What_is_colitis - What is colitis? What Pitfalls in the...

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Unformatted text preview: What is colitis? What Pitfalls in the microscopic diagnosis K. Geboes, KULeuven, 2004 Normal colon Normal • Epithelium – Surface • Flat - regular – Crypts • Tubular – perpendicular base reaches muscularis mucosae • intercryptal distance and internal diameter similar – Cells • Columnar cells Normal colon Normal • Lamina propria – Immune competent cells • Organized lymphoid tissue • Lamina propria lymphocytes • Intraepithelial lymphcoytes – Extracellular matrix • Muscularis mucosae What is colitis? Statistical approach (morphometry) • Chronic inflammatory infiltration total cellularity increase • Surface epithelial height to crypt epithelial height. In normal mucosa the surface epithelial cell height exceeds the height of crypt epithelium • Redistribution of infiltrating cells so that there is a similar density in the basal third to that of the superficial third > IBD Jenkins e.a. J Clin Pathol 1988; 41; 72-79 What is colitis? • The normal mucosa is a dynamic structure – Epithelial cell turnover – Traffic of immune competent cells • A pure morphometric approach of one time point may have limitations Normal mucosa vs Colitis Normal – Lamina propria cellular infiltrate : increase in intensity; composition & distribution – Organized lymphoid tissue : stimulation – Epithelium : • surface epithelium – terminally differentiated cells DAMAGE & REPAIR (restitution) • crypts – differentiating cells, proliferative compartment INCREASED PROLIFERATION (mitotic activity) • normal turnover : increased turnover Basic lesions : Inflammation Basic • Inflammation pattern I – Patchy, focal – Diffuse Basic lesions : Inflammation Basic • Inflammation pattern II – Diffuse upper third (Infections such as Shigella colitis) – Diffuse transmucosal (IBD) Basic lesions : Inflammation Basic • Inflammation composition – Mononuclear – Mixed • Active disease when combined with epithelial damage – Eosinophils – Mast cells (tryptase) Basic lesions : Architecture Basic • Surface – Flat or irregular Basic lesions : Architecture Basic • Crypt architecture – Crypt density • 7/8 crypts per 1 mm mucosal length (IBD 4 to 5) • Closely packed – Variable or constant intercryptal distance Basic lesions : Architecture Basic • Crypt architecture – Straight or branching tubes (infrequent branching < 10% may be normal) – Base reaching muscularis mucosae – Variable or constant internal diameter Ulcerative colitis : Bifid crypts – Ulcerative transverse section Basic lesions : Architecture Basic • Crypt architecture – Straight or branching tubes (infrequent branching < 10% may be normal) – Base reaching muscularis mucosae – Variable or constant internal diameter Regular crypts with solitary giant cell; UC – shortened crypts Basic lesions : Epithelial cells Basic • Restitution • Mitotic activity Basic lesions : Epithelial cells Basic • Increased mitotic activity indicates repair : Ki67 in Ulcerative colitis : upregulation Basic lesions : Epithelial cells Basic • Metaplasia – Paneth cell metaplasia – Ulcer associated cell lineage Clinical Situations Clinical • No clinical information – Non specific colitis • Normal macroscopy – Microscopic colitis • Collagenous colitis; lymphocytis colitis; giant-cell colitis; microscopic colitis otherwise not specified (mos) • Inflammatory diarrhoea – – – – Infectious colitis Drug-induced colitis Inflammatory bowel disease Miscellaneous No clinical information “Non-specific inflammation” Tsang & Rotterdam, Am J Surg Pathol 1999; 23: 423-30 Increase in inflammatory cells beyond what would be Increase expected physiologically in the corresponding anatomic sites. Crypts may