Pembrolizumab-Induced Thyroiditis Shows PD-L1Expressing Histiocytes and Infiltrating T Cells in Thyroid Tissue - A Case Report.

Context: Immune-related adverse events frequently take place after initiation of immune checkpoint inhibitors (ICI) therapy. The thyroid gland is the endocrine organ most commonly affected by ICI therapy, the pathological mechanism is still poorly understood. Case Description: A 60-year old Upper Austrian male melanoma patient under pembrolizumab therapy received thyroidectomy because of a suspicious FDG avid thyroid nodule. Histopathology showed a pattern comparable with thyroiditis de Quervain. The inflammatory process consisted predominantly of T lymphocytes with a dominance of CD4+ T helper cells. In addition CD68+ histiocytes co-expressing PD-L1 were observed. Conclusion: Clusters of perifollicular histiocytes expressing PD-L1 were observed in this case of pembrolizumab induced thyroiditis - probably induced by the former ICI therapy. This finding might indicate the initial target for the breakdown of self tolerance. In context with other data the immunological process seems to be driven by CD3+ lymphocytes infiltrating the thyroid.

A hungry Histiocyte, altered immunity and myriad of problems: Diagnostic challenges for Pediatric HLH.

INTRODUCTION: Hemophagocytic lymphohistiocytosis (HLH) is an immune deregulation disorder with varied clinical presentation which clinically overlaps with widespread tropical infections. METHODS: We conducted a retrospective chart review of children diagnosed with HLH at our center from February-2017 to October-2020. RESULTS: Out of the nine diagnosed patients, genetic predisposition was present in three children; two had identified infectious triggers. The mean age of presentation was 30 months with male predominance. The most common clinical findings were fever, organomegaly, and pancytopenia. The median value of fibrinogen was-156 mg/dL, ferritin-12 957 ng/mL and for triglycerides-349 mg/dL, respectively. In children with identified genetic predisposition, serum ferritin levels were usually more than 10 000 ng/mL. The majority of our patients had evidence of hemophagocytosis on bone marrow examination. In our experience, although nonspecific, very high ferritin and serum triglycerides with low fibrinogen in a patient with bi-cytopenia, pancytopenia was the most suggestive evidence of HLH. Genetic evaluation in our series identified three children, one with primary HLH genetic mutation and two with underlying immune deficiency syndrome. The presence of HLH in the accelerated phase of Chediak-Higashi and AD Hyper IgE syndrome with HLH is extremely rare. Leishmaniasis (in nonendemic area) and Ebstein-Barr virus (EBV) was identified as an infectious trigger in two cases. Most of our cases received treatment as per HLH 2004 protocol. Three children died during the initial diagnosis and treatment. HLH with subcutaneous panniculitis-like T-cell lymphoma recovered well. CONCLUSION: HLH remains a life-threatening disorder associated with a variety of underlying illnesses as highlighted by our case series.

Morphologic Spectrum of Lymphadenopathy in Adult-onset Immunodeficiency (Anti-interferon-γ Autoantibodies).

Adult-onset immunodeficiency syndrome (AOIS) caused by anti-interferon-γ autoantibodies is an emerging disease. Affected patients present typically with systemic lymphadenopathy, fatigue, and fever. We studied 36 biopsy specimens, 31 lymph nodes, and 5 extranodal sites, of AOIS confirmed by serum autoantibody or QuantiFERON-TB Gold In-Tube assay. We describe the morphologic features and the results of ancillary studies, including special stains, immunohistochemistry, and molecular testing. The overall median age of these patients was 60.5 years (range, 41 to 83 y) with a male-to-female ratio of 20:16. All biopsy specimens showed nontuberculous mycobacterial infection, and most cases showed the following histologic features: capsular thickening with intranodal sclerosing fibrosis, irregularly distributed ill-formed granulomas or histiocytic aggregates with neutrophilic infiltration, interfollicular expansion by a polymorphic infiltrate with some Hodgkin-like cells that commonly effaces most of the nodal architecture and proliferation of high endothelial venules. In situ hybridization analysis for Epstein-Barr virus-encoded RNA showed scattered (<1%) to relatively more common (4% to 5%) positive cells in 29 of 30 (97%) tested specimens, reflecting immune dysregulation due to an interferon-γ defect. In the 31 lymph node specimens, 23 (74%) cases showed increased immunoglobulin G4-positive plasma cells (4 to 145/HPF; mean, 49.7/HPF) with focal areas of sclerosis reminiscent of immunoglobulin G4-related lymphadenopathy, 4 (13%) cases resembled, in part, nodular sclerosis Hodgkin lymphoma, and 9 (29%) cases mimicked T-cell lymphoma. Among 33 patients with available clinical follow-up, 20 (61%) showed persistent or refractory disease despite antimycobacterial therapy, and 1 patient died of the disease. We conclude that the presence of ill-defined granulomas, clusters of neutrophils adjacent to the histiocytic aggregates, and some Epstein-Barr virus-positive cells are features highly suggestive of AOIS. A high index of clinical suspicion and awareness of the morphologic features and differential diagnosis of AOIS are helpful for establishing the diagnosis.

