Follicular lymphoma

We report the case of a 73-year-old man who presented with a 2- to 3-month history of epigastric discomfort and guaiac-positive stool. An upper gastrointestinal endoscopy revealed a diffuse erythematous nodular mucosa and submucosal thickening in the stomach. Diffuse mucosal nodularity was also found in the second portion of the duodenum. A complete workup with histologie, immunohistochemical, and molecular studies revealed 2 distinct, apparently unrelated lymphomas, namely, a gastric marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue type) in a background of Helicobacter pylori gastritis and a grade 1/3 duodenal follicular lymphoma. The patient was then treated with an H pylori eradication regimen. No therapy was given for his duodenal follicular lymphoma because his symptoms were thought to be due to the gastric disease and because the duodenal lesion was small. A 6-month follow-up with upper gastrointestinal endoscopy revealed only focal biopsy scarring in the stomach and an apparently normal duodenum. The follow-up biopsies revealed significant regression of his mucosa-associated lymphoid tissue lymphoma, but persistence of his duodenal follicular lymphoma. The combination of these 2 lymphomas in the same patient and the different clinical responses to antibiotic treatment make this case unique.

(Arch Pathol Lab Med. 2004;128:1035-1038)

Marginal zone B-cell lymphoma (mucosa-associated lymphoid tissue [MALT] type) is the most common low-grade lymphoma of the stomach. The association between Helicobacter pylori and MALT lymphoma is well documented. Mucosa-associated lymphoid tissue lymphoma can regress on eradication of H pylori by antibiotics.1-3 Primary follicular lymphoma of the duodenum is a rare disease that has been recently recognized as a potentially distinct clinicopathologic entity. A few studies of duodenal follicular lymphoma have shown that it has features similar to those of conventional nodal follicular lymphoma with an indolent clinical course, and histologic and immunohistologic features indistinguishable from nodal follicular lymphoma.4-7

We present a case of coexisting gastric MALT lymphoma associated with H pylori gastritis and duodenal follicular lymphoma. On eradication of H pylori with antibiotics, the gastric MALT lymphoma regressed considerably, whereas the duodenal follicular lymphoma persisted. To our knowledge, no similar case has been reported in the literature.

REPORT OF A CASE

A 73-year-old man with a past medical history notable only for atrial fibrillation presented with a 2- to 3-month history of epigastric discomfort and guaiac-positive stool. He did not report nausea, vomiting, change in bowel habits, or weight loss. An upper gastrointestinal endoscopy at the time of presentation revealed gastritis and a normal esophagus and duodenum. He was started on omeprazole and esomeprazole magnesium treatment and reported resolution of his abdominal discomfort. A 1-month follow-up endoscopy showed a diffusely erythematous nodular and granular mucosa with submucosal thickening in the fundus and body of the stomach. Diffuse mucosal nodularity was also found in the second portion of the duodenum. Biopsies of these sites were taken, and the patient was diagnosed with H pylori gastritis, gastric marginal zone B-cell lymphoma, and grade 1/3 duodenal follicular lymphoma. A complete staging evaluation showed no lymphadenopathy or other organ involvement. The patient was then treated with a standard H pylori eradication regimen, which included Helidac (bismuth subsalicylate, metronidazole, and tetracycline hydrochloride) and Nexium (esomeprazole magnesium). No therapy was given for his duodenal follicular lymphoma since it was not thought to be responsible for his symptoms. A 6-month follow-up endoscopy showed no significant pathology in the stomach and an apparently normal duodenum.

MATERIALS AND METHODS

All biopsies were fixed in formalin and embedded in paraffin. Slides were stained with hematoxylin-eosin. The diagnosis and classification were made according to World Health Organization Classification of hematopoietic and lymphoid tumors. Special stains, including Giemsa and thiazine stains, were performed on selected slides.

Immunoperoxidase staining was performed on paraffin-embedded tissue by the avidin-biotin complex technique (Vector Laboratories, Inc, Burlingame, Calif). Monoclonal antibodies L26 (CD20, Dako Corporation, Santa Barbara, Calif); Bcl-2 (Dako); CD3, CD5, CD10, and CD21 (Novocastra Laboratories Ltd, Newcastle upon Tyne, United Kingdom); and rabbit polyclonal antibodies to immunoglobulin heavy and light chains (Dako) were used.