show reactive changes, such as an increase in mitoses and slight irregularity in shape. Lack of sufficient clinical data or distinctive Lack histopathological features precludes further classification into specific etiologic types of colitis No clinical information “Non-specific inflammation” Tanaka & Riddell, Hepato-gastroenterol 1990; 37: 18-31 Hepato Predominantly chronic inflammatory cell infiltrate in the absence Predominantly of architectural distortion and multiple basal lymphoid aggregates or plasma cells immediately above the muscularis mucosae. Such a pattern can be seen in resolving infections, complicated Such diverticular disease, drug-induced colitis and bile-salt malabsorption, but may include CD. However, it is currently impossible to make a positive diagnosis of CD in these circumstances, although in a patient with known CD the lesions may well represent local involvement Normal endoscopy Normal • Pts with clinical suspicion irritable bowel syndrome (IBS) and normal colon at endoscopy • Mucosal inflammation present in 27% of pts with chronic diarrhoea and negative macroscopic findings – Whitehead R. Virch Arch Pathol Anat 1990; 47; 187 Prolonged Diarrhea Prolonged Normal endoscopy No new case of IBD Melanosis coli - Microscopic colitis – 59 patients : colonoscopy for anemia : normal biopsy McIntosh e.a. Am J Gastroenterol 1992; 87; 1407 McIntosh – 100 consecutive patients : symptoms ? : 22 pathologic biopsy Prior e.a. Dis Dis Sci 1987 – 111 patients : 20 pathologic biopsy, Marshall e.a. Marshall 1994 Normal endoscopy Normal • • • • Infections Post infectious IBS Drug-related disease Microscopic colitis – Collagenous colitis – Lymphocytic colitis • Idiopathic • Infectious • Drug-related – Giant cell colitis – Microscopic colitis otherwise not specified Human Intestinal Spirochetosis Human • ♂>♀ • Less common in children ? • Usually asymptomatic • Pathogen/commensal ? • incidence in homosexual men and immunocompromised (AIDS) pts Infections & Colitis Infections – Enterohemorragic E. coli : important in western world – lesions in terminal ileum and colon – Microscopy Normal Acute inflam Ischemic type Normal 12 / 31 10 / 31 5 / 11 12 Combination Pseudomembranous colitis Combination 4/11 4 / 11 4/11 (Griffin e.a. Gastroenterology 1990, 99, 142; Kelly e.a. Am J Clin Pathol 1987, 88, 78) Infections & Colitis Infections macrophages • Lou e.a. Hum Path 1971; 2; 421 Colonic histiocytosis : 34/50 (68%) consecutive rectal biopsies : small collections of PAS+ cells • Bejarano e.a. Am J Surg Pathol 2000; 24; 1009 40% of biopsies +; associated changes point to healing phase Macrophages (476367) or Storage Macrophages diseases (698451) Infections & Colitis Infections macrophages • Bile salt colitis • Storage diseases Post infectious IBS Post 25% of pts with Campylobacter colitis CD3 staining lamina propria lymphocytes. ***p<0.001 v controls. Spiller e.a. Gut 2000; 47; 804 Lamina propria (LP) T lymphocyte counts per high power field (hpf) in 52 IBS patients with diarrheal symptoms. Lymphocyte scores increased with increasing frequency of diarrhea. *p = 0.04 vs 2 days/wk of loose stools. **p = 0.012 vs 2 days/wk of loose stools. (Dunlop e.a. Am J Gastroenterol 2003; 98; 1578) Drug-Induced Colitis : The Problem • Diarrhoea is a frequent adverse event of drugs – 7% of all drug adverse effects – 4.1% in 5,669 pts with lansoprazole • More than 700 drugs have been implicated in causing diarrhoea • Colitis is less common and associated with less drugs Drug-Induced Colitis : Clinical Presentation • Acute Diarrhoea – Usually during the first days of treatment • Chronic Diarrhoea – Can appear long time after start of drug Drug-Induced Colitis :Pathogenesis of diarrhoea (& colitis) • Secretory