Normal Gastrointestinal Tract Inflammatory Cells PDF

Seminars in Diagnostic Pathology 38 (2021) 6–13 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Review article Normal gastrointestinal tract inflammatory cells and review of select benign hematolymphoid proliferations Jen...

Seminars in Diagnostic Pathology 38 (2021) 6–13 Contents lists available at ScienceDirect Seminars in Diagnostic Pathology journal homepage: www.elsevier.com/locate/semdp Review article Normal gastrointestinal tract inflammatory cells and review of select benign hematolymphoid proliferations Jennifer Y. Ju a, Edward B. Stelow b, Elizabeth L. Courville b, * a b Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St, Box 357470, Seattle, WA, United States Department of Pathology, University of Virginia, 1215 Lee Street, Box 800214, Charlottesville, VA, United States A R T I C L E I N F O A B S T R A C T Keywords: Gastrointestinal Histiocytic Lymphoproliferative Benign Hyperplasia Reactive The luminal gastrointestinal tract can be a site of robust immune response in which reactive lymphoproliferative processes can sometimes be difficult to distinguish from lymphoma. In this article, we review gastrointestinal tract normal resident inflammatory cells and common nonneoplastic lymphoproliferative responses with emphasis on their differential and links to lymphoma. Topics that are covered include lymphocytic esophagitis, gastric chronic inflammation, mucosa-associated lymphoid tissue, and ulceration, small intestinal lymphoid hyperplasia, celiac disease, microscopic colitis, inflammatory bowel disease, primary immunodeficiency, graftversus-host disease, and anti-programmed cell death protein-1 effect. We additionally present the less com­ mon differential of histiocytic processes within the gastrointestinal tract. The aim of this paper is to serve as a reference for practicing pathologists facing lymphoid, lymphoplasmacytic, or histiocytic processes in the luminal gastrointestinal tract. We hope to help the practicing pathologist distinguish benign from malignant entities and identify features requiring further workup. Introduction Esophagus The luminal gastrointestinal (GI) tract (GIT) contains a resident population of hematolymphoid cells including lymphocytes, plasma cells, eosinophils, histiocytes, and mast cells.1 In addition to morpho­ logic criteria such as monomorphism, cellular atypia, and architectural destruction, separating a benign from malignant diagnosis may require the clinical scenario and frequently requires additional techniques including immunohistochemistry, in situ hybridization (ISH), flow cytometry, and polymerase chain reaction (PCR) studies assessing for clonality.1,2 Knowledge of the normal histology of inflammatory cells and lymphoid tissue in the GIT and familiarity with nonneoplastic processes that can result in hematolymphoid proliferations can help the practicing pathologist distinguish benign from malignant and may aid in deciding which proliferations require further workup. In this article, we provide an overview of normal inflammatory cells in the GIT and highlight select benign hematolymphoid proliferations/processes which may present a diagnostic dilemma. The esophagus is normally mostly devoid of lymphoid tissue.1,3 A small number of intraepithelial lymphocytes (about 5–12 per high-power field) may be present, mostly comprised of CD8+ T cells.3–6 There may also be rare submucosal lymphoid follicles or chronic in­ flammatory infiltrates surrounding gland ducts.3 Langerhans and mast cells are common in the normal esophageal epithelium, while B cells and plasma cells are not.4 Involvement of the esophagus by hematolymphoid neoplasms is rare, and benign hematolymphoid proliferations in this region rarely cause diagnostic dilemmas.7 Acquired mucosa-associated lymphoid tissue (MALT) can very rarely form in the esophagus, where it may be secondary to gastroesophageal reflux disease (GERD), viral infection, or fungal infection.1,7 Increased intraepithelial lymphocytes with only rare or absent granulocytes can be seen in patients with esophageal dysmotility (most