Kids Like to Break the Rules: Gastrointestinal Pathology in Children
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1 Kids Like to Break the Rules: Gastrointestinal Pathology in Children Jeffrey Goldsmith MD Director of Surgical Pathology, Beth Israel Deaconess Medical Center; Consultant in Gastrointestinal Pathology, Children s Hospital Boston Harvard Medical School Boston, MA Immature immune system Adaptive and innate immunity not mature at birth Increased epithelial permeability High gastric ph Granulocytes are reduced in number at birth and have decreased surface protein expression (e.g. selectins) Decreased T-cell response compared to adults Lack of B-cell maturation at birth Immature immune system Intestinal colonization is critical for normal development of immunity. Colonization determined by genetics, gestational age, type of feeding. Alterations in normal flora development has been associated with allergic diseases and diabetes. 1
2 EE LC IBD EoE (Allergic / Eosinophilic Esophagitis) 2
3 3
4 PubMed = ( Allergic or Eosinophilic ) + Esophagitis Total EoE EoE 4
5 EoE GERD Few Eos GERD vs. EoE Lots of Eos 5
6 GERD vs. EE Increased numbers distally Uniform distribution GERD vs. EoE - Eosinophilic Microabscesses + GERD vs. EoE Minimal degranulation Lots of degranulation 6
7 GERD vs. EoE Uniform Distribution Increased Surface Density GERD vs. EoE - Eosinophilic Crust + Histology rules of thumb GERD <15-20 eos / hpf Uniform distribution of eosinophils throughout epithelium Reactive epithelial changes EoE >15-20 eos / hpf Increased lumenal density of eos Eosinophilic microabscesses Eosinophilic degranulation Surface eosinophilic exudate Reactive epithelial changes 7
8 BUT GERD EoE Symptomatic: Adults: GERD-like Children: EoE (Differences) EE: feeding aversion, vomiting, failure to thrive, dysphagia GERD: regurgitation, irritability, apnea EoE (Differences) Histologic differences unclear Index biopsies: 46 kids (9 years, 1-17y) 49 adults (49 years, 22-79y) 8
9 EoE (Differences) 62/hpf in adults vs 45/hpf in kids (p=0.002). Increased superficial/luminal eosinophil density: 13% of adults vs 38% of kids(p<0.001). Patchiness (variation between tissue fragments): 20% of adults vs 8.6 of kids (p=0.014) EoE (Differences) Qualitative and quantitative differences in histology that are worth knowing in diagnostic context. Biologic differences --? Diarrhea (Lymphocytic colitis) 9
10 Lymphocytic colitis Collagenous colitis Autoimmune enteropathy Immunodeficiency states CVID IgA deficiency Intractable diarrhea in neonates Abetalipoproteinemia Microvillous inclusion disease Tufted enteropathy Microscopic Colitis Lymphocytic Colitis Collagenous Colitis Lymphocytic Colitis Usually >60 years M=F 3X more common than collagenous colitis Associations: Diabetes mellitus Autoimmune thyroid disease 10
11 Lymphocytic Colitis Symptoms Profuse watery diarrhea, months to years No response to decreased oral intake +/- abdominal cramps Endoscopically normal, by definition 11
12 Lymphocytic Colitis Differential diagnosis Celiac disease Drugs Proton pump inhibitors NSAIDs Antibiotics Carbamazapine Gold salts Resolving Infection Collagenous Colitis Usually >60 years F >> M (3 10:1) Symptoms Much like lymphocytic colitis Nausea, vomiting, and weight loss more likely Collagenous Colitis Endoscopy: Usually normal Linear mucosal cracking ( cat-scratch colon ) Pseudomembranes 12
13 13
14 Lymphocytic / Collagenous Colitis in Kids Collagenous colitis Very rare 7 patients over 10 years at Cleveland Clinic (Liu et. al. Mod Pathol 2013) Few case reports. Often associated with other collagenous diseases of the GI tract May have slightly different presentation (e.g. constipation and higher association with autoimmunity in children) Lymphocytic / Collagenous Colitis in Kids Lymphocytic colitis Mashako et al, children (5.7 years, years). Same symptoms as adults Weight loss 4 of 5 resolved with medications used in adults 2 of 5 showed histologic resolution Lymphocytic / Collagenous Colitis in Kids Increased colonic IELs in kids: Najarian et. al. 2009: 20 cases (10.2 years, 1-17y) 2450 patients over same study period (0.8% of endoscopies) Presented with diarrhea and/or abdominal pain Autoimmune etiologies: 3 pts Lymphocytic colitis: 3 pts IBD: 4 pts Celiac disease: 2 pts 14
15 Autoimmune Enteropathy Symptoms Intractable diarrhea Failure to thrive Associations Multisystem autoimmune disease Hepatitis Diabetes mellitus Hemolytic anemia Membranous glomerulopathy Thyroid insufficiency Autoimmune Enteropathy Pathogenesis -- Unknown Immunodysregulation, polyendocrinopathy, enteropathy and X-linked syndrome (IPEX) Treg disorder FOXP3 mutations FOXP3 not uniformly seen in all cases of autoimmune enteropathy. Autoimmune Enteropathy Serology Anti-goblet cell / anti-enterocyte antibodies ~50% of cases Not entirely specific Anti-goblet cell Ab: IBD Anti-enterocyte Ab: AIDS 15
16 16