diarrhoea – Antineoplastics, gold salts, biguanides, cardiac glycosides, prostaglandins • Shortened transit time – Cisapride, erythromycin • Malabsorption of fat & carbohydrates – Gold salts (auranofin) .. • Osmotic diarrhoea – Lactulose, antacids, sugar substitutes Drug-Induced Colitis :Pathogenesis of diarrhoea (& colitis) • Protein-loosing enteropathy – Antineoplastics, antibacterials • Toxic and immunologic injury • Promotion of infections – Antibacterials, antineoplastics, immunosuppressive agents.. • Allergic reaction • Impairment of cell proliferation Drug-Induced Colitis : Patterns • Eosinophilic colitis – Aspirin – Psychotropic drugs (carbamazepine) – Ticlodipine • Microscopic colitis (Lymphocytic more common) – Proton pump inhibitors – NSAIDs – Veinotonics H2 receptor antagonists Ticlodipine Carbamazepine Microscopic colitis Microscopic • Collagenous colitis – Chronic watery diarrhoea – Discontinuous thickening of subepithelial collagen table – Multiple biopsies – Changes with treatment Microscopic colitis Microscopic Collagenous colitis • Normal crypt architecture • Increased subepithelial collagen band (nl 0-3 µm; more than 7, 10 or 15 to 20 µm) • Increase number of intraepithelial lymphocytes (nl = 4/100) • Increase of mononuclear cells in lamina propria • Paneth cell metaplasia (more severe disease; relation with IBD?) Microscopic colitis Microscopic Collagenous colitis • Biopsies of the whole colon are required as sigmoid and rectum may fail to show significant thickening of collagen band – Jessurun e.a. Hum Pathol 1987; 18; 839 – Offner e.a. Hum Pathol 1999; 30; 451 • Staining for tenascin may be useful for the diagnosis of minimal collagenous colitis – Muller e.a. Virch Arch 2001; 438; 435-41 Microscopic colitis Microscopic • Lymphocytic colitis – Normal architecture – Flattened – cuboidal surface ep cells – Increase in interepithelial lymphocytes (>20/100) – Increase in lamina propria cells Microscopic colitis Microscopic • Microscopic colitis with giant cells – Libbrecht e.a. Histopathology 2002; 40; 335 – Sandmeier & Bouzourene Int J Surg Pathol 2004; 12; 45 • Cryptal lymphocytic coloproctitis – Rubio & Lindholm J Clin Pathol 2002; 55; 138 Microscopic colitis Microscopic Microscopic colitis not other wise specified (NOS) Warren BF, Histopathology 2002; 40 in stead of nonspecific colitis – Patients with chronic diarrhoea and normal colonoscopy – Increase in inflammatory cells in multiple biopsies Microscopic colitis & IBD Microscopic – 26 pts with a diagnosis of IBD and microscopic colitis (based on a review of 12 centres : 9 Europe; 3 North America) • Panaccione e.a. Gastroenterology 1999; 116: A833 • Geboes IOIBD, unpublished – Progression towards Ulcerative colitis • 4 pts : elderly patients, pancolitis, Geboes IOIBD • Pokorny e.a. J Clin Gastroenterol 2001; 32; 435 – Progression towards Crohn’s disease • 2 pts : Geboes IOIBD – Healing (?) after IBD Inflammatory diarrhea Inflammatory Acute unclassified colitis (6 wks duration) Notteghem e.a. Gastroenterol Clin Biol 1993, 17, 811-815 104 pts; results : – 16 – 88 follow-up : 2.5-3yrs Lost for follow-up - 46 (52.3%) > IBD 54% = UC 33% = CD 13% = Unclass - 42 (47.7%) > no relapse Infective-type colitis Infective Spectrum of microscopic features – normal biopsy toxins • Vibrio ch; Klebsiella – oedema – active inflammation invasion • Yersinia, Campylo – fulminant lesions (extensive necrosis) – residual lesions Oedema Oedema • Drug-induced – Laxatives, enema • Infections Infective-type colitis (593579) Infective Infective-type colitis Infective Microscopic features • Architecture – NORMAL (except ...) String of Pearls • Inflammation – DISTRIBUTION : focal – patchy – COMPOSITION • NEUTROPHILS (active acute) – early (day 