often CD4+ T cells), in association with GERD (particularly at the gastroesophageal junction), and in esophageal candidiasis.5,8,9 Examination for Candida, potentially with the use of special stains (Gomori silver or periodic acid-Schiff–diastase (PAS-D)), may be considered when there are increased intraepithelial granulocytes or fibrinopurulent debris.10,11 * Corresponding author. Department of Pathology, University of Virginia, 1215 Lee Street, Box 800214, Charlottesville, VA 22908. E-mail address: [email protected] (E.L. Courville). https://doi.org/10.1053/j.semdp.2021.02.001 Available online 26 February 2021 0740-2570/© 2021 Elsevier Inc. All rights reserved. J.Y. Ju et al. Seminars in Diagnostic Pathology 38 (2021) 6–13 Fig. 1.. The image on the left (100x, H&E) shows a low power view of lymphocytic esophagitis showing abundant intraepithelial lymphocytes. On higher power (200x, H&E) there is associated mucosal injury in the form of edema and dyskeratosis. Features raising concern for lymphoma, such as tight lymphoid aggregates or cytologic atypia, are not appreciated. Fig. 2.. (A) An example of benign gastric mucosa-associated lymphoid tissue that was associated with Helicobacter pylori (100x, H&E). (B) The lack of lymphoe­ pithelial lesions is highlighted by a CD20 stain (100x). Additional stains for BCL2, BCL6, CD3, CD5, CD10, CD43, kappa/lambda ISH, and cyclin D1 were also performed in this case, confirming the benign nature of the follicle (not pictured). An example of a benign gastric ulcer with prominent lymphocytic infiltrate is shown at low power (C, 40x) and high power (D, 400x), both H&E staining. On low power, the ulcerated surface is seen while on high power the lymphocytes are small and variable in appearance, helping the designation of benign. This ulcer was also associated with Helicobacter pylori. (Fig. 1).5,10,12 Formal cell counts have not been established for lym­ phocytic esophagitis; however, a working definition is more than 20–30 intraepithelial lymphocytes per high-power field.5,8 In the absence of infection, GERD, and esophageal dysmotility, lymphocytic esophagitis First described in 2006, lymphocytic esophagitis is a histologic diagnosis characterized by increased intraepithelial lymphocytes in the peripapillary areas of the esophageal epithelium with associated edema and dyskeratosis, and few or no intraepithelial granulocytes 7 J.Y. Ju et al. Seminars in Diagnostic Pathology 38 (2021) 6–13 Fig. 3.. (A) An example of benign lymphoid follicles in the duodenum, as aided by preservation of architecture and cellular polymorphism (100x, H&E). (B) An example of celiac disease with frequent intraepithelial lymphocytes (400x, H&E). may be associated with Crohn’s disease among pediatric patients, but not adults.12 The endoscopic appearance of lymphocytic esophagitis may be normal or the mucosal surface may show rings, furrow, or strictures.5 Features that may prompt further immunohistochemical workup of increased intraepithelial lymphocytes out of concern for lymphoma include lymphocyte cytologic atypia or large size, the pres­ ence of lymphoid aggregates, abnormal endoscopy findings, or known other sites of disease involvement.2,7 and bring them into deeper areas of the mucosa, thus reducing the sensitivity of histologic evaluation.18,22 The presence of H. pylori or­ ganisms does not exclude a diagnosis of MALT lymphoma as the or­ ganisms are seen in a variable percentage of cases of MALT lymphoma.23 Features that may prompt further immunohistochemical workup of chronic gastritis for potential lymphoma include the presence of a dense lymphoid infiltrate with frequent lymphoepithelial lesions, marginal zone distribution pattern, follicular colonization, cytologic atypia of the infiltrating cells, or the presence of Dutcher bodies.2,15,24,25 Lymphoid follicles can be seen in both chronic gastritis and MALT lymphoma.13,15 Morphologic evaluation for the presence of gastric MALT lymphoma may utilize schema such as that developed by Wotherspoon.15,26 The presence of increased intraepithelial lymphocytes is not patho­ gnomonic for MALT lymphoma. Lymphocytic