Nodular Lymphoid Hyperplasia Research Articles

Identification of a novel de novo gain-of-function mutation of PIK3CD in a patient with activated phosphoinositide 3-kinase δ syndrome

Activated phosphoinositide 3-kinase δ (PI3Kδ) syndrome is a newly defined and relatively common primary immunodeficiency, which is caused by heterozygous gain-of-function (GOF) mutations in PIK3CD or PIK3R1. Here, we report a novel de novo GOF mutation (c.1570 T > A, p.Y524N) in PIK3CD in a 6-year-old Chinese girl. The patient suffered recurrent sinopulmonary infection, bronchiectasis, lymphoproliferation, herpesvirus infection, and distinctive nodular lymphoid hyperplasia of mucosal surfaces. Immunological analysis revealed increased CD4+ T cell senescence and B cell immaturity. Further analysis revealed an increase in almost all CD4+ T cell subsets to varying degrees, including effector T cells and Treg cells. Increased levels of plasma T cell-related cytokines corroborated these results. Hyperactivation of the PI3Kδ-Akt-mTOR signaling pathway was also confirmed. Treatment with rapamycin ameliorated the lymphoproliferative immunodeficiency caused by hyperactivation of mTOR. These results expand genetic spectrum of APDS and will facilitate further study of the genotype-phenotype correlation in those with PIK3CD mutations.

Pulmonary Nodular Lymphoid Hyperplasia with Mass-Formation: Clinicopathologic Characteristics of Nine Cases and Review of the Literature.

BackgroundPulmonary nodular lymphoid hyperplasia (PNLH) is a non-neoplastic pulmonary lymphoid disorder that can be mistaken for malignancy on radiography. Herein, we present nine cases of PNLH, emphasizing clinicoradiological findings and histological features. MethodsWe analyzed radiological and clinicopathological features from the electronic medical records of nine patients (eight females and one male) diagnosed with PNLH. IgG and IgG4 immunohistochemical staining was performed in three patients. ResultsTwo of the nine patients had experienced tuberculosis 40 and 30 years prior, respectively. Interestingly, none were current smokers, although two were ex-smokers. Three patients complaining of persistent cough underwent computed tomography of the chest. PNLH was incidentally discovered in five patients during examination for other reasons. The remaining patient was diagnosed with the disease following treatment for pneumonia. Imaging studies revealed consolidation or a mass-like lesion in eight patients. First impressions included invasive adenocarcinoma and mucosal-associated lymphoid tissue‒type lymphoma. Aspergillosis was suspected in the remaining patient based on radiological images. Resection was performed in all patients. Microscopically, the lesions consisted of nodular proliferation of reactive germinal centers accompanied by infiltration of neutrophils and macrophages in various degrees and surrounding fibrosis. Ultimately, all nine patients were diagnosed with PNLH and showed no evidence of recurrence on follow-up. ConclusionsPNLH is an uncommon but distinct entity with a benign nature, and understanding the radiological and clinicopathological characteristics of PNLH is important.

Gastrointestinal Disorders Associated with Primary Immunodeficiency Diseases.

There are now 354 inborn errors of immunity (primary immunodeficiency diseases (PIDDs)) with 344 distinct molecular etiologies reported according to the International Union of Immunological Sciences (IUIS) (Clin Gastroenterol Hepatol 11: p. 1050-63, 2013, Semin Gastrointest Dis 8: p. 22-32, 1997, J Clin Immunol 38: p. 96-128, 2018). Using the IUIS document as a reference and cross-checking PubMed ( www.ncbi.nlm.nih.pubmed.gov ), we found that approximately one third of the 354 diseases of impaired immunity have a gastrointestinal component [J Clin Immunol 38: p. 96-128, 2018]. Often, the gastrointestinal symptomatology and pathology is the heralding sign of a PIDD; therefore, it is important to recognize patterns of disease which may manifest along the gastrointestinal tract as a more global derangement of immune function. As such, holistic consideration of immunity is warranted in patients with clinically significant gastrointestinal disease. Here, we discuss the manifold presentations and GI-specific complications of PIDDs which could lead patients to seek advice from a variety of clinician specialists. Often, patients with these medical problems will engage general pediatricians, surgeons, gastroenterologists, rheumatologists, and clinical immunologists among others. Following delineation of the presenting concern, accurate and often molecular diagnosis is imperative and a multi-disciplinary approach warranted for optimal management. In this review, we will summarize the current state of understanding of PIDD gastrointestinal disease involvement. We will do so by focusing upon gastrointestinal disease categories (i.e., inflammatory, diarrhea, nodular lymphoid hyperplasia, liver/biliary tract, structural disease, and oncologic disease) with an intent to aid the healthcare provider who may encounter a patient with an as-yet undiagnosed PIDD who presents initially with a gastrointestinal symptom, sign, or problem.

Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome.

The activated phosphoinositide 3-kinase δ syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy, and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (encoding p110δ: APDS1 or PASLI-CD) and PIK3R1 (encoding p85α: APDS2 or PASLI-R1). While the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses, and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions are limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy, or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.

Pulmonary Nodular Lymphoid Hyperplasia: A Rare Case Mimicking Malignancy

Pulmonary nodular lymphoid hyperplasia (PNLH) is a reactive lymphoid proliferation manifesting as multiple solitary nodules or localized infiltrates in the lungs. It is a type of benign lymphoproliferative disease that can affect the lungs. We present the case of a 41-year-old female patient with respiratory symptoms such as productive cough, left chest pain, and dyspnea. Imaging findings revealed two lesions with lobulated contour in the left upper lobe apicoposterior segment and left lower lobe superior segment. After examining the minimally invasive diagnostic methods, this rare PNLH case mimicking malignancy was both diagnosed and treated by surgery. Further studies including more patients and longer follow-ups are needed for this rare disease.

Gastrointestinal manifestation of immunoglobulin G4-related disease: clarification through a multicenter survey.

Several reports on immunoglobulin (Ig)G4-related disease (IgG4-RD) with gastrointestinal involvement (IgG4-related gastrointestinal disease; IgG4-GID) have been published, although this entity has not been fully established clinicopathologically. Thus, we carried out a multicenter survey. Patients with possible IgG4-GID who underwent resection were collected. Histologic slides were reevaluated, and eight cases with diffuse lymphoplasmacytic infiltration but without numerous neutrophils, granulations or epithelioid granulomas were further analyzed. Overall, the IgG4 counts (87-345/high-power field) and IgG4/IgG-positive ratio were high (44-115%). The demographic findings included advanced age among the patients (55-80years) and male preponderance (six cases). Six lesions (five gastric, one esophageal), consisting of lymphoplasmacytic infiltration with neural involvement in the muscularis propria and/or bottom-heavy plasmacytosis in the gastric mucosa, were histologically regarded as highly suggestive of IgG4-RD. Storiform fibrosis and obliterative phlebitis were found in two cases, and the former gave rise to a 7-cm-sized inflammatory pseudotumor (IPT) in one case. Ulceration and carcinoma co-existed in three and two lesions, respectively. All the patients had other organ involvement (OOI), and serum IgG4 levels were markedly elevated (four of five patients). The remaining two cases with gastric IPTs featuring reactive nodular fibrous pseudotumor or nodular lymphoid hyperplasia were regarded as possible cases of IgG4-RD because of the histologic findings and lack of OOI. IgG4-GID is found in the setting of IgG4-RD, often with ulceration or cancer. Characteristic histologic findings are observed in the muscularis propria and gastric mucosa. Cases with IPT may be heterogeneous, and there may be mimickers of IgG4-GID.