1-7) Superficial upper part of lamina propria & upper part of crypts • MONONUCLEAR CELLS – late (day 9, 10) – superficial (except...) IBD and infection at diagnosis First attack of colitis • ASLC group • IBD group 78% + culture 21% + culture Schumacher e.a. Scand J Gastroenterol 1993, 28, 1077-85 IBD and superinfection at relapse IBD • • • • Species Species C. difficile Salmonella typhimurium Campylobacter jejuni Enteropathogenic E. coli Initial nr of patients Initial Total nr positive Total CD 4 0 1 3 49 9(18%) UC 1 1 0 0 15 2(13%) Weber e.a. J Clin Gastroenterol 1992, 14, 302-8 Weber Amoebiasis Amoebiasis Colonoscopy in inflammatory diarrhea Colonoscopy Where to biopsy? How many? Where Number of samples (Bentley e.a. J Clin Pathol 2002, 55; 955) Material & Methods 25 pathologists 60 cases with follow up (rectal & full colonoscopic series) Results Rectum full series Crohn’s disease : 24% > 64% Ulcerative colitis : 64% > 74% Colonoscopy & biopsy in Colonoscopy inflammatory diarrhea • Diagnostic accuracy : 92 – 96% – Pera e.a. Gastroenterology, 92; 1987 – Dejaco e.a. Endoscopy 35; 2003 Clinical data, endoscopy and biopsy = accurate diagnosis in 96% • Endoscopy is the first-line procedure in the initial evaluation of patients with unexplained diarrhea and suspected IBD because of – Direct visual appreciation of lesions – The ability to collect biopsy samples D.D Chronic Idiopathic Inflammatory Bowel D.D Disease - Acute Self Limiting (Infectious type) Colitis – Surawicz e.a. 1984 – Nostrant e.a. 1987 – Schmitz-Moorman & Himmelman, 1988 – Therskildsen e.a. 1989 – Notteghem e.a. 1993 – Schumacher e.a. 1994 D.D Chronic Idiopathic Inflammatory Bowel Disease - Acute D.D Self Limiting (Infectious type) Colitis • Surawicz e.a. 1984 : 148 pts, (44) - (22 short course IBD, 82 long course, 26 CD) – 75% of CD : crypt distorsion • Nostrant e.a. 1987 : 168 pts, (48) - (36 short course - 84 long course UC) – Histopathology differentiates ASLC from UC (crypt distorsion - plasmacytosis) • Therskilden e.a. 1989 : 32 pts – lesions absent at 1 mth, no predictive value D.D Chronic Idiopathic Inflammatory Bowel Disease - Acute D.D Self Limiting (Infectious type) Colitis Basic lesions mucosal architecture • regular - irregular surface • crypt distorsion inflammatory infiltrate • basal plasmacytosis Chronic Idiopathic Inflammatory Bowel Disease Chronic Ulcerative colitis Biopsy Diagnosis & IBD - Evolution in Biopsy Time Schumacher e.a. Scand J Gastroenterol 1994 Schumacher Colonoscopy in inflammatory diarrhea Colonoscopy Repeat Endoscopy! • Repeat endoscopy can help to establish a precise diagnosis – 12 pediatric pts with indeterminate colitis > UC Markowitz Am J Gastroenterol 88; 1993 – 14% (out of 96) developed a pattern more consistent with UC Langevin e.a. Am J Gastroenterol 15; 1992 • Repeat biopsy can help to establish a precise diagnosis Drug-Induced Colitis : Lesions, type & distribution & evolution • Microscopy Normal Infectious-type colitis IBD-like pattern Specific features Variable oedema ischemic-type colitis microscopic colitis • Evolution – Complete remission after elimination of offending agent Drug-Induced Colitis : Patterns • Infective-type colitis – Antibacterials – NSAIDs – Cyclosporin • Ischemic-type colitis – Cardiovascular drugs (diuretics, digoxin, antihypertensive drugs…) – Oral contraceptives – Ergot alkaloids – NSAIDS Drug-Induced Colitis : Patterns • IBD-like pattern : Crohn’s disease without granulomas – Mycophenolate mofetil • IBD-like pattern : Crohn’s disease with granulomas – Diclofenac – Clofazimine • IBD-like pattern : Ulcerative colitis – Diclofenac – Amionogluthemide (antineoplastic agent) • Graft-versus-host-like pattern (mofetil) Graft-versus-host-disease (1070784) Graft