The Pathology of Lymphocytes, Histiocytes, and Immune Mechanisms in Mycobacterium tuberculosis Granulomas.

Granuloma formation is the pathologic hallmark of tuberculosis (TB). Few studies have detailed the exact production of cytokines in human granulomatous inflammation and little is known about accessory molecule expressions in tuberculous granulomas. We aimed to identify some of the components of the immune response in granulomas in HIV-positive and -negative lymph nodes. We investigated the immunohistochemical profiles of CD4+, CD8+, CD68+, Th-17, Forkhead box P3 (FOXP3) cells, accessory molecule expression (human leukocyte antigen [HLA] classes I and II), and selected cytokines (interleukins 2, 4, and 6 and interferon-γ) of various cells, in granulomas within lymph nodes from 10 HIV-negative (-) and 10 HIV-positive (+) cases. CD4+ lymphocyte numbers were retained in HIV- granulomas, whereas CD4+:CD8 + cell were reversed in HIV+ TB granulomas. CD68 stained all histiocytes. Granulomas from the HIV+ group demonstrated a significant increase in FOXP3 cells. Interleukin-2 cytoplasmic expression was similar in both groups. Interferon-gamma (IFN-γ) expression was moderately increased, IL-6 was statistically increased and IL-4 expression was marginally lower in cells from HIV- than HIV+ TB granulomas. Greater numbers of cells expressed IFN-γ and IL-6 than IL-2 and IL-4 in HIV- TB granulomas. This study highlights the varied cytokine production in HIV-positive and -negative TB granulomas and indicates the need to identify localized tissue factors that play a role in mounting an adequate immune response required to halt infection. Although TB mono-infection causes variation in cell marker expression and cytokines in granulomas, alterations in TB and HIV coinfection are greater, pointing toward evolution of microorganism synergism.

Spatial signatures identify immune escape via PD-1 as a defining feature of T-cell/histiocyte-rich large B-cell lymphoma.

T-cell/histiocyte-rich large B-cell lymphoma (TCRLBCL) is an aggressive variant of diffuse large B-cell lymphoma (DLBCL) characterized by rare malignant B cells within a robust but ineffective immune cell infiltrate. The mechanistic basis of immune escape in TCRLBCL is poorly defined and not targeted therapeutically. We performed a genetic and quantitative spatial analysis of the PD-1/PD-L1 pathway in a multi-institutional cohort of TCRLBCLs and found that malignant B cells harbored PD-L1/PD-L2 copy gain or amplification in 64% of cases, which was associated with increased PD-L1 expression (P = .0111). By directed and unsupervised spatial analyses of multiparametric cell phenotypic data within the tumor microenvironment, we found that TCRLBCL is characterized by tumor-immune "neighborhoods" in which malignant B cells are surrounded by exceptionally high numbers of PD-L1-expressing TAMs and PD-1+ T cells. Furthermore, unbiased clustering of spatially resolved immune signatures distinguished TCRLBCL from related subtypes of B-cell lymphoma, including classic Hodgkin lymphoma (cHL) and DLBCL-NOS. Finally, we observed clinical responses to PD-1 blockade in 3 of 5 patients with relapsed/refractory TCRLBCL who were enrolled in clinical trials for refractory hematologic malignancies (NCT03316573; NCT01953692), including 2 complete responses and 1 partial response. Taken together, these data implicate PD-1 signaling as an immune escape pathway in TCRLBCL and also support the potential utility of spatially resolved immune signatures to aid the diagnostic classification and immunotherapeutic prioritization of diverse tumor types.

