, long comment explaining what these tiny insignificant things mean.”

“but don’t tell Joel – you’ll get me into trouble”

Henry D Appelman





CIBD and microscopic colitis

• clinical and endoscopic correlation all important

• the term ‘microscopic colitis‘ infers a normal endoscopy……..

• a normal endoscopy is very unusual at the index endoscopy in CIBD, especially UC (but beware children)

• cases must fulfil three criteria for an MC diagnosis:

clinical: chronic watery diarrhoea endoscopic: normal………. histological: chronic inflammation +/- the other features


Colonoscopic abnormalities in microscopic colitis

Koulaouzidis A, Saeed AA. Distinct colonoscopy findings of microscopic colitis: Not so microscopic after all? World J Gastroenterol 2011; 17: 4157-4165.


CIBD and microscopic colitis

• clinical correlation all important

• the two can co-exist: drugs used to treat CIBD can cause microscopic colitis


Microscopic colitis: ‘new types’

• microscopic colitis with giant cells Libbrecht et al, 2002

• four cases: 3 with CC, 1 with LC

• fusion of subepithelial macrophages

(CD 68 +)

• note apoptotic activity


Microscopic colitis: ‘new types’

• microscopic colitis with granulomatous reaction

Saurine et al, 2004

• association with NSAIDs, allopurinol & antibiotics

• cryptolytic and superficial granulomas

• with thanks to Bob Eckstein, Sydney, Australia


Case report

• 81F

• chronic watery diarrhoea

• normal colonoscopy

• “In the first published series of this entity, drugs were thought to be a prominent cause of granulomatous microscopic colitis. Is there any significant drug history in this patient?”


Case report

“She takes buscopan and feels this helps as do probiotics and she is also on aspirin, paracetamol, GTN, omeprazole, isosorbide mononitrate, nicorandil, ferrous fumarate, tiazem, ezetimibe, loperamide and colofac.”

Mimics of inflammatory bowel disease:

take home messages • infections are an important mimic of CIBD: TB, yersinia, amoebiasis, LGV and

campylobacter cause the most problems

• there is an extraordinary relationship between drugs and CIBD. They cause (?), they mimic, they exacerbate, they induce and they treat!!

• there are overlaps between the mimics of CIBD and CIBD itself, eg diverticular colitis and ulcerative colitis, microscopic colitis complicating CIBD treatment

• pathologists often confuse focal active colitis and microscopic colitis with CIBD

• nowhere is context more important in gastroenterology than in colorectal biopsies taken for potential CIBD

• don’t be too concerned: CIBD is common and very close mimics are rare

Documents

Mimics of inflammatory bowel disease - British Division of ...bdiap.org/wp-content/uploads/2017/04/Shepherd.pdf · summary as implying UC and treat as such ... Pathological mimics