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Immunoproliferative small intestinal disease (IPSID) is an uncommon disease of the small intestine. There is a similarity in the clinical presentations of enteropathic diseases, including celiac disease, tropical sprue, IPSID, and Whipple's disease. A differentiation between them is based on the use of a highly specific serological test for celiac disease and specific histological characteristics. We found that IgA-anti-tissue transglutaminase antibody (IgA-tTG Ab) is falsely elevated in a subset of patients with IPSID. The levels of IgA-tTG Ab fall with the treatment of IPSID. The healthcare professional should be aware of the conditions that lead to a false-positive anti-tTG Ab. Intestinal mucosal biopsies even in the presence of anti-tTG Ab should be done in endemic regions as they provide an opportunity for making a diagnosis of alternative and uncommon diseases before the diagnosis of celiac disease., (© 2023. Indian Society of Gastroenterology.)

We herein report an 80-year-old man diagnosed with immunoproliferative small intestine disease (IPSID) via small bowel endoscopy with a biopsy. He developed persistent diarrhea and subsequently presented with hypoproteinemia and moderate anemia. Transanal double-balloon endoscopy showed prominent villous edema in the middle and lower ileum, while a histological examination showed high lymphocyte/plasma cell infiltration in the mucosal layer. Furthermore, an immunostaining analysis showed that Cluster of differentiation (CD) 3 and CD20 were partially positive, while CD138 was diffusely positive. Immunoglobulin A positivity was also observed. He was diagnosed with IPSID and received a nutritional agent and minocycline. After three months, the patients' symptoms improved.

Immunoproliferative Small Intestinal Disease (IPSID) is a disease characterized by extra-nodal marginal zone B-cell lymphoma with villous atrophy in the small intestine, causing chronic intermittent non-bloody diarrhea. Although originally associated with the Mediterranean region, this disease is present in many countries worldwide and may have been underreported due to its complicated diagnosis and scarce scientific literature, especially in regards to treatment. This study aims to review IPSID clinical features, therapeutic options, and treatment outcomes to help physicians identify and treat IPSID. Using PRISMA guidelines, a systematic review of articles was conducted on PubMed database with search terms including IPSID, therapy, treatment, and outcomes. Inclusion and exclusion criteria were used to select 33 English language articles published from the year 2000-2020 that included relevant clinical information about IPSID treatment. Data were extracted independently by at least two authors to reduce the introduction of potential bias. There were 22 case reports, 7 reviews, 1 research article, 1 prospective study, 1 letter to the editor and 1 memoriam in which 76 patients were identified. Epidemiological analysis showed a mean patient age of 32 years old, 2.4:1 mal to female ratio and heterogeneous ethnicities, with 16 Europeans (43.2%) and 12 Asians (32.4%). Chief symptoms included chronic diarrhea (53/76, 69.7%), weight loss (49/76, 64.4%), malabsorption (38/76, 50%), abdominal pain (32/76, 42.1%), and finger clubbing (24/76, 31.6%). Patients stratified into the early disease stage (Galian A) were treated with tetracycline antibiotics, corticosteroids, and non-pharmacological supplements with mostly with complete or partial remission. Late stages (Galian B or C), were treated mostly with anthracycline-based chemotherapy, and occasionally surgery, radiotherapy, or rituximab. This work offers a targeted approach to diagnosing and treating IPSID to aid physicians and serve as a treatment guideline recommendation for future public policies and clinical studies., Competing Interests: The authors have declared that no competing interests exist.

Immunoproliferative small intestinal disease is an extranodal marginal zone B-cell lymphoma that arises from mucosa-associated lymphoid tissue and is associated with defective α heavy chain protein secretion. We present a case of an 18-year-old male patient admitted with diarrhea and weight loss who had previously received a liver transplant at the age of 19 months to treat biliary atresia. He underwent a thorough investigation and was diagnosed with immunoproliferative small intestinal disease lymphoma. The patient was switched from tacrolimus to everolimus and commenced on doxycycline treatment for 6 months and achieved long-term remission. Currently, 7 years after diagnosis, he is asymptomatic without evidence of histological relapse. This is the first case of immunoproliferative small intestinal disease described in a liver transplant recipient.

Purpose of Review: The purpose of this review is to discuss current knowledge and recent findings regarding pathogenesis, outcome, and treatment for heavy chain disease (HCD) involving the small bowel, focusing on alpha HCD or immunoproliferative small intestinal disease (IPSID), the HCD subtype typically affecting the small bowel., Recent Findings: A link between Campylobacter jejuni infection and IPSID has been established, but there is controversy as to the role played by this organism in disease pathogenesis. While cytogenetic abnormalities involving various immunoglobulin loci and PAX5 have been reported, these have been described in rare, single cases, limiting their ability to shed further light on disease pathogenesis. IPSID is typically regarded as a pre-lymphomatous condition with eventual progression to frank lymphoma; however, recent reports of longstanding non-progressive cases have expanded its clinical spectrum. IPSID is an uncommon disorder affecting the small intestine. This review focuses on current knowledge and novel insight regarding its pathogenesis, outcome, and treatment, with an emphasis on future directions.

