L y mp h o c y t i c D i s o r d e r s of t h e G a s t Robert r o M. i Genta n t e s t i Caris n alife l Sciences, T rirving, a ctexas t Dallas VAMC UT Southwestern Dallas, Texas Esophagus Stomach Small Intestine Colon Lymphocytic esophagitis Lymphocytic gastritis DIL Sprue Lymphocytic colitis Collagenous colitis Unifying theory What does too many mean? Too many lymphocytes = Lymphocytic [organ]+itis 1. More than a certain number established by someone who has counted them in normal subjects 2. More than I usually see If she has to ask, she cannot afford it If I have to count them, it is not 1
High-power field = π [(Eyepiece diameter/40)/2] 2 0.050 mm 2 0.235 mm 2 0.450 mm 2 10 30 Lymphocytes in the normal esophageal epithelium Walker et al., (Gastroenterology 2010;139:112) < 8 / HPF 12 56 106 Haque & Genta (Gastroenterology 2010;138:S-56) < 40 / mm 2 (<10 / HPF) 35 year old man Progressive dysphagia (months) Normal esophagoscopy r/o eosinophilic esophagitis Lymphocytic esophagitis Rubio et al, Karolinska Inst., Sweden (Am J Clin Pathol, 2006;125:432) Peripapillary CD3 + infiltration 55% children 8 of 20 patients had Crohn s disease Rubio et al (Int J Clin Exper Pathol, 2008;28:531) Also baboons have LyE 2
Lymphocytic esophagitis Purdy et al, U Michigan (Am J Clin Pathol, 2008;130:508) 42 patients with increased lymphocytes in the esophagus Extracted from a large database all esophageal biopsies in which increased lymphocytes were mentioned Reviewed slides Selected 40 patients 2008-2009 No endoscopic or clinical associations detected Henry Appelman declares it a non-entity and refuses to diagnose it. Explored clinical correlations Determined tentative criteria and disseminated them to our group Haque & Genta (Gastroenterology 2010;138:S-56) Peripapillary infiltrates and spongiosis Patchy CD3+ infiltrates 3
Jun 2009 Dec 2010 129,252 unique patients Normal esophagus Esophagitis (all grades) Barrett s esophagus EoE 28,435 (22%) 42,654 (33%) 23,266 (18%) 3,877 (3%) Lymphocytic esophagitis 151 (0.12%) Clinical correlations LyE EoE Others (p) Increased esophageal lymphocytes in Crohn s disease Median age Male sex Dysphagia Suspected EoE 61 38% 50% 31% 43 66% 63% 58% 57 45% 23% 13% <.001 <.001 <.0001 <.0001 - Reported by Rubio (2006) and Purdy (2008) - 20% of patients with documented lower GI Crohn s have increased esophageal lymphocytes - No significant spongiosis GERD DIL 20% 8% 19% 2% 23% 1% n.s. <.0001 - Usually concurrent inflammation in sub-epithelial layers Sprue 6% 1% 3% <.0001 Lymphocytic Esophagitis A histopathologic finding characterized by: 1. Dense collections of lymphocytes in peripapillary squamous epithelium 2. Intense spongiosis Possible correlations - An association with dysphagia/odynophagia - >30% of the patients are suspected of having EoE - Use of PPIs is virtually universal - A significant proportion of patients have a lymphocytic diathesis - Pathologists tend not to report lymphocytic infiltrates in the esophagus - The prevalence of lymphocytic esophagitis is likely underestimated - True associations may emerge when most cases are reported 4
Lymphocytes in the normal gastric mucosa IEL: 0 LP: few 50 year old woman Dyspepsia UBT for H. pylori: negative Gastroscopy: mild gastritis Lymphocytic Gastritis A histopathologic finding characterized by: 1. > 20 intraepithelial lymphocytes/100 epithelial cells 2. No plausible explanation for the intraepithelial lymphocytosis Increased gastric IEL H. pylori gastritis: usual Real: H. pylori infection Celiac disease Ménétrier Anecdotal: Medications Crohn s disease Proximity of tumors 5
H. pylori gastritis: no IEL H. pylori gastritis: unusual H. pylori gastritis with increased IEL Varioliform gastritis H. pylori gastritis with prominent lymphocytic response To differentiate from lymphocytic gastritis, suggest biopsies 3 to 6 months after the successful eradication of H. pylori Lymphocytic gastritis has a typical endoscopical appearance consisting of nodules, erosions, and large folds predominating in the gastric body. Jules Haot et al., Gut;1988 Mod Pathol, Long Course, 2002 Collagenous gastritis 6