Molecular analysis was performed in the Brigham and Women's Hospital Diagnostic Molecular Laboratory, following standard procedures.8 DNA was isolated from paraffin-embedded tissue from both the gastric and the duodenal biopsies using a commercial kit (Centra, Minneapolis, Minn), according to the manufacturer's instructions. B-cell monoclonality was assessed by polyacrylamide gel electrophoresis of polymerase chain reaction (PCR) products obtained with consensus primers to the variable (V) and joining (J) regions of the immunoglobulin heavy-chain (IgH) gene. Presence of t(14,18) was assessed by agarose gel electrophoresis of PCR products obtained with a consensus primer to the IgH gene and primers to the major and minor breakpoint cluster region of the bcl-2 gene.

PATHOLOGIC FINDINGS

The initial stomach biopsy showed a dense, diffuse lymphoid infiltrate in the lamina propria with a focal, vaguely nodular pattern (Figure 1, A). Occasional lymphoepithelial lesions were present (Figure 1, B). The lymphocytes were small to medium-sized and had the appearance of marginal zone B cells with slightly irregular nuclei and moderate amounts of pale cytoplasm. Rare organisms consistent with H pylori were demonstrated on a thiazine stain.

Immunohistochemical studies showed that the infiltrating lymphocytes were B cells that stained positive with antibodies to CD20 and Bcl-2, but negative with antibodies to CD3 and CD10. With antibodies to immunoglobulin light chains ([kappa] and [lambda]), there was a suggestion of excess [kappa] staining within plasma cells. A stain for CD21 delineated a few reactive follicles that were CD10 positive and Bcl-2 negative. The CD10-negative, Bcl-2-positive neoplastic lymphoid cells were present diffusely outside the follicle centers. The immunoperoxidase staining pattern, together with the morphologic features on routine sections, supported the diagnosis of extranodal marginal zone B-cell lymphoma (MALT type).

The initial biopsy from the second portion of the duodenum also showed a dense lymphoid infiltrate. In contrast to the stomach, a prominent follicular pattern was observed (Figure 2, A). The infiltrate was composed of a mixed population of small cleaved cells (centrocytes) and rare large cells. Immunohistochemical studies showed that the lymphocytes in the duodenum were B cells that stained positive with antibodies to CD20, CD10, and Bcl2 in a follicular pattern (Figure 2, B). The B cells were negative for CDS. A slight excess of [kappa] light chain staining was also noted in a follicular pattern. CD3 stained scattered interfollicular T cells. These findings are characteristic and diagnostic of a follicular lymphoma.

Molecular studies of IgH rearrangement were also performed. Analysis of IgH PCR products showed intense, discrete, single bands from the paraffin-embedded gastric and duodenal specimens; however, the band obtained from the gastric biopsy differed in size from the band obtained from the duodenal biopsy (Figure 3, A). Polymerase chain reaction analysis of the IgH/bcl-2 fusion gene showed a single, intense, and discrete band from the duodenal tissue, but not from the gastric tissue (Figure 3, B).

Following several courses of the H pylori eradication regimen, the posttreatment gastric biopsy showed an edematous lamina propria with a few scattered lymphocytes and a small lymphoid aggregate. Focal intestinal metaplasia was present. No H pylori organisms were identified. No significant changes in the follicular lymphoma were noted on the posttreatment duodenal biopsy when compared with the pretreatment biopsy, either by morphologic or immunohistochemical studies.

COMMENT

The gastrointestinal tract is the most common extranodal primary site for non-Hodgkin lymphoma, accounting for 40% of all primary extranodal lymphomas and 50% of all MALT lymphomas. The stomach is the most commonly involved site; 85% of gastrointestinal MALT lymphomas arise in the stomach.9,10 Mucosa-associated lymphoid tissue lymphomas arising in some sites are known to be associated with preexisting chronic inflammatory processes. The earliest report by Wotherspoon and colleagues11 documented H pylori infection in 92% of gastric MALT lymphoma cases. Risk factors for MALT lymphomas in other sites include Sjögren syndrome and Hashimoto thyroiditis.