Objectives: Persistent diarrhea is a common complication after solid-organ transplant, including kidney transplant. Data on duodenal villous atrophy as a cause of persistent diarrhea in renal transplant recipients are scarce., Materials and Methods: We conducted a prospective analysis of 207 patients who received renal transplants from 2009 to 2012 with persistent diarrhea and who underwent upper gastrointestinal endoscopy and duodenal biopsies. Duodenal biopsies were examined for duodenal villous atrophy. Age, sex, transplant duration, and drugs were compared between patients with and without duodenal villous atrophy. After exclusion of known causes of duodenal villous atrophy, a 3-month course of antibiotics was given and outcomes were analyzed., Results: Of 207 renal transplant recipients, 104 patients (49.8%) displayed duodenal villous atrophy. Of these, 92 (88.5%) were male patients. The mean age of patients with duodenal villous atrophy was 34.9 ± 10.3 years. The mean onset of persistent diarrhea in DVA-positive patients posttransplant was 2.16 ± 0.8 years. Celiac disease serology was positive in 18 (17.3) patients. Giardiasis was demonstrated in 11 patients (10.7%), whereas immunoproliferative small intestinal disease was shown in 7 patients (6.8%). The remaining 68 patients (65.38%) received antibiotics, with 50 recipients (74.6%) showing complete response, although 13 of these patients (26%) relapsed. Among the remaining 18 patients (26.47%), 9 (50%) had other causes and 9 (50%) had no cause found. Isoniazid prophylaxis showed statistically significant negative association with duodenal villous atrophy., Conclusions: Duodenal villous atrophy is highly prevalent in renal transplant recipients irrespective of age, sex, and posttransplant duration. We found tropical sprue, giardiasis, immunoproliferative small intestinal disease, and celiac disease to be important causes of duodenal villous atrophy. Therefore, duodenal biopsy is recommended in renal transplant recipients with persistent diarrhea.

Marginal zone lymphomas (MZL) represent around 8 % of all non-Hodgkin lymphomas. During the last decades a number of studies have addressed the mechanisms underlying the disease development. Extranodal MZL lymphoma usually arises in mucosal sites where lymphocytes are not normally present from a background of either autoimmune processes, such as Hashimoto thyroiditis or Sjögren syndrome or chronic infectious conditions. In the context of a persistent antigenic stimulation, successive genetic abnormalities can progressively hit a B-cell clone among the reactive B-cells of the chronic inflammatory tissue and give rise to a MALT lymphoma. The best evidence of an etiopathogenetic link is available for the association between Helicobacter pylori-positive gastritis and gastric MALT lymphoma. Indeed, a successful eradication of this micro-organism with antibiotics can be followed by gastric MALT lymphoma regression in more than 2/3 of cases. Other microbial agents have been implicated in the pathogenesis of MZL arising in the skin (Borrelia burgdorferi), in the ocular adnexa (Chlamydophila psittaci), and in the small intestine (Campylobacter jejuni). The prevalence of hepatitis C virus (HCV) has also been reported higher in MZL patients (particularly of the splenic type) than in the control population, suggesting a possible causative role of the virus. In non-gastric MALT lymphoma and in splenic MZL the role of the antimicrobial therapy is, however, less clear. This review summarizes the recent advances in Marginal Zone Lymphomas, addressing the critical points in their diagnosis, staging and clinical management.

Campylobacter has been associated with immunoproliferative small intestinal disease (IPSID), on the basis of 16S rDNA sequencing, in situ hybridization, and immunohistochemistry. Here, for the first time, we have cultured Campylobacter from the stools of a patient with IPSID. Phenotypic analysis and whole genome sequencing identified Campylobacter coli. PCR on a IPSID tissue biopsy sample was positive for Campylobacter coli and negative for Campylobacter jejuni. These findings further support a causative role for Campylobacter in the development of IPSID., (© 2014 The Authors Clinical Microbiology and Infection © 2014 European Society of Clinical Microbiology and Infectious Diseases.)

Introduction: Primary small intestinal lymphoma (PSIL) is the second Non-Hodgkin lymphoma (NHL) of the digestive tract (after gastric NHL)., Purpose: To evaluate during the past 28 years the epidemiological, anatomoclinical and therapeutic changes of PSIL in Tunisia through an acquired experience of more than a quarter of a century., Methods: Our retrospective study included patients with histologically confirmed small intestinal lymphoma from 1981 to 2008 in Tunisia at Salah Azaiz Institute. The cohort of 210 patients was divided into two groups: A group from 1981 to 1992 (152 patients) and B group from 1993 to 2008 (58 patients). We analysed the epidemiological, anatomoclinical, histological, and therapeutic characteristics., Results: We observed a significant decrease in the annual incidence of PSIL but also a significant transition of diffuse immunoproliferative small intestinal disease (IPSID) also known as "Mediterranean" PSIL, which were progressively replaced by "Western" lymphomas. Laparotomy with or without a debulking surgery, largely performed in group A, has disappeared at the cost of a primary chemotherapy (p < 0.001). Five-year actuarial global and relapse free survivals were respectively 60.5 and 57.3%., Conclusion: PSIL in Tunisia were subjected to a triple transition: epidemiological, histological and therapeutic.

Immunoproliferative small intestinal disease (IPSID), also known as alpha chain disease, is a rare disease. In the recent WHO classification of hematopoietic and lymphoid tissue, IPSID is considered as a variant of extranodal mucosa-associated lymphoid tissue (MALT) lymphoma. Campylobacter jejuni is a specific pathogen, found to be related to IPSID. Diagnosis is based on histology and immunochemistry (± fluorescent in situ hybridization), with presence of many variable levels of abnormal immunoglobulin in the serum, identified to be truncated alpha-heavy chains. Early-stage disease is treated by antibiotics (tetracyclines). Chemotherapy is recommended up front for patients with advanced disease at presentation or refractory to antibiotics. The chemotherapy schedule used is the CHOP (cyclophosphamide, vincristine, doxorubicin, and prednisone) regimen., (Copyright © 2011 Elsevier Masson SAS. All rights reserved.)