Hemostasis Technique Using an Adjustable Nylon Tie in Dog with Splenic Hematoma and Lymphoid Hyperplasia

Background: Splenic hematoma is an encapsulated blood accumulation, which is macroscopically indistinguishable from malignant spleen. The treatment of choice and final diagnosis were by splenectomy and exploratory laparotomy followed by biopsy and histopathological examination, respectively. Nylon tie bands are devices made of polyamide 6.6, same material of surgical nylon wires, and has been used in different surgical procedures in animals. The present report case aimed to describe the use of nylon tie bands polyamide 6.6 in a 2.3-year-old Golden retriever dog diagnosed with splenic hematoma and lymphoid hyperplasia; and the clinical presentation, diagnostic evaluation, histological diagnosis of splenic hematoma and lymphoid hyperplasia.Case: A 2.3-year-old intact male Golden retriever dog was presented with history of anorexia, apathy, regurgitation and weight loss. During the physical examination was identified a mass in the left side of abdomen. The complete blood count (CBC), serum biochemistry, urinalysis, and thoracic radiographs were no alteration. Abdominal ultrasound revealed splenomegaly and heterogeneous hypoechoic structure. Splenectomy using an adjustable nylon ties polyamide 6.6 for hemostasis technique was performed during an exploratory laparotomy. The spleen presented hematoma and lymphoid hyperplasia at the histopathological examination, as well as the presence of siderocalcinotic plate in the trabecular spleen. The dog presented with no regurgitation, apathy or anorexia after 10 days of surgery. CBC, serum biochemistry analysis, thoracic radiographs and abdominal ultrasound revealed no abnormalities. Video laparoscopy did not showed any sign of adherence on the local where used the nylon tie bands. One year and three months after the surgery, the owner was contacted by telephone, since he had changed to other city, and he reported that the dog was healthy without any clinical signs.Discussion: The present case report describes the using of nylon tie polyamide 6.6 bands in a 2.3-year-old Golden retriever dog diagnosed with splenic hematoma and lymphoid hyperplasia. According to the author’s knowledge, the present case is the first report regarding to using nylon tie bands in splenectomy, and clinical characteristics of hematoma and lymphoid hyperplasia in young dog. The adjustable nylon tie bands allowed a secure and faster ligature when compared with traditional nylon surgical suture wires in different surgical procedures in animals and humans patients, and was considered well tolerated and non-toxic. Reports concerning to complications to the use of nylon tie in veterinary surgery were present in the literature. Otherwise, these complications were related to surgical technique failure and inadequate aseptic technique; inadequate use of nylon tie bands before assigning it as a hemostatic material. Partial splenectomy is recommended for treatment of splenic hematoma and lymphoid hyperplasia in dogs whenever possible; however, the macroscopic findings concerning splenic disorders are not enough to set the distinction between benign and malignant disorders. Clinical sign associated with splenic disorders in the present case was abdominal distension due to hematoma and nodular lymphoid hyperplasia. An adjustable nylon tie polyamide 6.6 band can be used to clamp the spleen vessels, gastroepiploic artery, gastric artery and omento veins.

Splenomegaly in small-breed dogs: 45 cases(2005-2011).

OBJECTIVE To assess causes of splenomegaly and postsurgical outcomes in small-breed (ie, < 16-kg [< 35.2-lb]) dogs that underwent splenectomy and evaluate associations among malignant disease, hemoperitoneum, and survival time in these patients. DESIGN Retrospective case series. ANIMALS 45 client-owned dogs. PROCEDURES Medical records of 2 veterinary facilities were reviewed to identify small-breed dogs that underwent splenectomy and had a histologic diagnosis recorded. Data analyzed included signalment, diagnosis, presence or absence of hemoperitoneum, and survival time. RESULTS 21 dogs had malignant neoplasia and 24 had benign splenic diseases. Hemangiosarcoma was the most common malignancy (14/21 [67%] dogs) and lymphoid nodular hyperplasia, hematoma, or extramedullary hematopoiesis (alone or in combination) was most commonly diagnosed in dogs with benign disease (17/24 [71%]). Wheaton Terriers were significantly more likely to have malignant splenic disease than were dogs of other breeds. Malignant splenic disease and the presence of hemoperitoneum had significant negative associations with survival time. Malignant disease was not significantly associated with the presence of hemoperitoneum. CONCLUSIONS AND CLINICAL RELEVANCE Causes for splenomegaly and survival times were similar to those previously reported for populations that primarily included large-breed dogs. There were approximately equal numbers of benign and malignant causes for splenomegaly in this population. Results suggested that Wheaton Terriers with splenomegaly had a higher likelihood of malignant neoplasia than other breeds and that hemoperitoneum may not be a significant predictor of malignancy in small-breed dogs. However, further research including a larger number of dogs is needed to confirm these findings. (J Am Vet Med Assoc 2017;250:1148-1154).