gastritis is a rare form of chronic gastritis found in 1–5% of chronic gastritis biopsies, associated with celiac disease and possibly H. pylori, and is defined by at least 25 intraepithelial lymphocytes per 100 surface epithelial cells.6,27–29 Lymphocytic gastritis may not be a distinct clinicopathologic entity, but rather a pattern of injury secondary to a variety of causes and does not itself seem to indicate an increased risk of lymphoma.27,28 Immunohistochemistry workup can be invaluable in excluding gastric MALT lymphoma, with a panel that includes CD3, CD20 and cytokeratin stains to further define lymphoepithelial lesions and assess the distribution of T and B cells; CD5 and CD43 to look for abnormal expression in B cells; and kappa and lambda light chain assessment by ISH to evaluate for restriction in plasma cells and/or B cells (Fig. 2).2,30 IGH clonality or translocation studies for t(11;18)(q21;q21) API2-­ MALT1 fusion may be indicated, although such studies are not recom­ mended in the absence of clinical suspicion.2,15 Occasionally, even with immunohistochemical workup and ancillary studies, the distinction between chronic gastritis and gastric MALT lymphoma cannot be made on a single biopsy specimen and a descriptive diagnosis may be best.2 Stomach Normal The stomach is ordinarily mostly devoid of lymphoid tissue except for a few scattered plasma cells and lymphocytes in the lamina propria and rare scattered intraepithelial T cells (1–4 per 100 epithelial cells).1,6,13,14 Mucosal lymphoid aggregates may also occasionally be seen in normal stomach, though these typically lack germinal centers.6,13 Chronic gastritis versus MALT lymphoma A commonly encountered differential is between chronic gastritis and MALT lymphoma.1,2,15 Chronic gastritis is most commonly caused by Helicobacter pylori infection; however, there are other causes of chronic gastritis including chemical agents and autoimmune proc­ esses.16–18 Chronic gastritis is characterized histologically by expansion of the lamina propria by small lymphocytes and plasma cells.18 The localization of this infiltrate towards the luminal aspect of the mucosa and associated mucosal neutrophils (active gastritis) are suggestive of H. pylori gastritis.18 If H. pylori infection persists, the gastric mucosa may develop glandular atrophy, intestinal metaplasia, and MALT forma­ tion.16 The architecture of GI MALT is similar to that in a lymph node with secondary follicle formation with germinal centers (Fig. 2A-B).13 Prolonged H. pylori infection is believed to provide the stimulation for the development of clonal expansion leading to gastric MALT lym­ phoma.2,18,19 Gastric MALT lymphoma may have a wide variety of endoscopic findings such as petechial hemorrhage, thickened folds, polypoid surface, erosions/ulcerations, or even just a normal endoscopic appearance making it potentially difficult to distinguish from benign gastritis.20,21 By histology, H. pylori organisms are found predominantly by the apical side of gastric surface cells.18 Evaluation may be aided by the use of special stains or targeted immunohistochemical stains.22 The use of proton pump inhibitors may reduce the density of H. pylori organisms Gastric ulcer versus gastric diffuse large B-cell lymphoma Gastric ulcers may have a benign cause, commonly H. pylori infection or non-steroidal anti-inflammatory medications (NSAIDs), or could occur in association with benign or malignant tumors, including lym­ phoma.31 Gastric diffuse large B-cell lymphomas (DLBCL) commonly have associated ulcers.32,33 Occasionally, the necroinflammatory debris, granulation tissue, and chronic inflammation within the base of a benign ulcer may raise the differential of lymphoma (Fig. 2C-D). Alternatively, the changes associated with mucosal ulceration may mask the presence of an underlying lymphoma. By endoscopy, malignant ulcers are more likely to be multiple and have larger size, irregular shape, uneven bases, 8 J.Y. Ju et al. Seminars in Diagnostic Pathology 38 (2021) 6–13 as well as be present next to disrupted “moth-eaten” rugaes.34,35 Careful microscopic