This study describes the frequency, demographics, clinical presentation, endoscopic findings, histopathological features, treatment and outcome of 'Immunoproliferative small intestinal disease' (IPSID). Archives contained a total of 27 cases of IPSID diagnosed and treated over an 18-year period. A M: F ratio of 2.4:1 was seen with a mean and median ages of 28.7 and 25 years. Most patients (68.8%) presented with abdominal pain and diarrhoea. In the majority (62.5%), duodenum was the primary site of involvement. Endoscopy showed polypoidal, raised or flat lesions. Biopsy findings included blunting or flattening of villi with dense plasma cell infiltrate and lymphoepithelial lesions. Twenty-four cases were categorized as stage A and B (benign and intermediate) and three were categorized as stage C (malignant, diffuse large B-cell lymphoma with plasmacytoid features). Stage A and B patients responded well to antibiotic treatment (tetracycline) with regression of the lesions while for stage C patients standard CHOP chemotherapy was administered.

A 20-year-old male presented with low-grade fever, abdominal pain, anorexia, and weight loss of 4-month duration. On examination, he was emaciated. Barium meal follow-through examination showed extensive nodularity and thickening of duodenal and jejunal folds. Contrast-enhanced computed tomography of the abdomen revealed extensive proximal small-bowel thickening with mesenteric lymphadenopathy. Upper gastrointestinal endoscopy and enteroscopy revealed thickening of folds with multiple small superficial ulceration involving antrum, duodenum, and jejunum. The duodenal and jejunal biopsy was suggestive of immunoproliferative small intestinal disease, stage 0 (Salem) or stage A (Galian). Antral biopsy showed presence of Helicobacter pylori infection. He underwent H. pylori eradication following which he had significant clinical improvement; repeat evaluation at 6 months showed dramatic improvement in his clinical, radiological, and histological parameters.

We report a case of the nonsecretory variant of immunoproliferative small intestinal disease involving the distal small bowel and the mesenteric and retroperitoneal lymph nodes in a 19-year-old woman from Mexico. This variant extranodal marginal zone B-cell lymphoma appeared similar in the different sites of involvement, with more interspersed large cells and greater plasmacytic differentiation present in intestinal specimens. Characteristic lymphoepithelial lesions and follicular colonization were seen in intestinal and lymph node sections, respectively. The neoplastic B cells were cytoplasmic immunoglobulin (Ig) A heavy-chain restricted and lacked surface and cytoplasmic light-chain expression by flow cytometric analysis. Serum and urine protein electrophoresis/immunofixation revealed hypogammaglobulinemia with no paraprotein. Molecular studies showed absence of immunoglobulin heavy-chain (IgH) gene rearrangement, with a nonfunctional clonotypic rearrangement of the kappa light-chain gene. This case highlights the role for kappa light-chain gene evaluation in immunoproliferative small intestinal disease, because IgH gene rearrangement analysis is often negative.

Immunoproliferative small intestinal disease (IPSID) was recently added to the growing list of infectious pathogen-associated human lymphomas. Molecular and immunohistochemical studies demonstrated an association with Campylobacter jejuni. IPSID is a variant of the B-cell lymphoma of mucosa-associated lymphoid tissue (MALT), which involves mainly the proximal small intestine resulting in malabsorption, diarrhea, and abdominal pain. Geographically, IPSID is most prevalent in the Middle East and Africa. IPSID lymphomas reveal excessive plasma cell differentiation and produce truncated alpha heavy chain proteins lacking the light chains as well as the first constant domain. The corresponding mRNA lacks the variable heavy chain (V(H)) and the constant heavy chain 1 (C(H)1) sequences and contains deletions as well as insertions of unknown origin. The encoding gene sequence reveals a deletion of V region and parts of C(H)1 domain. Cytogenetic studies demonstrated clonal rearrangements involving predominantly the heavy and light chain genes, including t(9;14) translocation involving the PAX5 gene. Early-stage IPSID responds to antibiotics (30%-70% complete remission). Most untreated IPSID patients progress to lymphoplasmacytic and immunoblastic lymphoma invading the intestinal wall and mesenteric lymph nodes, and may metastasize to a distant organ. IPSID lymphoma shares clinical, morphologic, and molecular features with MALT lymphoma, lymphoplasmacytic lymphoma, and plasma cell neoplasms.

In a young female patient originally coming from Albany, immunoproliferative small intestinal disease (IPSID) could be diagnosed as a cause for severe maladsorption. Considering clinical and histological criteria an early disease stage of IPSID could be diagnosed. Under the continuous treatment of doxycycline for more than 3 1/2 years, all disease manifestations like watery diarrhea, vomiting, pain in the upper abdomen and loss of weight disappeared. After discontinuation of the antibiotic therapy the patient reached a sustained response.