Gastric MALT lymphoma usually affects elderly patients and has an equal distribution in men and women. Presenting symptoms often mimic those of gastritis or peptic ulcer disease and include epigastric discomfort or pain, nausea and vomiting, and less frequently, bleeding and weight loss.12 The lymphoma is indolent, with the disease confined to the stomach in most cases. Many remain localized for years, even without therapy.13 The discovery of the association between H pylori and gastric MALT lymphoma has engendered completely new treatment options. Multiple medical centers have reported regression of lowgrade gastric MALT lymphoma with eradication of H pylori. The response rates range from 60% to 90%.3,14,15

Complete regression of gastric MALT lymphoma is characterized by an empty-appearing lamina propria, basal aggregates of small lymphocytes, and scattered plasma cells. Partial regression shows areas of empty lamina propria with foci of atypical lymphoid cells and lymphoepithelial lesions.14

Primary follicular lymphoma of the gastrointestinal tract is rare. Misdraji et al4 reported the first case of primary follicular lymphoma of the duodenum in 1997. Since then, several other studies have been published suggesting that follicular lymphoma of the duodenum may be a distinct clinicopathologic entity.5,6 Patients usually present with symptoms related to bowel thickening. In some cases, symptoms are mild and nonspecific; patients often have relatively long-lived symptoms before seeking medical attention. Most of the tumors are found in the second portion of the duodenum, in the area of the ampulla of Vater. Most patients are alive at last follow-up, suggesting that the lymphoma is indolent and has a slowly progressive clinical course and a favorable outcome.

Follicular lymphoma of the duodenum has histologic features and immunophenotypes that are similar to those of its nodal counterpart. A predominantly follicular growth pattern and expression of CD20, CD10, and Bcl-2 are noted in most cases. Genetic studies demonstrate t(14,18), or bcl2 gene rearrangement, in analyzed cases.4-6

Duodenal follicular lymphoma is extremely rare. To our knowledge, coexisting gastric MALT lymphoma and duodenal follicular lymphoma in the same patient is unprecedented and makes this case unique. Our patient had a gastric marginal zone lymphoma and duodenal follicular lymphoma, with distinct histologie, immunophenotypic, and genetic features supporting the presence of 2 different types of indolent B-cell lymphoma in adjacent anatomic sites. Most interestingly, the gastric MALT lymphoma showed regression with treatment of gastritis and eradication of H pylori, while the duodenal follicular lymphoma failed to show any significant changes. The fact that the gastric MALT and the duodenal follicular lymphoma showed different responses to antibiotic treatment suggests that different etiologies or mechanisms are involved in the pathogenesis of these lymphomas.

References

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3. Wotherspoon AC, Doglioni C, Diss TC, et al. Regression of primary lowgrade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet. 1993)342:575-577.

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11. Wotherspoon AC, Ortiz-Hidalgo C, Falzon MR, Isaacson PC. Helicobacter pylori-associated gastritis and primary B-cell gastric lymphoma. Lancet. 1991; 338:1175-1176.

12. Isaacson PC. Gastrointestinal lymphoma. Hum Pathol. 1994:25:10201029.

13. Chan JK. Gastrointestinal lymphomas: an overview with emphasis on new findings and diagnostic problems. Semin Diagn Pathol. 1996:13:260-296.

14. Thiede C, Wundisch T, Alpen B, et al. Long-term persistence of monoclonal B cells after cure of Helicobacter pylori infection and complete histologie remission in gastric mucosa-associated lymphoid tissue B-cell lymphoma. J Clin Oncol. 2001:19:1600-1609.

15. de Jong D, Boot H, Taal B. Histological grading with clinical relevance in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Recent Results Cancer Res. 2000;156:27-32.

Zuoqin Tang, MD; Wen Jing, MD; Neal Lindeman, MD; Nancy Lee Harris, MD; Judith A. Ferry, MD

Accepted for publication April 20, 2004.

From the Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Mass (Drs Tang, Jing, Harris, and Ferry); and the Diagnostic Molecular Laboratory, Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, Mass (Dr Lindeman).

The authors have no relevant financial interest in the products or companies described in this article.

Reprints: Judith A. Ferry, MD, Department of Pathology, Massachusetts General Hospital, 55 Fruit St, Boston, MA 02114 (e-mail: jferry@ partners.org).

Copyright College of American Pathologists Sep 2004
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