examination will usually reveal a mixed inflammatory infiltrate in the benign ulcer bed and, importantly, the absence of a diffuse proliferation of atypical lymphocytes. If needed, an immuno­ histochemical panel to include a B-cell marker such as CD20, a T-cell marker such as CD3, and possibly a histiocytic marker such as CD68, can be helpful.32,36 Of note, before making a diagnosis of DLBCL associated with ulceration, either in the stomach or elsewhere in the GIT, the entity of Epstein-Barr virus (EBV)-positive mucocutaneous ulcer should be considered. This entity most commonly presents in the oral cavity, and has a distinct clinical picture of an isolated lesion in a patient with im­ mune compromise. Recognition of this entity is important as it has been reported to have an indolent behavior.37–39 modifications/revisions.6,44 As the histologic features in celiac disease are not entirely specific, the diagnosis of celiac disease also depends on confirmatory clinical features and serologic data.6,45 A small number of patients with celiac disease may have refractory celiac disease (RCD), defined by persistent or recurrent malabsorptive symptoms and villous atrophy despite strict adherence to a gluten-free diet for ≥6–12 month.45,46 The diagnosis of RCD excludes other cau­ ses of nonresponsive treated celiac disease (for example microscopic colitis or bacterial overgrowth) and overt lymphoma.45,46 In type 1 RCD, the histology is similar to that seen in uncomplicated celiac disease, the intraepithelial lymphocytes have a normal immunophenotype, and T-cell gene rearrangement studies are polyclonal.45,46 In type 2 RCD, the intraepithelial lymphocytes show immunophenotypic aberrancy (including lack of CD8 and variable downregulation or loss of other T-cell antigens) and T-cell gene rearrangement studies are clonal.6,44,45,47 Additionally, the villous atrophy is usually severe and small aggregates of lymphocytes may be seen in the lamina propria, though significant cytologic atypia of the intraepithelial lymphocytes is lacking.46,47 There may also be ulcerative mucosa with variable chronic inflammation and a relative paucity of intraepithelial lymphocytes (ul­ cerative jejunitis).45,47 The specificity of immunohistochemical analysis of intraepithelial lymphocytes (particularly CD8 loss) and T-cell clon­ ality in distinguishing type 1 from type 2 RCD may depend on the patient population under evaluation, the criteria for establishing CD8 loss, and the specimen source for PCR (formalin-fixed, paraffin-embedded tissue versus fresh tissue).46 Enteropathy-associated T-cell lymphoma (EATL) is a complication of celiac disease or other gluten-sensitive enteropathy and may be pre­ ceded by type 2 RCD.47 Endoscopically, the presence of ulcerated nodular mucosa, an occluding mass, or stricture should suggest EATL over RCD.45,47 Mesenteric lymphadenopathy could be seen in either.45,47 Histologic features that should raise concern for EATL versus celiac disease include lymphocyte cytologic atypia, including medium-to-large sized cells, prominent nucleoli, and moderate-to-abundant pale-staining cytoplasm, as well as a dense lym­ phocytic infiltrate.47 Angiocentricity, angioinvasion, and necrosis are also concerning features.47 In EATL, there may be intermixed inflam­ matory cells, including histiocytes, and eosinophils.47 Immunohisto­ chemical studies can be helpful, in which CD30 expression supports transformation to EATL.47 Although very rare, another entity to keep in the differential with celiac or EATL is indolent T-cell lymphoma.47,48 Small intestine Normal The small intestine normally contains nodules of lymphoid tissue, including endoscopically visible Peyer’s patches in the distal ileum.1,3 There are also normally scattered CD4+ T cells, B cells, plasma cells, macrophages, and dendritic cells in the lamina propria, as well as scattered intraepithelial CD8+ T cells more concentrated at the base of the villi.3,6 The duodenum contains the highest concentration of normal intraepithelial lymphocytes in the small intestine (usually less than 26–29 per 100 epithelial cells), with