Erdheim-Chester disease: An in vivo human model of Mϕ activation at the crossroad between chronic inflammation and cancer.

Erdheim-Chester disease (ECD) is a rare histiocytosis characterized by infiltration of multiple tissues by CD68+ foamy Mϕs (or 'histiocytes'). Clinical manifestations arise from mass-forming lesions or from tissue and systemic inflammation. ECD histiocytes harbor oncogenic mutations along the MAPK-kinase signaling pathway (BRAFV600E in more than half of the patients), and secrete abundant pro-inflammatory cytokines and chemokines. Based on these features, ECD is considered an inflammatory myeloid neoplasm, and is accordingly managed with targeted kinase inhibitors or immunosuppressive and cytokine-blocking agents. Evidence is emerging that maladaptive metabolic changes, particularly up-regulated glycolysis, represent an additional, mutation-driven feature of ECD histiocytes, which sustains deregulated and protracted pro-inflammatory activation and cytokine production. Besides translational relevance to the management of ECD patients and to the development of new therapeutic approaches, recognition of ECD as a natural human model of chronic, maladaptive Mϕ activation instructs the understanding of Mϕ dysfunction in other chronic inflammatory conditions.

Fine-needle aspiration specimens of 3 cases of intra-abdominal Rosai-Dorfman disease with comprehensive review of the literature.

INTRODUCTION: Rosai-Dorfman disease (RDD) is a rare usually self-limited non-Langerhans cell histiocytosis of unknown etiology. Nodal and extranodal RDD appear to represent distinct conditions with different molecular alterations and prognosis. They also pose different diagnostic challenges on biopsies and fine-needle aspiration (FNA) cytology. The aim of this study was to report on 3 cases of intra-abdominal RDD and perform an extensive review of the literature on FNA findings of RDD. MATERIALS AND METHODS: We reviewed FNA specimens from cases diagnosed histologically or cytologically as RDD during the past 10 years. We searched the PubMed and Google Scholar databases for cases of RDD sampled by FNA. RESULTS: We identified 3 cases of intra-abdominal RDD, involving the kidney, periportal lymph node, and pancreas. FNA of the latter was hypocellular with fibrosis and was nondiagnostic. FNA of the first 2 yielded hypercellular smears that were diagnosed as RDD due to the identification of emperipolesis occurring in large uni- or binucleated histiocytes with large nuclei, fine chromatin, and prominent nucleoli in smears and cell-block sections. Immunohistochemistry showed positive staining for S100 and CD68 and negative staining for CD1a. The large histiocytes with emperipolesis were more difficult to identify histologically and their demonstration required immunohistochemical stains. CONCLUSION: Our experience and an extensive review of the literature suggest that extranodal RDD can be diagnosed on FNA, and that the recognition of histiocytes with emperipolesis may be less challenging cytologically than histologically. The fibrosis frequently seen in extranodal RDD may lead to nondiagnostic aspirates, however.

Complement receptor-associated CD163+/CD18+/CD11c+/CD206-/CD209- expression profile in chronic histiocytic intervillositis of the placenta.

INTRODUCTION: Chronic histiocytic intervillositis of unknown etiology (CIUE) is a non-infectious, most probably immunologic placenta lesion. CIUE is associated with recurrent miscarriage, intrauterine growth restriction and stillbirth. Among the pathologic-anatomic defined placental lesions this entity displays the highest risk of recurrence in following pregnancies (about 67-100%). The histiocytic cells accumulate in the placental blood space but do not infiltrate into the villi or decidua. Sparsely known is the expression profile of these intervillous cells regarding histiocytic markers. METHODS: We analysed 5-22 markers by immunohistochemistry in a total of 41 placenta samples and evaluated decidual, villous and intervillous histiocytic cells. RESULTS: In CIUE, intervillous CD163+ histiocytes over-express CD11c/CD18 and down-regulate CD206/CD209, while CD163+ decidual and Hofbauer cells show low CD11c/CD18 and higher CD206/CD209 protein expressions. DISCUSSION: CD163 expression indicates a M2-like polarisation. CD11c and CD18 form the complement receptor 4 which could be related to a complement mediated trigger for aberrant cell accumulation in CIUE.