A delicate balance of PI3K activation is required for CD8 T cell survival and generation of memory cells

Abstract The p110d subunit of phosphatidylinositol-3-OH kinase (PI(3)K) is selectively expressed in leukocytes and is critical for lymphocyte biology. We previously reported patients heterozygous for three different germline, gain-of-function mutations in PIK3CD (encoding p110d). Patients presented with sinopulmonary infections, lymphadenopathy, nodular lymphoid hyperplasia and CMV and/or EBV viremia, suggestive of immune dysfunction. We established a mouse model (PIK3cd E1024K) that recapitulates features of this disease including lymphopenia, yet enlarged secondary lymphoid organs, as well as increased Akt phosphorylation and hyperactivation of the metabolic checkpoint kinase mTOR. In response to TCR stimulation, mutant T cells proliferate, but rapidly die via a Fas/FasL-mediated apoptosis. The few surviving mutant CD8 T cells exhibit features of short-lived effectors, expressing abundant cytokines and elevated granzymes, and kill target cells more efficiently than WT counterparts. This phenotype is mirrored at early time points following viral infection. However, at late time-points post-viral infection, mutant CD8 T cells fail to sustain expression of proteins critical for maintenance of long-lived memory cells. Thus, our data suggests that activated p110d limits effective CD8 T cell memory. Our mouse model therefore recapitulates facets of the human primary immunodeficiency, revealing insight into the pathogenesis of this disease.

Clinicopathological and Ileocolonoscopic Characteristics in Patients with Nodular Lymphoid Hyperplasia in the Terminal Ileum.

Nodular lymphoid hyperplasia (NLH) in the small intestine is a rare benign lesion, characterized by the presence of multiple small nodules on the surface of the intestine. To define the clinicopathological and colonoscopic characteristics in Chinese patients with ileal NLH, we collected 65 patients with NLH in the terminal ileum from the endoscopic database in our hospital and clinical data from medical records. Histology and immunohistochemical staining were performed in the biopsies. The results demonstrated that the main symptoms included diarrhea (70.8%), abdominal pain (60.0%), hematochezia (46.2%), anemia (40.0%), and hypoproteinemia (21.5%). Enteroscopy revealed multiple, sporadic, granular or round-shaped nodules with diameters between 2 and 5 mm in the terminal ileum. The histology revealed the nodules consisted of mass lymphoid follicles in the lamina propria and submucosa of the terminal ileum. The follicles contained mitotically active germinal centers surrounded by well-defined lymphocyte mantles and composed predominantly of CD20+ B cells. The diseases found in patients with NLH included chronic diarrhea, Crohn's disease, ischemic enterocolitis and allergic purpura. The level of hemoglobin in NLH patients who had diarrhea and hematochezia remarkably decreased as compared with those in patients with chronic diarrhea. In conclusion, ileocolonoscopic screening is an important step to find the NLH in terminal ileum patients with diarrhea, abdominal pain, hematochezia, and hypoproteinemia. Histological examination is necessary for the exclusion of malignancy and chronic inflammation.

Adults with common variable immunodeficiency: a single-center experience.