decreasing numbers towards the terminal ileum (about 2 per 100 epithelial cells).3 Lymphoid hyperplasia versus lymphoma In the duodenum, normal lymphoid follicles (Fig. 3A) may raise the differential of follicular lymphoma, including the specific variant of duodenal-type follicular lymphoma.40 The latter entity is found pre­ dominantly in the second portion of the duodenum and can present as multiple small polyps.40 Follicular lymphoma can be recognized by the loss of normal germinal center polarization, infiltration of abnormal cells outside the follicles, poorly circumscribed Ki67, and gain of BCL2 staining in the lymphoma cells.1,40 Biopsies of the terminal ileum with abundant lymphoid tissue are occasionally difficult to interpret, particularly with poor quality biopsies (small, fragmented, and/or poorly oriented).41 In cases with morpho­ logic atypia (including disrupted follicular architecture, sheets of cells, or clusters of large lymphoid cells), immunohistochemical stains can be helpful.41 CD3 and CD20 will demonstrate the T- and B-cell compart­ ments, respectively. The use of CD10, BCL6, and BCL2 immunohisto­ chemical stains can confirm normal germinal center immunophenotype and CD21 can confirm an intact follicular dendritic cell (FDC) mesh­ work.1,2,41 CD43 may be helpful but has been reported in the peri­ follicular or mantle cell regions in the terminal ileum so should not be over-interpreted as concerning for MALT lymphoma.41,42 Proliferation rate assessment by Ki67 immunohistochemical stain may help by demonstrating the normal high proliferation rate within a benign germinal center.1 B-cell clonality studies may also be helpful but should only be ordered when there is concern for lymphoma based on morphologic and immunohistochemical features, and need to be inter­ preted in context.41 Colon Normal Normal colon typically shows less than 5 intraepithelial lymphocytes per 100 surface epithelial cells.3,49 The colonic lamina propria contains plasma cells, macrophages, mast cells, and B and T lymphocytes, with more inflammatory cells in the proximal than distal colon.6,49,50 A small number of lymphoid follicles can be a normal component of the colonic mucosa.51 While not entirely normal, a not uncommon finding in the rectum is focal lymphoid hyperplasia where it is known as a rectal tonsil.52,53 Reactive versus neoplastic histiocytic process Celiac disease versus enteropathy associated T-cell lymphoma Histiocytosis in the GIT can be caused by a variety of mechanisms, from reactive to neoplastic, and most commonly occur in the colon.54–61 Use of clinical history and immunohistochemical/special stains will aid in the differential for histiocytic lesions. Nonneoplastic processes resulting in GIT histiocytosis include Crohn’s disease, Chediak-Higashi syndrome, sarcoidosis, medication effect, xanthomas, malakoplakia, and infection.54,55,57 Crohn’s disease, Chediak-Higashi syndrome, sarcoidosis, and medication effect tend to have more epithelioid granulomas and/or giant cells.55 GI xanthomas Celiac disease is an immune-mediated enteropathy against dietary gluten characterized histologically by shortened villi (less than 3-to-1 villous-to-crypt ratio) and increased intraepithelial lymphocytes (>20 per 100 epithelial cells by hematoxylin and eosin stain or >25 per 100 epithelial cells by CD3 or CD8 immunohistochemical stains) (Fig. 3B).6,43,44 The histopathology of celiac disease can potentially be subdivided based on the Marsh classification system and 9 J.Y. Ju et al. Seminars in Diagnostic Pathology 38 (2021) 6–13 Fig. 4.. Examples of microscopic colitis with (A) lymphocytic colitis (400x, H&E) and (B) collagenous colitis (400x, H&E), each of which show varying amounts of increased lymphocytes. Additionally, examples of inflammatory bowel disease with increased lymphoplasmacytic infiltrates in (C) Crohn’s disease (400x, H&E) and (D) ulcerative colitis (400x, H&E). Overall, the polymorphism and infrequent intraepithelial lymphocytes help distinguish these entities as benign hematopoiesis processes. Small granulomas are also seen in this example of Crohn’s