The Elusive Role of Placental Macrophages: The Hofbauer Cell.

In this review, we discuss the often overlooked tissue-resident fetal macrophages, Hofbauer cells, which are found within the chorionic villi of the human placenta. Hofbauer cells have been shown to have a phenotype associated with regulatory and anti-inflammatory functions. They are thought to play a crucial role in the regulation of pregnancy and in the maintenance of a homeostatic environment that is crucial for fetal development. Even though the numbers of these macrophages are some of the most abundant immune cells in the human placenta, which are sustained throughout pregnancy, there are very few studies that have identified their origin, their phenotype, and functions and why they are maintained throughout gestation. It is not yet understood how Hofbauer cells may change in function throughout normal pregnancy, and especially in those complicated by maternal gestational diabetes, preeclampsia, and viral infections, such as Zika, cytomegalovirus, and human immunodeficiency virus. We review what is known about the origin of these macrophages and explore how common complications of pregnancy dysregulate these cells leading to adverse birth outcomes in humans. Our synthesis sheds light on areas for human studies that can further define these innate regulatory cells.

Recommendations for the Use of Etoposide-Based Therapy and Bone Marrow Transplantation for the Treatment of HLH: Consensus Statements by the HLH Steering Committee of the Histiocyte Society.

Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome requiring aggressive immunosuppressive therapy. Following 2 large international studies mainly targeting pediatric patients with familial disease and patients without underlying chronic or malignant disease, the HLH-94 protocol is recommended as the standard of care when using etoposide-based therapy by the Histiocyte Society. However, in clinical practice, etoposide-based therapy has been widely used beyond the study inclusion criteria, including older patients and patients with underlying diseases (secondary HLH). Many questions remain around these extended indications and published reports do not address several practical issues. To tackle these concerns, the HLH Steering Committee of the Histiocyte Society decided to issue guidance for use of the HLH-94 protocol. The group convened in a structured consensus finding process to define recommendations that are based largely on expert opinion backed up by available data from the literature. The recommendations address all main elements of HLH-94 including corticosteroids, cyclosporin, etoposide, intrathecal therapy, and hematopoietic stem cell transplantation (HSCT) and consider various forms of HLH and all age groups. Aspects covered include indications, applications, dosing, side effects, duration of therapy, salvage therapy, and HSCT. These recommendations aim to provide a framework to guide treatment decisions in this severe disease.

The utility of FDG-PET/CT imaging in the evaluation of multicentric reticulohistiocytosis: A case report.

INTRODUCTION: Multicentric reticulohistiocytosis (MRH) is a rare histiocytic disorder that involves the skin, joints, and visceral organs. CASE PRESENTATION: We report a 67-year-old woman with MRH who presented with a 2-years history of polyarthralgia and skin nodules. Her symptoms were an inflammatory polyarthropathy with punched-out lesions of the distal interphalangeal (DIP) joints of both hands. Doppler ultrasonography of the hands showed large bone erosions with power Doppler signals in the DIP joints. F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) demonstrated increased FDG uptake in cutaneous papules surrounding the affected joints, suggesting an inflammatory process. There was no evidence of malignancy. Biopsy samples of skin nodules exhibited dermal infiltration with CD68-positive histiocytes and multinucleated giant cells. The patient was diagnosed with MRH and treated with combination therapy comprising a steroid (prednisolone), tacrolimus, methotrexate, and infliximab, which resulted in clinical improvement. Following infliximab treatment, there was a significant decrease in a bone resorption marker (tartrate-resistant acid phosphatase 5b: TRACP-5b), suggesting that tumor necrosis factor-α targeting therapy may inhibit osteoclast formation and resorption activity in patients with MRH. CONCLUSION: MRH is a progressive destructive arthritic condition, and early diagnostic and therapeutic strategies are necessary to improve the outcome. FDG-PET/CT and joint ultrasonography might be noninvasive imaging modalities that could help diagnose MRH.

Clinical, histological and molecular predictors of metastatic melanoma responses to anti-PD-1 immunotherapy.

