Heavy Chain Disease of the Small Bowel.

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.

The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance.

Extranodal marginal zone (MZ) B-cell lymphomas of the mucosa-associated lymphoid tissue (MALT) arise from lymphoid populations that are induced by chronic inflammation in extranodal sites. The best evidence of an etiopathogenetic link is provided by the association between Helicobacter pylori-positive gastritis and gastric MALT lymphoma. Indeed, successful eradication of this microorganism with antibiotics can be followed by gastric MALT lymphoma regression in most cases. Other microbial agents have been implicated in the pathogenesis of MZ lymphoma arising at different sites. Apart from gastric MALT lymphoma, antibiotic therapies have been adequately tested only in ocular adnexal MALT lymphomas where upfront doxycycline may be a reasonable and effective initial treatment of patients with Chlamydophila psittaci-positive lymphoma before considering more aggressive strategies. In all other instances, antibiotic treatment of nongastric lymphomas remains investigational. Indeed, there is no clear consensus for the treatment of patients with gastric MALT lymphoma requiring further treatment beyond H pylori eradication or with extensive disease. Both radiotherapy and systemic treatments with chemotherapy and anti-CD20 antibodies are efficacious and thus the experience of individual centers and each patient's preferences in terms of adverse effects are important parameters in the decision process.

Immunoproliferative small intestinal disease: current concepts.

Immunoproliferative small intestinal disease is a distinctive lymphoproliferative disorder. Among these disorders, it is the only disease associated with a specific and characteristic abnormal protein, and also an identifiable, at least in some patients, early phase with a benign-looking histo-pathologic expression. Whether the disease at this stage is malignant or not is not known. Treatment of this early phase with antibiotics may cause remission in some patients. This observation is significant and raises the question of chemoprevention in lymphomas. In contrast to primary nonimmunoproliferative small intestinal lymphomas, in which the pathology in the intestine is usually focal and involving specific segments of the intestine and leaving the segments between the involved areas free of disease, the pathology in immunoproliferative small intestinal disease is diffuse, with a mucosal cellular infiltrate involving large segments of the intestine and sometimes the entire length of the intestine, thus producing malabsorption. Preliminary recent epidemiological data have shown a decrease in the incidence of this disease in endemic areas, and therefore environmental factors are suspected to play a major role in its pathogenesis. Additional research is indicated not only to understand this specific lymphoproliferative disorder but also to understand lymphomas in general.

Immunoproliferative small intestinal disease (IPSID): a model for mature B-cell neoplasms.

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.

Effects of dietary protein source on Basenjis with immunoproliferative enteropathy.

The effects of 3 experimental diets that varied only in the source of dietary protein (ie, poultry, cereal, red meat) were compared in Basenjis (n = 8) with immunoproliferative enteropathy and healthy Beagles (n = 8). Significant differences in fecal character, serum IgA concentration, and intestinal digestive and absorptive function were not induced by the different sources of dietary protein. The results of this study do not support a causal role for dietary protein source in the pathogenesis of immunoproliferative enteropathy of Basenjis.

Immunoproliferative small intestinal disease: a study of 13 cases with alpha heavy-chain disease.

The pathology of 13 cases of immunoproliferative small intestinal disease (IPSID) associated with alpha-heavy-chain disease--one an apparent non-secretor and another with localized infiltration--is described. Four cases exhibited immunohistological light-chain monotypia. In one of these, evolution of a light-chain negative cell population was observed over a 7-year period. In the intestine, centrocyte-like cells produced lympho-epithelial lesions in 11 cases and enlarged lymphoid follicles in three. In lymph nodes, perifollicular infiltration was observed in 11 cases and abnormal follicles in six. Of three patients with high-grade lymphoma at presentation, one died untreated at 2 months, and two are alive at 34 and 91 months. Of 10 patients with low-grade disease at presentation, two died--one at 76 months, the other after transforming to high-grade lymphoma at 73 months. Eight patients with low-grade disease are alive, an average of 67 months after presentation. Four of five conservatively treated low-grade cases (including three in remission) showed evidence of monoclonality at presentation (light-chain monotypia in two and gene rearrangement in two), while two of the five exhibited DNA aneuploidy. It is concluded that IPSID with alpha-heavy-chain disease is neoplastic in all its stages and is a variant of mucosa-associated lymphoma. The role of centrocyte-like cells and the response to conservative therapy are discussed.

A new form of alpha-chain disease with generalized lymph node involvement.

An autopsy case of alpha-chain disease (ACD) clinically manifesting generalized lymph node swelling, slight splenomegaly and long-standing ichthyosiform skin eruptions, was reported. Autopsy revealed systemic superficial and profound lymph node swelling and slight splenomegaly, but little or no tumorous lesion in any part of the alimentary tract or pulmonary tissue. The histologic picture of the lymph nodes showed a diffuse monomorphic plasmocytic lymphoma, and there was tumor cell infiltration in the spleen and bone marrow. Immunohistochemistry demonstrated that the tumor cells contained IgA devoid of light chains, i.e. ACD protein. Immunoelectron microscopy revealed that this abnormal immunoglobulin was localized in the rough endoplasmic reticulum and perinuclear space. Persistent chronic inflammation with infiltration mainly of helper-inducer T cells were found in the skin and dermatopathic lymphadenopathy was confirmed in the lymph node biopsies. From these peculiar clinicopathological features, this case is considered to be a previously unknown form of ACD.