Background: Immunoproliferative small intestinal disease (also known as alpha chain disease) is a form of lymphoma that arises in small intestinal mucosa-associated lymphoid tissue (MALT) and is associated with the expression of a monotypic truncated immunoglobulin alpha heavy chain without an associated light chain. Early-stage disease responds to antibiotics, suggesting a bacterial origin. We attempted to identify a causative agent., Methods: We performed polymerase chain reaction (PCR), DNA sequencing, fluorescence in situ hybridization, and immunohistochemical studies on intestinal-biopsy specimens from a series of patients with immunoproliferative small intestinal disease., Results: Analysis of frozen intestinal tissue obtained from an index patient with immunoproliferative small intestinal disease who had a dramatic response to antibiotics revealed the presence of Campylobacter jejuni. A follow-up retrospective analysis of archival intestinal-biopsy specimens disclosed campylobacter species in four of six additional patients with immunoproliferative small intestinal disease., Conclusions: These results indicate that campylobacter and immunoproliferative small intestinal disease are associated and that C. jejuni should be added to the growing list of human pathogens responsible for immunoproliferative states., (Copyright 2004 Massachusetts Medical Society)

We describe a 30-year-old woman of Turkish descent presenting with abdominal pain and signs of malabsorption. The cause of her complaints turned out to be immunoproliferative small intestinal disease which is a very uncommon disorder in our geographical region. We discuss the differential diagnosis of this disease and the therapeutical options.

There are a number of clinical syndromes associated with chronic diarrhea, malabsorption, and lymphoplasmacytic proliferation of the small intestine. In Middle-Eastern and Mediterranean countries immunoproliferative small intestinal disease is endemic, whereas in other parts of the world (including Northwestern Europe and North America) celiac sprue, and other sprue-like syndromes refractory to dietary gluten withdrawal, predominate. All of these syndromes appear to involve chronic stimulation of intestinal mucosa-associated lymphoid tissue and are associated with a heightened risk of malignant transformation. The clinicopathological features of these diseases, and distinction of the Middle Eastern syndromes from those more common in the Western hemisphere, have been reviewed.

The objective of this study was to further characterize the clinical and immunopathologic features of heavy chain deposition disease (HCDD), a recently described entity. Four patients were diagnosed as having HCDD on a kidney biopsy. All presented with nodular glomerulosclerosis with deposition of gamma1 heavy chains lacking CH1 epitopes, but without light chains. Two different patterns were observed in the serum. First, patients 1 and 2 had a circulating monoclonal IgGlambda containing a short gamma1 heavy chain lacking CH1 epitopes, with an apparent molecular weight of 40 kD consistent with a complete CH1 deletion. Biosynthetic experiments also showed that the deleted heavy chain was produced in excess compared with light chains, and was secreted in vitro together with half Ig molecules, although these abnormal components were not detected by Western blot analysis of whole serum. Second, patients 3 and 4 had a circulating monoclonal IgG1lambda with an apparently normal, nondeleted heavy chain subunit, but serum fractionation followed by immunoblotting revealed an isolated monoclonal gamma1 chain lacking CH1 epitopes. These data strongly suggest that renal deposition of a CH1-deleted heavy chain circulating in low amounts in the serum as a free unassembled subunit is a major feature of HCDD. The CH1 deletion is most likely responsible for the premature secretion in blood of the heavy chain by a clone of plasma cells.

Immunoproliferative small intestinal disease (IPSID) is a subtype of lymphoma of mucosa-associated lymphoid tissue. Notable for a high production of alpha-heavy chains, it is designated alpha-heavy-chain disease. IPSID is a debilitating disease that has a predilection for impoverished populations of developing countries. It has been documented primarily in subjects of Middle Eastern countries and thus was previously referred to as Mediterranean lymphoma. We report the case of a 42-year-old man from Senegal who presented with chronic diarrhea, dehydration, and weight loss. The endoscopic, pathologic, and serologic findings before, during, and after treatment with fludarabine phosphate are presented. We review the literature concerning current concepts on the etiology, pathogenesis, and management of IPSID.

Immunoproliferative small intestinal disease (IPSID), a proliferative disorder affecting the intestinal immune system, has only been reported sporadically in India. Fifteen patients with malabsorption syndrome who were diagnosed to have IPSID were included in this study. Mucosal biopsies from all patients, full thickness surgical biopsies from 10 and autopsy material from four patients were examined by light microscopy and immunohistochemistry. The patients were predominantly young (aged 16-36 years) and male (13 of 15). Diarrhoea, weight loss, vomiting and abdominal pain were the major symptoms. The upper small bowel was involved in all cases. Involvement of large bowel was detected antemortem in three patients, but was found in all autopsied patients. Involvement of the stomach was noted in one patient at autopsy. Mesenteric lymph nodes were involved in all patients who underwent laparotomy. The plasmacytic infiltrate was uniformly positive for alpha-heavy chain, and either negative for light chain production or showed monotypic light chain production. Some of the blasts were also positive for alpha-heavy chain. Three patients died before therapy could be commenced. One patient with stage A disease is alive and clinically free of disease at 7 years. Of the remainder, there have been four long-term survivors with chemotherapy. Immunoproliferative small intestinal disease occurs in southern India and has characteristics similar to that in other parts of the world. Early diagnosis may improve outcome in this disease.

Immunoproliferative small intestinal disease (IPSID) is a rare lympho-proliferative disorder of the upper small intestine. It is considered a special form of MALT lymphoma with propensity to malignant transformation. This disorder is rare in pediatric literature. We report a case of IPSID in a 16-year-old boy with low-grade malignant transformation, presenting as severe malnutrition and a possible association with Helicobacter pylori. The patient responded well to an extended treatment with tetracycline and eradication of H. pylori.