BACKGROUND: Prescribing anti-programmed death-1 (PD-1) immunotherapy for advanced melanoma is currently not restricted by any biomarker assessment. Determination of programmed death-ligand-1 (PD-L1)-expression status is technically challenging and is not mandatory, because negative tumours also achieve therapeutic responses. However, reproducible biomarkers predictive of a response to anti-PD-1 therapy could contribute to improving therapeutic decision-making. METHODS: This retrospective study on 70 metastatic melanoma patients was undertaken to evaluate the relationships between clinical, histological, immunohistochemical and/or molecular criteria, and the 6-month objective response rate. RESULTS: Better objective response rates were associated with metachronous metastases (P = 0.04), PD-L1 tumour- and/or immune-cell status (P = 0.01), CD163+ histiocytes at advancing edges (P = 0.009) of primary melanomas and NRAS mutation (P = 0.019). Moreover, CD163+ histiocytes at advancing edges (P = 0.04) were associated with longer progression-free survival (PFS), and metachronous metastases with longer overall survival (P = 0.02) and PFS (P = 0.049). CONCLUSIONS: Combining these reproducible biomarkers could help improve therapeutic decision-making for patients with progressive disease.

A Newly Recognized Histologic Pattern of IgG4-related Lymphadenopathy: Expanding the Morphologic Spectrum.

Immunoglobulin (Ig)G4-related sclerosing disease is a fibroinflammatory disorder characterized by tumor-forming lesions at multiple anatomic sites and by increased serum levels of IgG4. IgG4-related lymphadenopathy, defined as lymphadenopathy developing in patients with IgG4-related sclerosing disease, is known to manifest in 5 histologic patterns: (1) multicentric Castleman disease-like; (2) reactive follicular hyperplasia; (3) interfollicular plasmacytosis with immunoblasts; (4) progressive transformation of germinal centers-like; and (5) inflammatory pseudotumor-like. Herein, we describe a 37-year-old man with an additional pattern of IgG4-related lymphadenopathy that we designate as infectious mononucleosis-like. This pattern is characterized by effacement of the nodal architecture by an infiltrate composed of numerous mature plasma cells, plasmacytoid cells, large basophilic transformed lymphocytes (immunoblasts), and small-sized to medium-sized lymphocytes and histiocytes. Perivascular fibrosis and karyorrhectic debris with fibrin deposition were also focally identified. Epstein-Barr virus-encoded small RNA in situ hybridization showed scattered positive small lymphocytes, 1% to 2%. The initial spike of IgG4 in serum (>4400 mg/dL) decreased by half after 1 month of steroid therapy. His condition was stable during 1 year of follow-up. We report this case because the findings expand the morphologic spectrum of IgG4-related lymphadenopathy.

Current Perspectives on Erythema Multiforme.

Recognition and timely adequate treatment of erythema multiforme remain a major challenge. In this review, current diagnostic guidelines, potential pitfalls, and modern/novel treatment options are summarized with the aim to help clinicians with diagnostic and therapeutic decision-making. The diagnosis of erythema multiforme, that has an acute, self-limiting course, is based on its typical clinical picture of targetoid erythematous lesions with predominant acral localization as well as histological findings. Clinically, erythema multiforme can be differentiated into isolated cutaneous and combined mucocutaneous forms. Atypical erythema multiforme manifestations include lichenoid or granulomatous lesions as well as lesional infiltrates of T cell lymphoma and histiocytes. Herpes simplex virus infection being the most common cause, other infectious agents like-especially in children-Mycoplasma pneumoniae, hepatitis C virus, Coxsackie virus, and Epstein Barr virus may also trigger erythema multiforme. The second most frequently identified cause of erythema multiforme is drugs. In different studies, e.g., allopurinol, phenobarbital, phenytoin, valproic acid, antibacterial sulfonamides, penicillins, erythromycin, nitrofurantoin, tetracyclines, chlormezanone, acetylsalicylic acid, statins, as well as different TNF-α inhibitors such as adalimumab, infliximab, and etanercept were reported as possible implicated drugs. Recently, cases of erythema multiforme associated with vaccination, immunotherapy for melanoma, and even with topical drugs like imiquimod have been described. In patients with recurrent herpes simplex virus-associated erythema multiforme, the topical prophylactic treatment with acyclovir does not seem to prevent further episodes of erythema multiforme. In case of resistance to one virostatic drug, the switch to an alternative drug, and in patients non-responsive to virostatic agents, the use of dapsone as well as new treatment options, e.g., JAK-inhibitors or apremilast, might be considered.