disease. positive for CD68 (variably), S100, and CD1a.57,60 The GIT can also rarely be the primary site of a histiocytic or den­ dritic cell neoplasm.57 Sheets of infiltrating epithelioid cells with ve­ sicular chromatin and large nucleoli may raise the differential of a histiocytic sarcoma.66 Spindled cells in a storiform or whorling pattern may raise the differential of a FDC sarcoma.57,67 The use of immuno­ histochemistry assists in the differential.57,66,67 will show lipid-laden, “foamy” histiocytes in the lamina propria; they are not necessarily associated with hyperlipidema.57 Malakoplakia is characterized by histiocytic aggregates with focal intracytoplasmic concentrations (Michaelis-Gutmann bodies) from a defective response to bacteria.54,55 Malakoplakia may form a polypoid mass and can be associated with prominent lymphoid aggregates with germinal centers, which can obscure the lesional histiocytes, raising the differentiation of lymphoma.54,55 The Michaelis-Gutmann bodies can be highlighted by special stains (PAS-D, Von Kossa, or iron).54,55 An infectious process should be excluded with stains for acid fast bacilli and Tropheryma whipplei.54,55,57 Polarization should be performed to check for foreign material.58 Additionally, given the possibility of concomitant disease, immunostaining to evaluate for lymphoma would be prudent.54,55 Rarely, the GIT (especially the colon) may be involved by ErdheimChester disease (ECD), Rosai-Dorfman disease (RDD), or Langerhans cell histiocytosis (LCH), which can manifest endoscopically as pigmented lesions,59 ulcers,58,60 or polyps/masses.57,60–62 While other sites may be involved, they could also be exclusive to the GIT.60–63 ECD may show architectural distortion, be accompanied by lymphocytes and plasma cells, as well as scattered eosinophils and giant cells, and be positive for CD68 and Factor XIIIa, but will be negative for CD1a and S100.57,58,64,65 Characteristic radiographic features of bilateral, symmetric osteo­ sclerosis of long bones may help with the diagnosis of ECD.57,64 RDD will show prominent emperipolesis and accompanying plasma cells, and be positive for CD68, S100, and OCT2 while negative for CD1a.57,61–63,65 LCH will have nuclear grooves, have accompanying eosinophils, and be Microscopic colitis and inflammatory bowel disease versus lymphoma Multiple nonneoplastic disease processes can increase the number of lymphocytes in the colon. Microscopic colitis, characterized by a distinct clinicopathologic phenotype and a lack of significant endoscopic find­ ings, includes lymphocytic colitis (Fig. 4A) and collagenous colitis (Fig. 4B).49,68 Both may show a prominent lymphoplasmacytic infiltrate within the lamina propria and increased intraepithelial cells; with collagenous colitis showing these features to a lesser extent.49,68 In­ flammatory bowel disease (IBD), including Crohn’s colitis (Fig. 4C) and ulcerative colitis (Fig. 4D) are associated with abnormal endoscopic findings.50 Both involve histologic evidence of chronic injury including Paneth cell hyperplasia in the right colon, metaplasia in the rest of the colon, crypt architectural distortion, and chronic inflammation charac­ terized by lymphocytes and plasma cells often extending to the base of the mucosa.50,69 On initial presentation and without adequate treat­ ment, there is also active or acute inflammation characterized by neu­ trophils in the crypt epithelium.50,69 Inflammatory pseudopolyps may 10 J.Y. Ju et al. Seminars in Diagnostic Pathology 38 (2021) 6–13 Fig. 5.. (A) An example of chronic variable immunodeficiency in the duodenum showing a paucity of plasma cells (400x, H&E). (B) An example of graft-versus-host disease in the duodenum showing abundant apoptotic bodies in the epithelium (200x, H&E). (C) An example of anti-PD-1 effect in the duodenum with scattered apoptotic bodies and patchy increased intraepithelial lymphocytes (200x, H&E). Overall, clinical correlation is important for distinguishing between these entities. develop in IBD with chronically inflamed and distorted mucosa forming a mass.50 Whether there is an increased risk for