Background: Currently, there is no agreement regarding optimal treatment strategies for immunoproliferative small intestinal disease (IPSID). In this article, the authors report the treatment outcomes of a group of 23 Turkish patients with IPSID., Methods: Between December 1988 and July 1993, 23 consecutive patients with IPSID, including 5 with secretory type, were included in the study. Seven patients with Stage A disease (according to the criteria of Galien et al.) received tetracycline (1 g/day, orally) for a median duration of 7 months (range, 6-11 months) initially, whereas the remaining patients (9 Stage B patients and 7 Stage C patients) received combination chemotherapy (cyclophosphamide, vincristine, procarbazine, and prednisolone [COPP regimen]) followed by tetracycline at a dose of 1 g/day for 6 more months in patients with complete response (CR) after the COPP regimen., Results: The median follow-up was 68 months (range, 38-89 months). As first-line therapy in Stage A patients, tetracycline yielded a 71% CR and 43% disease free survival (DFS) rate. Eleven of 16 patients (69%) with Stage B or C disease who received the COPP regimen achieved CR and only 2 patients had a recurrence (DFS rate of 56%). The 5-year overall survival (OAS) rate for the entire group was 70%, and the 5-year DFS rate for patients with CR was 75%. However, the median OAS for 3 patients with immunoblastic lymphoma was only 7 months., Conclusions: The COPP regimen, with its acceptable toxicity, appears to be a good alternative as a first-line treatment for patients with Stage B or C IPSID with low grade lymphoma whereas tetracycline appears to be the initial treatment of choice for patients with Stage A disease.

We report a case of Mediterranean lymphoma treated with antibiotics. A 74-year-old woman visited the hospital due to abdominal pain. Endoscopic examination showed erosions and ulcerations on duodenal mucosa. Biopsy specimens histologically revealed massive infiltration of small-sized lymphocytes and plasma cells in subepithelial mucosa. Immunoperoxidase staining showed that the infiltrating cells were positively stained with anti-alpha heavy chain. Serum IgA concentration was elevated and immunoelectrophoresis of the serum demonstrated monoclonal protein composed of alpha heavy chain. During the antibiotic treatment her symptoms disappeared and serum IgA concentration was normalized. Endoscopic examination also showed healing of the duodenal ulceration. The similarities between Mediterranean lymphoma and gastric mucosa-associated lymphoid tissue (MALT) type lymphoma, both of which may be related to bacterial infection and can be treated with antibiotics, are discussed in this report.

A 22-year-old Libyan patient suffering from chronic diarrhea presented with an alpha-heavy chain paraprotein and a lympho-plasmacellular lymphoma infiltration of the duodenal mucosa. These findings supported the diagnosis of "immunoproliferative small intestinal disease" (IPSID). In this disease, that occurs almost solely in countries with low socioeconomic status, a diffuse infiltration of small intestinal mucosa by neoplastic lymphoid cells causes chronic malabsorption. About 65% of patients exhibit a paraprotein in serum, urine or jejunal juice that consists of the heavy chain of immunoglobulin A (alpha-heavy chain). In advanced stages, IPSID resembles histologically and clinically high grade lymphoma: some patients develop masses in the gut wall, an abdominal lymphadenopathy and involvement of other organs including bone marrow. The disease is believed to be triggered by a chronic infectious antigenic stimulus. Thus, in early stages in some patients cure may be achieved by antibiotic therapy alone. In advanced disease, chemotherapy including anthracyclins is necessary.

Retrospectively, 41 Iranian patients with Mediterranean abdominal lymphoma (MAL) were studied; 21 patients had received anthracycline-based protocols, and 20 patients had been treated with regimens lacking anthracyclines. The study groups were comparable with respect to several factors, including age, performance status, histology of lymphoma, stage of disease, and the average relative dose intensity of their protocols. Our first group had a complete remission (CR) rate of 62%, mean disease-free interval (DFI) of 16.3 months and a 71% overall survival at 30 months. The second group showed a CR rate of 40%, mean DFI of 11.2 months, and a 35% overall survival at 30 months. The differences were significant in survival (P = .012) and DFI (p < .001). The incidence of serious toxicities and complications was similar.

This study was performed to confirm the existence of immunoproliferative small intestinal disease (IPSID) in Pakistan. Clinicopathological features of 12 patients with histologically confirmed disease were analysed. Patients were mostly young males with median age of 24.6 years. Two thirds belonged to poor socioeconomic class. Main presenting features were chronic diarrhoea and weight loss. Eleven patients had radiologic evidence of malabsorption syndrome. Endoscopic findings of mucosal thickening, edema, and flattened villi were present in the majority. Patients had both secretory and non-secretory types of disease. Six patients presented with stage A disease. Four responded to antibiotics or steroids, although mucosal abnormalities persisted in three. Two stage A patients evolved into stage C disease, one was lost to follow-up, the other is alive with disease. Three patients presented with stage B disease. Two responded completely to chemotherapy, the third refused treatment and expired after 16 months. Three patients had stage C disease at diagnosis. They received aggressive combination chemotherapy and remain in complete remission with a median follow-up of 2.2 years. This is the first series of patients with IPSID reported from Pakistan. Clinicopathological features and therapeutic results are consistent with the experience elsewhere. Increased awareness may result in early diagnosis and better management.

