Nonsecretory Variant of Immunoproliferative Small Intestinal Disease: A Case Report With Pathologic, Immunophenotypic, and Molecular Findings

Malignant lymphomas of the small intestine are relatively uncommon in the Western Hemisphere. The majority of lymphomas involving the small intestine are of diffuse large B-cell type, followed by extranodal marginal zone B-cell lymphoma and Burkitt lymphoma.1 In contrast, small intestine lymphomas are frequent in other areas of the world, particularly the Middle East, Africa, and the Far East, and they commonly represent immunoproliferative small intestinal disease (IPSID).2 Immunoproliferative small intestinal disease is a variant of mucosa-associated lymphoid tissue (MALT) lymphoma with a distinct clinical presentation and unique laboratory and pathologic features. Patients with IPSID commonly have increased levels of a truncated immunoglobulin α heavy chain lacking an associated light chain, and thus the term α heavy chain disease (αHCD) is often used interchangeably with IPSID. In this regard, the World Health Organization classification of hematopoietic and lymphoid tissue categorizes IPSID as a heavy-chain disease and uses the alternative nomenclature of αHCD.3 However, the World Health Organization classification fails to recognize the nonsecretory form of IPSID, which lacks the α heavy-chain protein in serum.4–6 We report on a 19-year-old woman who presented with malabsorption and was found to have the nonsecretory variant of IPSID with unique molecular findings.

A 19-year-old Hispanic woman from Mexico presented with a 12-month history of abdominal pain, diarrhea, nausea, vomiting, fever, and night sweats. A computed tomographic scan of the abdomen demonstrated mesenteric and retroperitoneal lymphadenopathy with diffuse thickening of the small bowel wall. An upper gastrointestinal endoscopy identified no mucosal lesions; random biopsies of the distal small bowel were taken for histologic evaluation. An initial fine-needle aspiration and needle core biopsies of an enlarged retroperitoneal lymph node were followed by a mesenteric lymph node excision. Morphology, flow cytometry, and molecular analyses were performed on the lymph node specimens, as detailed in the following. Mycobacterial, fungal, viral, and bacterial cultures of the lymph node were negative. A bone marrow evaluation was unremarkable, with no morphologic or immunophenotypic evidence of lymphoma. Serum protein electrophoresis demonstrated a low total protein level of 4.6 g/dL and hypogammaglobulinemia (0.41 g/dL). Both serum immunoglobulin (Ig) G (392 mg/dL; normal range, 768–1632 mg/ dL) and IgM (39 mg/dL; normal range, 60–263 mg/dL) were decreased, whereas the serum IgA was normal (95 mg/dL; normal range, 68–378 mg/dL). Serum and urine protein electrophoresis/immunofixation studies revealed no M component.

Following the diagnostic workup, the patient was given a 3-week oral regimen of amoxicillin, metronidazole, and pantoprazole. Her clinical symptoms improved substantially, with weight gain and a marked reduction in her diarrhea. A computed tomographic scan revealed a reduction in the size of her mesenteric lymphadenopathy and shrinkage of the small bowel wall. However, 1 month following completion of the oral antibiotic regimen, the patient experienced increasing abdominal pain and diarrhea. The patient was again placed on the same oral antibiotic regimen and is currently being treated for a total of 4 months. No anthracycline-based chemotherapy has been given to date because of financial considerations.

Biopsies of the distal small bowel show partial blunting of the intestinal villi, with a dense lymphoid infiltrate within the lamina propria (Figure 1). The lymphoid infiltrate consists of a mixed population of predominantly intermediate-sized centrocyte-like cells with moderately abundant cytoplasm, plasmacytoid lymphocytes, scattered immunoblasts, and occasional plasma cells. Numerous lymphoepithelial lesions characterized by aggregates of small lymphocytes are identified within glandular epithelium (Figure 2).

Retroperitoneal and mesenteric lymph node biopsies reveal effacement of the normal architecture by a lymphoid infiltrate that surrounds reactive follicles in a marginal zone pattern of distribution with disruption and invasion of many of the follicular structures (Figure 3). Similar cells forming confluent sheets expand the interfollicular areas. Most cells in the infiltrate have slightly irregular to rounded nuclear contours, condensed chromatin with inconspicuous nucleoli, and abundant cytoplasm (Figure 4). Only a few larger lymphoid cells are intermixed.

Immunohistochemical stains show that the lymphoma cells are strongly positive for CD20 and Bcl-2 and are negative for CD5, CD43, and CD10. Colonization of scattered follicles is highlighted by CD35. The sparse CD138-positive plasma cells have polytypic light-chain expression by in situ hybridization. Flow cytometric analysis on fresh tissue identifies a cytoplasmic IgA-restricted B-cell population with the following immunophenotype: CD19⁺, CD20⁺, FMC-7⁺, CD23⁻, CD5⁻, CD10⁻, and surface and cytoplasmic light-chain negative (Figure 5, A). The small plasma cell population shows no light-chain restriction.

Immunoglobulin heavy-chain and immunoglobulin κ (Igκ) light-chain polymerase chain reaction (PCR) were performed on both fresh and paraffin-embedded tissue, as previously described.7 No monoclonal IgH gene rearrangement was identified using a consensus framework region 3 (FR3) and joining region (J_H) primer set (Figure 5, B). Subsequent amplification of tumor DNA with a set of consensus V-region and J-region κ gene primers was negative; however, a monoclonal rearrangement of the Igκ gene was identified using a primer set directed to locus-specific κ-deleting element rearrangements7 (Figure 5, B).