In this study, we aimed to assess the clinical and immunological findings of our patients with common variable immunodeficiency (CVID). We analyzed the records of 31 adult patients with CVID (12 females, 19 males). The patients were classified into clinical and immunophenotypic subgroups for statistical comparisons. Our patients had some clinical signs in considerable frequencies, such as low body weight (45.2%), urinary tract infections (41.9%), various dermatoses (35.5%), and oral aphthae (32.3%). The histological findings in the biopsy specimens of the gastrointestinal tract (nodular lymphoid hyperplasia, villous atrophy, and lymphocytic infiltrates at mucosa) were significantly associated with splenomegaly, hepatomegaly, or low body weight (P = 0.005, 0.045, and 0.007, respectively). The patients with low CD4/CD8 ratios had lower IgG levels and a lower percentage of CD19+ B cells, but a higher percentage of activated T cells (P = 0.023, 0.011, and 0.028, respectively). In adults with CVID, there existed some clinical signs at considerable frequencies, but these are not overemphasized in the literature. The CD4/CD8 ratio is an important factor in antibody production and the clinical presentation of CVID. It seems that the adaptive immune system is on alert and subclinical immune activation insidiously continues in patients with CVID.

Diffuse Nodular Lymphoid Hyperplasia of Colon in a Child- A Case Report with Review of Literature

Diffuse Nodular Lymphoid Hyperplasia of Colon in a Child- A Case Report with Review of Literature

Nodular lymphoid hyperplasia: A thin grey zone between hyperplasia and Pathological aggregate

Introduction: The clinical-pathological characteristics of 12 patients with intestinal nodular lymphoid hyperplasia (NLH) are described with the aim to try and delineate between hyperplasia and pathological aggregate of lymphoid tissue in the intestine and its association with other diseases from Indian subcontinent. Materials and Method: 12 diagnosed cases of NLH were retrieved out of 2256 intestinal punch biopsy done at our centre and were evaluated as per histological criteria laid down by various authors including their clinical and pathological features. Results: Most frequent symptom includes diarrhoea and weight loss and the severity of these symptoms were directly proportional to the number and location of the lymphoid nodules. Prominent lymphoid nodules in mucosa and/or submucosa were documented histologically in all cases. One patient had associated common variable immunodeficiency which on follow up developed intestinal lymphoid malignancy of NHL type (DLBCL) and the other was having hypogammaglobulinemia. All cases showed absence of plasma cells, except one with predominant symptoms of Gastroesophageal reflux disease (GERD) rather than diarrhea. Conclusion: NLH runs as a benign course, but these cases should be followed up with histology as well as thorough clinical and biochemical evaluation to detect early lymphoma that can be managed efficiently.

No definite clinical features of immunoglobulin G4–related disease in patients with pulmonary nodular lymphoid hyperplasia

Pulmonary nodular lymphoid hyperplasia (PNLH) may show heavy lymphoplasmacytic infiltrates with increased immunoglobulin G4 (IgG4)-positive plasma cells as in IgG4-related disease (IgG4-RD). However, it is unclear whether PNLH could be a manifestation of IgG4-RD. A recent study reported the presence of Epstein-Barr virus (EBV) in IgG4-related lymphadenopathy. We postulated that a subset of PNLH might represent IgG4-related lung disease with EBV-positive lymphocytes as has been reported in IgG4-related lymphadenopathy. IgG and IgG4 immunohistochemistries were performed on 26 PNLH cases in our files (1994-2014) and on 9 controls including diffuse lymphoid hyperplasia of the lung without nodularity (n=2), usual interstitial pneumonia with increased lymphoplasmacytic infiltrates (n=5), and thoracic lymphadenopathy (n=2). EBV in situ hybridization was performed in the cases with the highest IgG4+ count (n=15). Median IgG4+ plasma cell count in PNLH was 36 cells per high-power field (interquartile range, 7-65) with median IgG4+/IgG+ ratio of 0.24 (interquartile range, 0.12-0.37). Three of 26 cases had a markedly increased IgG4+ count (range, 55-139) and IgG4+/IgG+ ratio (>0.4). Serum IgG4 level available in 1 of these cases was not elevated, and all 3 patients had alternate medical diagnoses. Absolute counts of IgG4+ plasma cells in PNLH did not significantly differ from the other control groups. Result of EBV in situ hybridization was negative in all cases tested. In conclusion, most PNLH cases had low IgG4+ cells, and there was no clinical evidence of IgG4-RD or EBV among those with increased IgG4+ cells.