A case of alpha chain disease, involving stomach, small and large intestine, and caecum with poor prognosis is reported. Endoscopic examination revealed gastric erosion, edematous mucosa with enlarged villi of duodenum and jejunum, multiple hyperplastic lymph follicles of terminal ileum and thickening mucosa of caecum. Light microscopy revealed a conspicuous infiltration of plasma cells and lymphocytes in gastric, duodenal, jejunal and caecal lamina propria. Immunohistochemistry demonstrated alpha heavy chain protein devoid of light chain in these plasma cells. The patient developed paralytic ileus and died of septic shock on the 179th hospital day.

We report on a 28 year old Turkish woman, who was admitted to our hospital with the symptoms of malabsorption and protein-loosing enteropathy. Histologically, on duodenal biopsy, a lymphoplasmacellular infiltration of the submucosa with partial to subtotal atrophy of the villi was found. An immunoproliferative small intestinal disease (IPSID) was diagnosed. A short remission whilst on a glutenfree diet and tetracycline therapy, was followed by a laparatomy because of ileus in the small intestine. A high-grade-malignant Non-Hodgkin's Lymphome of B-cell type with intracellular production of alpha-Heavy-Chains (AHCD) was diagnosed histologically. Following chemotherapy with CEOP-IMVP-Dexa (Cyclophosphamide, Epidoxorubicin, Vincristine, Prednisolone, Ifosfamide, VP-16, Dexamethason, Methotrexat) the patient is still in complete remission three years after starting the therapy. We discuss here a case of AHCD in IPSID, the differential diagnosis of protein losing enteropathy and malabsorption, and we also present conservative (diet, medical treatment) and operative therapies.

Immunoproliferative small intestinal disease (IPSID), most common in Mediterranean countries, is characterized by lymphomatous infiltration of the small intestine and is usually associated with the synthesis of anomalous immunoglobulin alpha heavy chains. Flow cytometric analysis of DNA content, S phase fraction, and quantitative analysis of the proliferation-associated nuclear antigen, P105, were performed in 23 patients with IPSID to determine if they could be used as prognostic indicators in this disease. Eighteen patients had low-grade, two had intermediate-grade, and three had high-grade lymphoma. Eight patients had clinical stage IE disease, 12 had stage IIE, and three had stage IIIE disease. Eleven patients survived > 5 yr (good prognosis), four survived between 2-5 yr (intermediate prognosis), and eight survived 2 yr or less (poor prognosis). The S phase fraction of patients with poor prognosis was significantly higher than those with intermediate or good prognosis (P < 0.004). Flow cytometric evaluation of S phase fraction may offer important prognostic information in patients with IPSID and could be useful in the clinical management of patients with this highly variable clinical syndrome. Further studies evaluating the value of DNA flow cytometry in larger groups of patients with IPSID are warranted.

In this retrospective study, 470 patients with non-Hodgkin's lymphoma (NHL) who had been followed in the Hacettepe University Medical Oncology Department between 1973 and 1990, were evaluated to establish their epidemiologic, clinical and therapeutic characteristics. Out of 470 patients, 302 (62.2%) were male and 168 (37.8%) were female. The ages ranged from 16 to 85, with a median of 44 years. Constitutional symptoms were present in 46.4% of the patients. According to the Working Formulation, low, intermediate, and high-grade lymphomas comprised 33.4%, 54.9%, and 12.7%, respectively. The most common extranodal presentation was gastrointestinal. The chemotherapy regimens most commonly used were CVP (cyclophosphamide, vincristine, prednisone), BCNOP (bleomycin, cyclophosphamide, mitoxantrone, vincristine, prednisone), CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) and CHOP-Bleo (cyclophosphamide, doxorubicin, vincristine, prednisone, bleomycin). The response rates and the survival figures attained with these regimens were not statistically significantly different (P > 0.05). In the Cox multivariate model, pathologic grade, leukopenia, responsiveness to chemotherapy, bone marrow involvement and age were the important factors influencing the disease-free survival, while responsiveness to chemotherapy, age, presence of constitutional symptoms, pathologic grade, extranodal presentation and stage were the important factors influencing the overall survival. The distribution of NHL according to grade and stage was similar to that in western societies, while constitutional symptoms and lymphomas of the small intestine including immunoproliferative small intestinal disease were more common in Turkey.

Primary gastrointestinal lymphoma comprises a group of distinctive clinicopathological entities, most of which are not included in current lymph node-based lymphoma classifications. They may be of B- or T-cell type, with primary gastrointestinal Hodgkin's disease being extremely uncommon. Most low grade B-cell gastrointestinal lymphomas are of mucosa-associated lymphoid tissue (MALT) type, so called because they recapitulate the features of MALT rather than those of lymph nodes. Paradoxically, however, most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. These gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacter pylori and their growth can be influenced by eradication of this organism from the stomach. Low grade MALT lymphomas, which usually have a very favorable clinical course, may undergo high grade transformation; high grade tumours also may arise de novo and these probably also belong to the MALT group. Immunoproliferative small intestinal disease (IPSID) is a special form of MALT lymphoma with a restricted geographic distribution, which is characterized by synthesis of alpha heavy-chain immunoglobulin. Other gastrointestinal B-cell lymphomas include mantle cell lymphoma, which presents as lymphomatous polyposis, and Burkitt's or Burkitt-like lymphoma. Enteropathy (celiac disease)-associated T-cell lymphoma (EATL) is the most common primary gastrointestinal T-cell lymphoma. This is a clinically aggressive tumor that arises from the intraepithelial T-cell population, which is increased in celiac disease.