Small Intestine Small Intestine IELs per 100 Enterocytes Duodenum < 20 Normal 21 25 Borderline > 25 Lymphocytosis Terminal ileum < 10 Normal 11 15 Borderline > 15 Lymphocytosis 9 8 7 6 5 4 3 2 1 1 10 11 12 13 14 15 16 17 18 19 20 1 1 100 enterocytes What system should be used? Marsh Marsh modified by Oberhuber Marsh modified by Oberhuber modified by Villanacci Celiac Disease Diagnosis: Simple Rules Are Better Than Complicated Algorithms Catassi and Fasano, Am J Medicine 2010 7
Marsh 0 - Normal Marsh 1 Duodenal Lymphocytosis Marsh 2-3a Variable Villous Atrophy Marsh 3b-3c Celiac Disease Duodenal Intraepithelial Lymphocytosis (Lymphocytic Duodenosis) Normal villous architecture >25 IEL per 100 enterocytes Duodenal Intraepithelial Lymphocytosis 6.3% of duodenal biopsies in children (<18) 4.1% in adults In the US, peak Jan-April Seasonal incidence Infectious Diseases: defined incubation period GI conditions:? latency; general practitioner; gastroenterologist; waiting for endoscopy 8
Duodenal Intraepithelial Lymphocytosis Associations Small intestinal (= ileal) lymphocytosis Histologically latent sprue (10% 15%) - Malabsorption, positive serologies Pre-sprue (? <10% ) - Vague or no symptoms - Negative serologies - Develop sprue years later? < 1% of ileal biopsies Often associated with Lymphocytic Colitis Poor predictor of DIL or Celiac Sprue Helicobacter gastritis (<10%) - DIL regresses or disappears with eradication in a small percentage Gluten-sensitive enteropathy (Celiac disease) Villous flattening Low villus:crypt ratio Intraepithelial lymphocytosis Mixed infiltrate in lamina propria Villous flattening Low villus:crypt ratio Intraepithelial lymphocytosis Mixed infiltrate in lamina propria Biopsy prevalence: 0.9% in adults 0.65% in children Flat mucosa Duodenal biopsies for celiac disease Celiac disease Refractory sprue Autoimmune enteropathy Microvillous inclusion disease Protein intolerance Common variable immunodeficiency Tropical sprue Bacterial overgrowth Giardia infection Eosinophilic gastroenteritis r/o sprue Malabsorption with supporting data Positive serology Adherence to recommended (4) number of biopsies 30% - 50% 3% - 5% <0.1% 4 9
Stomach and Small Intestine Stomach and Small Intestine Gastric IEL Celiac disease is known (history or simultaneous duodenal biopsy) Diagnosis: lymphocytic gastritis associated with celiac disease Lymphocytic diathesis Condition Total LG (%) OR (95% CI) Normal duodenum Celiac sprue DIL 94,935 636 4,376 183 67 37 (0.2) (10.5) (0.8) 1 61 (45.5 81.6) 4.41 (3.10 6.30) 99,948 patients with gastric and duodenal biopsies Giardia intestinalis 28 year old man Recurrent diarrhea (months) Previous diagnosis: DIL possible sprue DIL? 10
Adenovirus ISH Colon Colon IELs per 100 enterocytes R Cecum Don t even think of counting IEL Paski SC, et al. The importance of recognizing. increased cecal inflammation in health and avoiding the misdiagnosis of nonspecific colitis. Am J Gastroenterol. 2007;102:2294 2299 L Mid- and left Colon < 20 Normal 21 25 Borderline > 25 Lymphocytosis 64 year old woman Chronic watery diarrhea (3 months) Normal colonoscopy 11
Collagenous colitis Lymphocytic colitis > 20 IEL / 100 enterocytes Mucin depletion Normal crypt architecture Lymphoplasmacytic infiltrate in lamina propria with eosinophils rare neutrophils Biopsy prevalence: 0.6% in adults 0.2% in children 64 year old woman Chronic watery diarrhea (3 months) Normal colonoscopy 25 μm 15 μm 15 μm 12
Collagenous colitis Collagen band > 15μm (irregular; lacy ) Lymphocytosis and mucin depletion Normal crypt architecture Lymphoplasmacytic infiltrate in lamina propria with eosinophils rare neutrophils Detachment artifact Biopsy prevalence: 0.4% in adults 0.1% in children Collagenous and lymphocytic colitis: associations Autoimmune conditions Use of NSAIDs and PPIs Celiac sprue and DIL from lymphocytic to collagenous Conclusions Recognized lymphocytic conditions (those with a name) are found in 2% to 5% of gastrointestinal biopsies A minority of patients may have a lymphocytic diathesis (2 or more sites involved) Reporting the unnamed is the key to discovering new conditions 13