A Case of Diffuse Nodular Lymphoid Hyperplasia (NLH) of Duodenum in a Patient with Selective IgA Deficiency and Helicobacter Pylori Infection

Introduction: Nodular lymphoid hyperplasia (NLH) is characterized by the presence of multiple small nodules, between 2-10 mm in diameter, distributed more commonly in the small intestine, sometimes in the stomach and large intestine. It affects individuals with or without immunodeficiency and is associated with diseases such as common variable immunodeficiency, selective IgA deficiency (sIgAD), giardia, celiac disease and helicobacter pylori (H pylori) infections. We present a case of diffuse duodenal NLH in a patient with sIgAD and H Pylori infection. Case: A 59 year old female with history of sIgAD presents with generalized weakness for 2 months. Hemoglobin at presentation was 9.1 g/dL (12-16 g/dL), IgA levels were 6.1 mg/dL (68-423 mg/dL). She denied melena, hematemesis or GI bleed. She underwent colonoscopy and endoscopy for normochromic normocytic anemia. Colonoscopy was unremarkable. Upper endoscopy showed nodular mucosa in the entire duodenum (figure 1), erythema in gastric antrum, and a single 7 mm sessile polyp in gastric body (figure 2). Pathology was consistent with NLH in duodenum (figure 3), gastric adenomatous polyp with low grade dysplasia and positive H pylori. She was started on treatment with clarithromycin, amoxicillin and pantoprazole. She underwent upper endoscopy with endoscopic ultrasound for resection of gastric adenoma which again showed nodular mucosa in duodenum consistent with NLH.Figure 1Figure 2Figure 3Discussion: The incidence of NLH is unknown but rare condition in adults. Histologically it is defined as hyperplastic, mitotically active germinal centers with well-defined lymphocyte mantles in lamina propria. In immunodeficiency states NLH may result from an accumulation of plasma-cell precursors due to a maturational defect in the development of B-lymphocytes. In H pylori infection, pathogenesis involves immune stimulation by H pylori. It is usually asymptomatic but can present with abdominal pain, chronic diarrhea, bleeding, intussusception or intestinal obstruction. The diagnosis is established by endoscopy or contrast barium studies and confirmed histologically. Treatment involves treating the associated conditions. NLH is a risk factor for both intestinal and extra-intestinal lymphomas. Some authors recommend surveillance, however, the duration and intervals are undefined. Conclusion: The case illustrates the rare impressive endoscopic findings of NLH in a patient with sIgAD and H. pylori infection.

Diffuse Nodular Lymphoidhyperplasia with Selective IgA Deficiency Syndrome Presenting with Intestinal Lymphoma

Diffuse Nodular Lymphoidhyperplasia with Selective IgA Deficiency Syndrome Presenting with Intestinal Lymphoma

Experiencia de cápsula endoscópica en sangrado de origen obscuro y dolor abdominal crónico recurrente en Pediatría del CMN «20 de Noviembre» del ISSSTE