Background: The observed seasonal and geographic variations in the incidence of immunoproliferative small intestinal disease (IPSID) suggest that environmental factors contribute to its pathogenesis. One such environmental factor, the Epstein-Barr virus (EBV), has been associated with other B-cell lymphoproliferative disorders., Methods: IPSID tissues obtained at the time of initial diagnosis were retrieved from the American University of Beirut pathology archives (1972-1983) and examined for EBV genetic information by colorimetric in situ hybridization (ISH) and polymerase chain reaction (PCR). Eight patients were identified, four of whom also had serologic and immunohistochemical evidence of alpha-heavy chain disease. Thirteen tissue samples from these eight patients were available for study: eight were intestinal and five were nodal. Non-Hodgkin's B-cell lymphoma cases (nine) were randomly selected from the same archive to serve as a control for EBV in that geographic location. The ISH method used a probe to the "W" repetitive region of EBV, with the human placental DNA probe as a control for sample preparation. The PCR method amplified a 110 base pair region in the long internal direct repeat with amplification of beta-actin as control for DNA preservation. Both assays used formalin fixed paraffin embedded Raji cells as a positive control., Results: Neither ISH nor PCR demonstrated EBV in any of the eight patients with IPSID: The results for one of seven control blocks with adequate DNA preservation were positive when PCR was used but were negative when ISH was used., Conclusions: These findings do not support a role for EBV in the induction of B-cell proliferation in IPSID:

Worsening of long-lasting diarrhea, abdominal discomfort and weight loss were main symptoms in a 27-year-old Moroccan woman who had lived in Germany for 18 years. Pseudomonas, salmonella and lamblia cysts were found in stools. Histological examination of the gastrointestinal tract showed immunoproliferative small intestinal disease (IPSID), characterized by atrophy of the villi and lymphoplasmocytic infiltrates. alpha 1-heavy chains were found immunohistologically in the biopsy specimen, but not in serum, urine or jejunal juice. HLA-typing gave evidence of A9. Antibiotic treatment was successful for almost one year. Clinical, histological and immunological diagnosis of IPSID in an African woman living for nearly 20 years in Europe shows that, besides environmental factors, genetic disposition is an essential factor in the development of IPSID.

Purpose: The clinicopathologic findings in 45 adult Chinese patients with primary small-intestinal lymphoma (PSIL) are described and compared with those in Western countries and in underdeveloped nations. The efficacy of combination chemotherapy is also assessed., Patients and Method: Six patients had immunoproliferative small-intestinal disease (IPSID) indicated by the presence of alpha-heavy chain protein (alpha-CP) in body fluids or tumor tissues. Thirty-nine patients had non-IPSID, including one with postrenal transplant lymphoma. Thirty-three non-IPSID patients received a minimum of four cycles of combination chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)., Results: All IPSID patients presented with the clinical and laboratory features of severe intestinal malabsorption, and all had diffuse lymphoplasmacytic infiltration in the mucosa of the small bowel. Lymphomas were localized mainly in the jejunum and mesenteric nodes. The histologic subtypes were diffuse large cell in two, immunoblastic in three, and diffuse mixed in one. All patients responded poorly to chemotherapy, with a median survival duration of 10.5 months. The common presenting symptoms of the 39 non-IPSID patients included abdominal pain (90%), weight loss (31%), abdominal mass (26%), obstruction (26%), and perforation (23%). Diffuse large-cell and immunoblastic lymphomas constituted 82% of cases. Four patients had stage IE, 19 stage II 1E, and 16 stage 112E disease according to the Musshoff's criteria; 22 had bulky tumors and 19 had multiple tumors. The tumors were completely resected in 14 patients. Of 33 patients treated with combination chemotherapy, 73% achieved a complete remission. With a median follow-up duration of 90 months, there have been four relapses, with only one at the primary tumor site. The overall 5-year survival and disease-free survival rates for non-IPSID patients who were treated with chemotherapy were 59% and 54%, respectively., Conclusion: Intensive chemotherapy produces long-term disease-free survival in locally advanced non-IPSID PSIL.

For 6 months diarrhea and weight loss of 30 kg occurred in a 28 year old man from the Emirates. The endoscopic examination suggested a small intestinal lymphoma affecting the entire small intestine, which was confirmed by biopsies, immunohistochemistry, immunologic proof of monoclonal IgA-gammopathy in serum and urine. The patient acquired a malignant MALT-lymphoma of B-cell-type, a alpha-Heavy Chain Disease, synonym mediterranean lymphoma or immunoproliferative small intestinal disease (IPSID), stage A with transition in stage B. The patient was treated with ciprofloxacine in association with metronidazole with no influence of the course of the disease.

The clinicopathologic findings in eight Mexican patients with immunoproliferative small intestinal disease (IPSID) are analyzed. Four of these cases have been previously reported and the remainder were found in a retrospective review of 42 lymphoproliferative disorders of the small bowel (9.5% of the cases at our institution). There were six male and two female patients with an average age of 30 years. Laparotomy with intestinal resection was performed in seven cases. Malignant lymphoma was documented in five and the early phase of IPSID in two patients. The remaining case was diagnosed by means of several endoscopic biopsies. It is concluded that although IPSID seems to be a rare disease in the mestizo population of our country, it may not be exceptional and its diagnosis has probably been overlooked.