We report on a 19-year-old woman with the distinct clinical presentation and unique laboratory and pathologic features characteristic of IPSID, a rare variant of MALT lymphoma. Immunoproliferative small intestinal disease is primarily a disease of older children and young adults, with a mean age at presentation of 25 to 30 years.2 Most cases occur in the Middle East, Africa, and the Far East.2 However, sporadic cases have been reported in the Western Hemisphere, particularly in Mexico and Central America.8,9 Patients typically present with intermittent diarrhea, malabsorption, abdominal pain, and weight loss of months' to years' duration; patients typically are of low socioeconomic status and live in areas of poor sanitation and hygiene.2 A subset of cases has a distinctive radiologic feature, termed the postage stamp sign, characterized by thickening of the mucosal folds of the small intestine with spiculated folded edges.2,10 

Biopsies from our patient have the characteristic pathologic features of IPSID, including the dense lymphoplasmacytic proliferation within the small bowel lamina propria that extends into the submucosa, forming lymphoepithelial lesions.11 The overlying small bowel mucosa frequently has broadened and partially effaced intestinal villi with shortening of the crypts. Mesenteric lymph nodes are often enlarged and have an infiltrate histologically identical to that seen in the small intestine, as illustrated in this patient. The nonsecretory variant of IPSID is characterized by a proliferation of marginal zone (centrocyte-like) cells that often have less prominent plasma cell differentiation than the secretory form does.2 

In approximately 20% to 90% of IPSID cases, the serum contains free α heavy chains without associated light chains, and thus the term α heavy chain disease (αHCD) is used interchangeably with IPSID in describing this disorder. The αHCD protein is almost always the α1 species of IgA and consists of multiple polymers of different sizes, with a molecular weight between 29 000 and 35 000 d.2 The αHCD protein lacks the variable heavy chain (V_H) and the first constant heavy-chain domain (C_H1) because of internal deletions of V gene segment and parts of the C_H1 gene segment. In addition, the αHCD protein has an insertion of variable length near the C_H2 and C_H3 coding sequences and has various deletions and mutations of unknown origin.2 Because of the diversity of the IgA molecular forms, results of serum protein electrophoresis are often normal or show only hypogammaglobulinemia with no dominant M component identified. If αHCD is suspected clinically, serum immunofixation electrophoresis must be performed to detect the presence of the increased fraction of abnormal IgA. By definition, no light chains are detected in the serum by immunofixation electrophoresis.

Conventional IgH PCR analysis using consensus V_H-FR1, V_H-FR2, or V_H-FR3 primers for detection of clonality may often give false-negative results due to lack of primer binding sites resulting from the deletion of the variable heavy-chain gene segment (V_H) in the neoplastic cells of IPSID. In addition, mutations that have been shown to occur in both the heavy- and light-chain genes in IPSID may cause increased false-negative results with PCR analysis because of the lack of PCR primer-template homology. Despite these technical considerations, rearrangement of the IgH and κ light-chain genes has been demonstrated by Southern blot analysis.12 In the case described herein, the IgH gene rearrangement PCR analysis was negative as expected, presumably because of lack of target in the tumor DNA for the V_H consensus primers. However, the κ light chain gene was shown to be monoclonally rearranged, as evidenced by a positive V locus–specific κ-deleting element PCR result using a slightly modified version of the method recently described by Pai et al7 (Figure 5, B). This light-chain rearrangement was nonproductive, because no surface or cytoplasmic light-chain expression was detected by flow cytometric analysis (Figure 5, A).

The pathogenesis of IPSID has been the subject of recent debate in the literature.13,14 Lecuit et al13 have postulated that Campylobacter jejuni may play the same role in the development of IPSID as Helicobacter pylori plays in the development of gastric MALT lymphoma. Chronic small intestinal infection with C jejuni results in T-cell cytokine stimulation of B cells, leading to the emergence of a neoplastic B-cell clone. The link of chronic C jejuni infection to IPSID in our case is an attractive possibility, given the apparent initial response of the patient's disease to antibiotic therapy. Unfortunately, PCR analysis to investigate for the presence of C jejuni was not performed. Establishing universal primers directed at C jejuni rRNA will aid in future investigations of this relationship.

The treatment of IPSID is largely determined by the extent of disease. However, most studies have been retrospective, with no large prospective trials currently in the literature, primarily because of the rarity of the disease. Early-stage disease (with limited involvement of intestinal mucosa and mesenteric lymph nodes) has been shown to respond to antibiotic therapy (tetracycline or metronidazole and ampicillin/tetracycline).2 In our case, the patient exhibited initial clinical improvement with amoxicillin and metronidazole and the addition of the proton pump inhibitor pantoprazole. With this antibiotic regimen, the remission rate ranges from 30% to 70%.2 Early-stage patients who fail to improve with antibiotic therapy or patients with intermediate- to advanced-stage disease are often treated with anthracycline-based combination chemotherapy.

In conclusion, we present what is to our knowledge a unique case of the nonsecretory variant of IPSID that demonstrates the importance of incorporating clinical, morphologic, immunophenotypic, serologic, and molecular clonality findings to reach an appropriate diagnosis. Identifying this entity will become increasingly important as the etiology and associated treatment options are clarified.