BackgroundCapsule Endoscopy (CE) is a useful tool in diagnosis of small bowel diseases, enabling to evaluate regions that cannot be reached with other endoscopic procedures to be approach, whether surgical or medical. ObjetiveTo know and describe the principal etiology in the 2 main pediatric indications for the use of endoscopic capsule in a third level hospital. Material and methodsIn this transversal, descriptive and retrospective study, we review the medical files of patients referred to endoscopy with diagnosis of OGIB and CAP. Twenty seven patients, with ages ragging from 4 to 18 years old where studied in the period from 1th January 2008 to 31 December 2014 were included. ResultsWe obtained the following etiological diagnostics in diseases that produce OGIB and CAP: Patients with OGIB27.1% with lymphoid nodular hyperplasia, 13.3% hemangioma, 6.6% vascular dysplasia, 13.3% erosive jejunoileal inflamation, 13.3% ulcerative colitis, 6.6% telangiectasia, 6.6% polyposis, and 6.6% duodenal ulcer. Patients with CAP36.6% polyposis, 18.8% Crhon disease, 9.09% pseudo cecal pseudopolyp, 9.09% vascular ectasia, 9.09% pseudopolyp, 9.09% normal study, 9.09% intestinal limphangiectasia, and 9.09% jejunoileitis.There was only one report of an adverse event in a patient with crhon disease. DiscussionCapsule endoscopy is a diagnostic tool for small bowel disease in pediatric patients with OGIB and CAP, and it helps to determine the etiology of these diseases and helps to stablish the therapeutic approach, weather its surgical o medical.

Lymphoid Interstitial Pneumonia and Other Benign Lymphoid Disorders.

Benign pulmonary lymphoid disorders include a variety of rare lymphoid abnormalities characterized by a polyclonal lymphoid infiltrate with differing histopathologic patterns and clinicoradiologic features that may overlap. Histological examination is essential to reach a correct diagnosis and to exclude alternative causes, although this task can at times prove difficult. Further studies and clinical trials are needed to provide additional insights on pathogenesis and to guide the therapeutic management of these disorders. The purpose of this article is to review the histopathological, epidemiological, and clinicoradiologic features of several benign pulmonary lymphoid disorders, including lymphoid interstitial pneumonia, follicular bronchiolitis, nodular lymphoid hyperplasia (pulmonary pseudolymphoma), inflammatory pseudotumor, immunoglobulin G4-related disease, Castleman disease, posttransplantation lymphoproliferative disease, and drug-induced lymphoid disorders.

Nodular lymphoid hyperplasia of urinary bladder admixed with non-invasive low-grade urothelial carcinoma

Primary malignant lymphoma of urinary bladder is extremely rare, and benign nodular lymphoid hyperplasia has not been reported in bladder. Nodular lymphoid hyperplasia of bladder associated with bladder carcinoma has also not been reported. Herein the author describe a 64-year-old man who presented with dysuria and his cystscopic examination revealed a papillary tumor in bladder. A transurethral resection of bladder tumor was carried out, and histopathologic examination revealed a non-invasive pTa low-grade papillary urothelial carcinoma and nodular lymphoid hyperplasia that were mixed up. The nodular lymphoid hyperplasia was composed of inner germinal centers and outer marginal and mantle zones. The germinal centers were composed of tangible body macrophages, centrocytes and centroblasts, while the outer zone of mature lymphocytes. Immunohistochemical profile of nodular lymphoid hyperplasia was as follows: cytokeratin AE1/AE3-, cytokeratin CAM5.2-, CD45+++, CD20+++, CD79a++, CD138-, CD3-, CD45RO-, CD15-, CD30-, p53- Ki67 80% (confined to germinal centers), bcl-2-, bcl-6++, CD10++, MUM1-, cyclinD1-, light chains-, CD56-, TdT-, CD68-. The patient is now followed up without any treatments by periodical cystscopy with BCG injection and cytology. No recurrence is noted 13 months after the first presentation. In conclusion, an extremely rare case of nodular lymphoid hyperplasia mixed with non-invasive urothelial carcinoma in bladder is reported.