Gastrointestinal lymphoma, uncommon in the West, is far more prevalent in developing countries where it falls into two groups: 'Western'-type lymphomas, similar to those seen in developed countries, and the so-called Mediterranean-type lymphoma. It is now accepted that Mediterranean lymphoma represents, in the majority if not in all cases, the late stage of alpha heavy chain disease (alpha-HCD). This disease is characterized by abnormal secretion of an immunoglobulin fragment; alpha-HCD and Mediterranean lymphoma constitute two ends of a spectrum of pathology now classified as immunoproliferative small intestinal disease (IPSID). IPSID is associated predominantly with poor socioeconomic conditions; patients present with progressive malabsorption in the second and third decades of life. Diagnosis is established by small bowel biopsy, with or without high serum levels of the alpha heavy chain protein. Treatment consists of an initial staging laparotomy, with debulking of lymphomatous deposits if appropriate, followed by chemotherapy or radiotherapy. Overall prognosis is poor but the recent use of doxorubicin-based chemotherapy offers some hope for the future.

The clinico-pathological characteristics of a 22 years old mestizo mexican patient with immunoproliferative small intestinal disease (IPSID) are described. The patient coursed with chronic diarrhea, malabsorption, and a 30 kg weight loss. The laboratory tests revealed hypokalemia, hypocalcemia, hypoalbuminemia and decreased levels of immunoglobulins. The histological changes in the endoscopic biopsies included a dense lymphoplasmacytic infiltrate in the lamina propria that produced vellosity blunting and distortion of the crypts. The immunohistochemical analysis disclosed that almost every cell was positive to heavy chains and negative to light chains. The radiological studies showed thickening of the intestinal folds and mesenteric adenomegalies. In the full thickness biopsy of the yeyunum, in addition to the lymphoplasmacytic infiltrate, a high grade malignant lymphoma infiltrating the regional lymph nodes was documented. An ultrastructural study revealed viruses that resembled the morphology described for the Epstein-Barr virus. The main clinico-pathological findings of other eight mexican patients with IPSID previously reported are commented. It is concluded that the IPSID is a rare disease in our country but it can be found sporadically.

We report one case of immunoproliferative small intestinal disease with two rare characteristics. Firstly, the detection of monoclonal IgA-Kappa in serum and in the intestinal infiltrate and secondly, the advanced age of the patient at diagnosis. We checked up on Spanish literature and found an important number of patients that were diagnosed at such an age. We suggest that this disease may appear in elderly people in developed countries.

Immunoproliferative small intestinal disease (IPSID) is prevalent in the Mediterranean region and in many Third World countries but is rare in Southeast Asia. Between 1980-1990, 4 cases of IPSID were admitted to Ramathibodi Hospital, Bangkok. Three were males and the mean age was 32 +/- 20.2 years. All patients presented with chronic diarrhea of 7 months to 6 years duration, and weight loss of 15 to 31 kg. All were malnourished, three cachectic, and one patient showed growth retardation. Intestinal parasites were found in all cases: two had multiple infections and three had uncommon protozoal infections (coccidium, cryptosporidium). Barium radiographs revealed intestinal mucosal fold thickening with malabsorption pattern in all cases. Alpha chain IgA was detected in one patient. The remainder underwent exploratory laparotomy and the histological finding was of plasma lymphocytic infiltration of the small intestinal mucosa. All patients responded to oral tetracycline with complete remission occurring in one case. During the follow-up period, 3 cases had progressive retractable clinical courses but all died 2 to 5 years after the diagnosis. The causes of death in these patients were secondary bacterial infection (1 case), intestinal tuberculosis (1 case), fungal infection (1 case) and immunoblastic sarcoma in another case. The results of this study confirm the occurrence of IPSID in Thailand. IPSID responds to oral antibiotic therapy and complete remission may be achieved during the early reversible benign phase, thus an awareness of its occurrence is of clinical importance.

Unlabelled: Thirty-three patients with primary gastrointestinal lymphoma (GIL) followed at Ankara University Medical School have been evaluated. The most frequent locations of the disease are the small intestine (48.4%) and the stomach (39.3%). The intermediate and high grade lymphomas constitute 84.8% of the cases. The mean age of the patients with small intestinal lymphoma is 28.7 years and 47.1 years for those with gastric lymphoma. The patients treated with surgery and chemotherapy (S+CT) have a longer survival than those treated with chemotherapy (CT) alone., In Conclusion: 1) Small intestinal lymphoma occurs more frequently than gastric lymphoma in our study. 2) The median age of the Turkish patients with primary GIL is approximately 10 years less than those in the Western countries. 3) The therapeutic results of S+CT are superior to those of CT in the early stages of the disease.

For 2 years a 39-year-old Turkish man had had abdominal pain as well as weight loss of more than 10 kg over 4 months, associated with a raised ESR (33 mm/h) and recurrent gastrointestinal bleedings which endoscopy revealed to have been caused by a marked erosive duodenitis. Biopsies from the duodenum and terminal ileum demonstrated lymphoplasmocytic infiltration of the entire small intestine in the sense of immunoproliferative small intestinal disease (IPSID). By immunohistochemistry the lymphoplasmacellular infiltrate showed polyclonal expression of IgA without IgA increase in serum, urine and duodenal juice. The patient was treated with tetracycline (500 mg twice daily) for one year. The symptoms and histological lesions were much improved after 4 months. One year after diagnosis he was symptom-free.