Graft-versus-host-disease Graft • Differential diagnosis – conditioning regimen – toxic drug reactions – primary infections • Acute GVHD : focal crypt cell necrosis (apoptosis - “popcorn lesion”) • Chronic GVHD : extensive crypt cell degeneration - loss of crypts Mofetil Mycophenolate & Chronic diarrhoea • 3/20 pts with Crohn’s disease Hafraoui e.a. Gastroentérol Clin Biol 2002, 26, 17 • 26 pts (mean age 41.5yrs) with cadaveric organ transplant > persistent afebrible chronic diarrhoea – 13 infections (Campylobacter, CMV ..) – 13 Crohn’s-like morphology Mofetil Mycophenolate & Chronic diarrhoea Drug-Induced Colitis : Patterns • Specific patterns – Pancreatic enzyme supplements and colonic strictures – Crypt epithelial cell apoptosis – fluorouracil – NSAIDs (diclofenac, mefenamic acid) – Cyclosporin – Colchicine – Ranitidine – Ticlodipine Drug-Induced Colitis : Patterns • Specific patterns – Clofazimine and crystal-storing histiocytosis – (pseudo)melanosis coli – Kayexalate-sorbitol questran - colitis Drug-Induced colitis : Patterns Kayexalat-sorbitol colitis Miscellaneous Miscellaneous • Architectural abnormalities – Transition points (rectum, caecum) – Post-surgery – Radiation Radiation-induced disease (662079/6) Radiation • Acute • Chronic – Loss of crypts – Fibrosis hyalinization of stroma – vascular ectasias – limited inflammation Focal active colitis Focal • • • Def : focal crypt injury by neutrophils 39 pts : no history of IBD (average follow up 20 mths) Results – 20 pts ASLC – 6 pts antibiotic associated colitis – 3 pts IBS – 2pts ischemic colitis – 1 pt radiation colitis – 7 incidental finding - no further diagnosis Stern e.a. Gastroenterology 108; 1995, A922 Focal active colitis (671857) Focal Endometriosis Endometriosis • Intestinal endometriosis : prevalence – 3-37% of all endometriosis • Anatomic distribution : – rectosigmoid 50-90%, caecum 2-5%, appendix 3-18%, small intestine 2-16% • Asymptomatic Symptomatic – Ileal endometriosis : acute, chronic or recurrent distal small bowel obstruction • (Small) Intestinal endometriosis – may mimic CD – may be associated with CD Endometriosis (1036672) CK7 Endometriosis Diverticular disease-associated Colitis Diverticular • • • • Chronic colitis localized to the sigmoid colon and occurring in association with diverticular disease (Makapugay & Dean Am J Surg Pathol 1996, 20, 94-102; Ludeman & Shepherd Pathology 2002; 34; 568-572) Pathogenesis : multifactorial (mucosal prolapse, ischemia..) Microscopy – crypt distorsion, basal plasmacytosis > UC-like – fat wrapping, fissures - sinuses, granulomas > CD-like (Goldstein e.a. Am J Surg Pathol 2000, 24, 668-675) – no lesions proximal and distal Outcome – 3 / 23 > UC (Makapugay) – 2 / 25 > CD (Golstein) Pseudomembranous colitis Pseudomembranous • C. difficile induced • Wide range of mucosal lesions (Rocca e.a. 1984) – – – – No lesions Oedema & congestion Non-specific colitis Classic features 8% 8% 31% 53% Pseudomembranous colitis (678450/1) Pseudomembranous Pseudomembranous colitis (678138) Pseudomembranous Pseudomembranous & Ischemic colitis Pseudomembranous (Digna & Greenson 1997) • 25pts C. difficile 24 pts ischemic colitis • Hyalinisation of lamina propria 0/25 19/24 • Atrophic microcrypts 6/25 18/24 • Lamina propria hemorrhage 9/25 18/24 1021662 Ischemia & Pseudomembrane 1021662 683025 Ischemia : hyalinisation & 683025 atrophic crypts IBD & Therapy IBD • Improvement – Decrease of score – Disappearance of activity defined by the presence of neutrophils? • Remission – Healing – Disappearance of inflammation – persistent architectural abnormalities? – Normalisation has been observed in UC (and CD?) Crohn’s disease before and after Crohn’s remicade ...
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