Deciphering the Different Types of Refractory Celiac Disease

Universite Paris Descartes-Sorbonne Paris Centre Gastroenterology department, Hopital Europeen Georges Pompidou APHP, Paris Inserm U989, Hopital Europeen Georges Pompidou APHP Paris, France Fifteen years ago has emerged the concept of refractory celiac disease (RCD). [1,2] RCD is defined by persisting malabsorption and villous atrophy after one year of strict GFD ascertained by a dietician. RCD has been subdivided into two subgroups according to the normal (type I RCD (RCDI)) or abnormal phenotype of intraepithelial lymphocytes (IEL) (type II RCD (RCDII). RCDI is indistinguishable from active CD and is characterized by a polyclonal repertoire. Survival of patients with RCDI is slightly inferior to that of those with celiac disease. [3,4] In contrast, RCDII is a severe enteropathy with frequent intractable ulcerative duodeno-jejunitis. RCDII is characterized by a clonal repertoire and is considered as a low-grade intraepithelial lymphoma. [1,2] The five year survival rate of patients with RCDII is around 50%. This poor prognosis is due to severe malnutrition and increased risk of overt lymphoma. One of the current challenges in RCD is to ascertain the type of RCD. Indeed, diagnosis of RCD has become highly specialized. It requires small bowel endoscopic specialized investigations such as capsule endoscopy and double balloon enteroscopy. [5,6] Intestinal biopsy needs to be studied by different complementary techniques such as immunohistochemistry, flow cytometry, and Multiplex PCR, all necessary to ascertain the precise diagnosis. Recent studies have reported case series of chronic intestinal diseases mimicking the both types of RCD. RCDI needs to be distinguished from other causes of non clonal villous atrophy such as enteropathy associated with common variable immunodeficiency (CVID). [7] Demonstration of HLA haplotypes encoding HLA-DQ2 or DQ8 can be useful as their absence excludes CD or RCD as a cause of villous atrophy. [8] Nevertheless, genotypes HLA-DQ2/DQ8 are also found in 77% of CVID patients with enteropathy mimicking CD defined by intestinal intra-epithelial lymphocytosis. [7] So evidence of serum hypogammaglobulinemia and histopathological features such as intestinal plasmocytic rarefaction or nodular lymphoid hyperplasia appear essential to distinct CVID enteropathy from RCDI. [7] RCDII needs to be distinguished from other cases of clonal enteropathy with villous atrophy. Flow cytometry allows to tell the difference between RCDII and other intestinal clonal malignancies with villous atrophy. Indeed, demonstration of excess of CD4+IEL with a specific Vbeta repertoire is essential for diagnosis of intestinal CD4 lymphoproliferations. [9] Diagnosis may be particularly tricky when CD4 lymphoproliferation [9] or large granular lymphocytic leukemia (LGL) [10] complicate an authentic CD. Consequently, spectrum of RCD has been recently substantially extended. Advances in accuracy of diagnostic tools could reduce the number of undiagnosed RCD and increase the frequency of RCD currently estimated to 1 to 2% of CD patients. [11,12] Besides epidemiological interest, improvement of diagnostic tools allowed precise diagnosis of RCD type and appropriate treatment. By example, distinction between RCDII and CD complicated by LGL is crucial as cyclosporin, inefficient in RCDII, is in contrast very useful for treating LGL. Indeed, treatment of RCD remains another challenge particularly in case of RCDII patients who have poor prognosis and for whom referral treatment does not yet exist. Immunosuppressors are poorly efficient and may possibly trigger overt lymphoma. [13] Purine analogues such pentostatine or cladribine (2 CDA) have been largely used in the past with slight therapeutic effect. [4,14,15] Autologous haematopoietic stem cells transplantation represents an interesting alternative but when combined to chemotherapy for hopping sustained reduction of abnormal IEL. [16,17] We are currently evaluating this strategy in a prospective phase II trial. Many advances in the understanding of the pathogenesis of RCDII were made by deciphering the anti-apoptotic signaling pathway of the cytokine IL-15 which prevents the elimination of IEL in CD and RCDII. [18] The IL-15 induced antiapoptotic signaling pathway includes activation of IL15Rβγ, Jak3, STAT5 and Bcl-xL [19] which represent so many therapeutic targets. Blocking the effect of IL-15 appears of a particular interest in RCDII but may probably be useful in other types of RCD with possible involvement of IL-15 such as RCDI or LGL-complicated CD. [20] Continuing the characterization of the different forms of RCD will probably guide next pathogenic studies and permit to increase our therapeutic efficacy in the future.