DC-SIGN expression in Hofbauer cells may play an important role in immune tolerance in fetal chorionic villi during the development of preeclampsia.

Immune tolerance at feto-maternal interfaces is a complex phenomenon. Although maternal decidual macrophages are well-known immune cells, little is known about fetal-derived macrophages (Hofbauer cells) within chorionic villi. Preeclampsia (PE) is a major cause of maternal mortality in the field of obstetrics, and the innate immunological role of maternal decidual macrophages is well known. In this study, we assessed the differential phenotypes and marker expression in fetal macrophages, known as dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)-positive Hofbauer cells. We compared Hofbauer cell properties between normal and PE placenta chorionic villi and performed sequential staining of DC-SIGN, CD14, and CD68 to evaluate the existence of Hofbauer cells. Furthermore, to evaluate the immunological function of these cells, we stained the cells for CD163, a marker of immunoregulatory type 2 (M2) macrophages. Additionally, we examined the expression of the immunosuppressive cytokine interleukin (IL)-10, which is known to be produced by M2 macrophages. DC-SIGN+/CD14+, DC-SIGN+/CD68+, and CD163+/DC-SIGN+ cells were quantified based on photomicrographs. The results showed that CD14, CD163, DC-SIGN, and IL-10 levels were significantly downregulated in PE compared with normal. Additionally, CD163+/DC-SIGN+ Hofbauer cells were significantly less frequent in PE than in normal. DC-SIGN Hofbauer cells produced IL-10 at lower levels in the PE than in the normal. Thus, we speculate that fetal-derived Hofbauer cells may play an important role in normal pregnancy with immunosuppressive effects based on their M2 macrophage characteristics to maintain immune tolerance during pregnancy. Additionally, in PE, these functions were defective, supporting the roles of these macrophages in PE development.

Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia.

OBJECTIVES: T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a morphologic variant of large B-cell lymphoma whose flow cytometry findings are not well characterized. METHODS: Nineteen cases with flow cytometric immunophenotyping were identified from the case records of four institutions between 2001 and 2016. RESULTS: In most cases, neoplastic B cells were not detected by flow cytometry. Overall, cases showed a predominance of CD4+ T cells, which in some cases was marked. Significant coexpression of CD57 was seen on CD4+ T cells where this marker was analyzed, which correlated with PD-1 expression. Two cases also showed a profound systemic B-cell lymphopenia, which was associated in one case with hypogammaglobulinemia. CONCLUSIONS: Overall, our work challenges previous findings that cases of THRLBCL are rich in CD8+ T cells and highlights parallels between THRLBCL and nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL). Also, an association of THRLBCL with systemic B-cell lymphopenia has not been previously reported but may represent an underrecognized manifestation.

Erdheim-Chester Disease presenting with histiocytic colitis and cytokine storm.

BACKGROUND: Non-Langerhans histiocytosis is a group of inflammatory lymphoproliferative disorders originating from non-clonal expansion of hematopoietic stem cells into cytokine-secreting dendritic cells or macrophages. Erdheim-Chester Disease (ECD) is a rare type of non-Langerhans cell histiocytosis characterized by tissue inflammation and injury caused by macrophage infiltration and histologic findings of foamy histiocytes. Often ECD involves the skeleton, retroperitoneum and the orbits. This is the first report documenting ECD manifesting as segmental colitis and causing cytokine-release syndrome. CASE PRESENTATION: A 68-year old woman presented with persistent fever without infectious etiology and hematochezia. Endoscopy showed segmental colitis and pathology revealed infiltration of large foamy histiocytes CD3-/CD20-/CD68+/CD163+/S100- consistent with ECD. The patient was empirically treated with steroids but continued to have fever and developed progressive distributive shock. CONCLUSION: This case report describes the differential diagnosis of infectious and immune-mediated inflammatory and rheumatologic segmental colitis. Non-Langerhans histiocytosis and ECD are rare causes of gastrointestinal inflammation. Prompt diagnosis is imperative for the appropriate treatment to prevent hemodynamic compromise due to distributive shock or gastrointestinal bleeding. Importantly, gastrointestinal ECD might exhibit poor response to steroid treatment and other potential treatments including chemotherapy, and biologic treatments targeting IL-1 and TNF-alpha signalling should be considered.