lymphoma in patients with IBD is controversial.70,71 However, there is concern over the use of immunomodulatory therapy in IBD leading to an increased risk of non-Hodgkin lymphoma.70,72,73 Primary colonic lymphomas are rare, most commonly affect the cecum, and are more commonly B-cell lymphomas, particularly DLBCL.74,75 Histologic features that help distinguish an entity as lym­ phoma are the same as in other sites: monomorphism, cellular atypia and size, and architectural destruction.2,74,76 More than half of patients present with bulky disease, aiding in the diagnosis, though T-cell lym­ phomas can manifest as extensive mucosal ulcerations resembling IBD.74,75 Notably, monomorphic epitheliotropic intestinal T-cell lym­ phoma (MEITL) has been documented as being misdiagnosed as lym­ phocytic colitis and ulcerative colitis.76 MEITL was formally known as type 2 EATL, but is now considered a distinct entity with no clear as­ sociation to celiac disease.47 The presence of increased intraepithelial lymphocytes (>20 per 100 epithelial cells) and monomorphism should raise concern for MEITL.76 Additionally, the T cells in MEITL will be aberrantly negative for CD5 and positive for CD56, helping distinguish it from other T-cell lymphomas as well as indolent T-cell lymphoproli­ ferative disorder.76 NK/T-cell lymphomas may also be on the differen­ tial, but will be positive for EBV.76 Overall, in addition to immunohistochemical stains, clinical correlation and clonality studies may also aid in the diagnosis of colonic lymphoma.75 of GVHD is the presence of enterocyte apoptosis, crypt or basilar gland destruction, and/or mucosal denudation (Fig. 5B).84 GI toxicity associ­ ated with mycophenolate mofetil can mimic GVHD, though the presence of increased eosinophils or loss of neuroendocrine cell nests can help favor the former.84 Anti-programmed cell death protein-1 Immunotherapy targeting programmed cell death protein-1 (PD-1) has been increasingly used for various malignancies in order to turn host cytotoxic T-cell activity against the tumor.85,86 The blockade of PD-1 can result in immune related adverse events, including GI symptoms.85,86 Overall, GI biopsies may show lamina propria expansion by lymphocytes and plasma cells, increased intraepithelial lymphocytes or neutrophils, villous blunting, or increased apoptosis, thus mimicking a variety of other disease processes (Fig. 5C).17,85,86 Of note, anti-cytotoxic T-lym­ phocyte-associated protein-4 colitis can also show similar histologic patterns to anti-PD-1 therapy, though with predominantly CD4+ T cells instead of CD8+ T cells.85–87 Conclusion This paper presents an overview of benign lymphoplasmacytic and histiocytic entities that can occur in the luminal GIT, presented in the context of the normal resident inflammatory cells. We hope this paper can serve as a reference for practicing pathologists when faced with GI lymphoplasmacytic or histiocytic processes. In conjunction with knowledge of the malignant hematolymphoid process that can occur in the luminal GIT, the information in this paper can help the practicing pathologist decide which proliferations require further workup. Systemic processes Primary immunodeficiencies Primary immunodeficiencies can manifest in lymphoid hyperplasia and be associated with an increased risk of lymphoma, particularly Bcell lymphoma.77–80 Immunodeficiencies can mimic a variety of dis­ eases, including celiac disease or IBD; concomitant disease is also pos­ sible.78,80–82 Two of the most common primary immunodeficiencies to affect the GIT are immunoglobulin A (IgA) deficiency and common variable immunodeficiency (CVID).77 IgA deficiency and CVID are characterized by decreased immunoglobulin and will show markedly diminished-to-absent plasma cells in the lamina propria (specifically IgA plasma cells in IgA deficiency) which aids in the diagnosis, though clinical/serologic correlation is required (Fig. 5A).78,80,82 Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. References 1 Banks PM. Gastrointestinal lymphoproliferative disorders. 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