17 Autoimmune Enteropathy Appearances can also mimic celiac disease and graft versus host disease Findings outside the duodenum are commonly seen Masia et. al., Am J Surg Pathol
18 Autoimmune Enteropathy in Adults? Refractory celiac disease patients Akram et al, patients, median age 55 years 13 had other autoimmune disorders 13 had either anti-goblet cell or antienterocyte antibodies in serum 5 had positive TTGs Autoimmune Enteropathy in Adults Two histologic patterns Autoimmune enteropathy like Sprue like? Overlap / combination of diseases Collagenous colitis 1/3 less common than lymphocytic colitis. Lymphocytic colitis Differential diagnosis Celiac disease Drug effect Resolving infection Autoimmune Enteropathy (??) Collagenous colitis Very rare in children Lymphocytic colitis Differential diagnosis Celiac disease Autoimmune enteropathy Autoimmune enteropathy 18
19 IBD The Rectum Backwash Ileitis The Upper Tract Granulomas IBD Differences Why bother worrying about precisely categorizing IBD? Natural history Prognosis Surgery (Medical therapy) 19
20 20
21 21
22 UC IBD The Rules Diffuse continuous disease starts in the rectum, mostly. Colon only, mostly. Crohn s Disease Skip areas Rectal sparing common Granulomas Deep, knife-like ulcers Upper tract disease Patchy Disease Patchy disease in pediatric UC Glickman et. al. (2004, AJSP) 73 kids, 38 adults 16 patients had patchy disease 4 kids: Normal biopsies flanked by abnormal. 12 kids: Chronic inactive flanked by chronic active. 8 kids: Inactive flanked by active. No adults had any feature. 22
23 Rectal Sparing Rectal sparing in UC Originally studied by Markowitz et. al. (1993, Am J Gastro) 5 of 12 patients had relative rectal sparing compared with proximal biopsies. Glickman et. al. (2004, AJSP) 2 kids vs 0 adults had absolute rectal sparing 17 kids vs 1 adult had relative rectal sparing (no evidence of chronicity in the rectum) Rectal Sparing Rectal sparing in UC Robert (2004; AJCP) resection specimens No absolute sparing 5 of 15 kids with both rectal and proximal biopsies showed relative rectal sparing Rectal Sparing Rectal sparing in UC Robert et al (2004; AJSP) Kids (< 17 years) had less disease activity and chronic changes, in general, compared with adults. Rectal biopsies showed decreased inflammation / chronic changes but were not significantly different than proximal biopsies. 23
24 Patchiness and Rectal Sparing Biopsies can show patchy inflammation in index biopsies of UC patients. More common in kids Rectal sparing occurs in pediatric patients presentation of UC. Absolute sparing quite rare.? Due to differences in time to biopsy Backwash Ileitis Backwash Ileitis Backwash ileitis Endoscopically and/or histologically abnormal ileum in ulcerative colitis patients. Usually associated with pancolitis. Diagnostic criteria, potential significance, and pathogenesis remain controversial. 24
25 Backwash Ileitis Studies, chiefly in adults, suggest that about 20% of UC patients have ileal inflammation. Usually mild Only involves distal ileum Incidence seems to be equal between adults and kids Probably does not affect IPAA result. Questionable association with pouchitis. No other clear associations with UC complications. Backwash Ileitis USCAP 2010 (Najarian et. al.) 50 kids (3 20y), diagnostic endoscopy. No evidence of Crohn s on diagnostic workup or during follow-up. 25% of patients had ileal inflammation. Most patients had mild acute inflammation Associated with pancolitis, but not exclusive. Backwash ileitis seen in kids. Should not mitigate against a diagnosis of UC Upper Tract Findings 25
26 Ruuska (1994, JPGN) Upper Tract Findings Kids only; Crohn s (n=40) v UC (n=40) UC: 63% (stomach) and 15% (duodenum) Crohn s: 55% (stomach) and 23% (duodenum) Abdullah, et. al. (2002, JPGN) Kids only; Crohn s (n=81) v UC (n=34); chiefly Endoscopic study UC: 78% (stomach), 15% (duodenum) Crohn s: 59% (stomach) and 27% (duodenum) Upper Tract Findings Hummel, et. al. (2012, JPGN) Kids only; Crohn s (n=70) v UC (n=33) v non-ibd (n=68) Diffuse gastric inflammation, mostly chronic: 44% Crohn s, 39% UC, 7% non-ibd Sonneberg et. al (2011, IBD) 208 Crohn s disease, 280 UC, (kids and adults); 4943 healthy controls Gastritis rate in all Patients: 29% Crohn s, 14% UC Gastritis rate in kids (8 Crohn s, 15 UC): 37% Crohn s, 53% UC Granulomas Non necrotizing granulomas one of the few remaining features that distinguished Crohn s from UC on endoscopic biopsy. 26
27 Granulomas Much less common in adults: 54% v 18% (Rubio 2007, J Clin Path) Granulomas seem to decrease with treatment. 61% v 25% (De Matos 2008, JPGN) 27
28 Granulomas Complete endoscopy is required for maximal granuloma yield. 13.4% of granulomas are present in upper tract biopsies alone, and 23.2% in the TI, in kids (De Matos 2008, JPGN) Granulomas do not correlate with disease severity. Summary UC Rectal sparing Patchy disease at presentation Upper tract disease Crohn s Granulomas 28
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