Clinical features

The gastrointestinal tract is the most common site of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). MALT lymphomas develop in sites of inflammation in response to either infectious conditions or autoimmune processes. Within the GI tract, approximately 85% of MALT lymphomas occur in the stomach. MALT lymphoma is also the most common primary lymphoma of the small intestine in Western countries. There is a unique form of MALT lymphoma seen in Mediterranean areas and the Middle East referred to as immunoproliferative small intestinal disease (IPSID), which encompasses a spectrum of diseases including alpha heavy chain disease (discussed separately in this chapter).

Most gastric MALT lymphomas are associated with Helicobacter pylori infection. The normal stomach has no significant lymphoid compartment. Infection by H. pylori leads to development of a reactive lymphocyte response with typical B-cell germinal centers (MALT). Gastric lymphoma is thought to arise from this acquired lymphoid tissue. However, as lymphoma evolves from chronic gastritis, the density of microorganisms and detectability of H. pylori infection decreases.

Pathologic features

Gross findings

The endoscopic diagnosis of a MALT lymphoma is often difficult because of the various macroscopic patterns. Endoscopically, primary gastric lymphomas display a variety of morphologies: ulcerated (single, multiple, or diffuse), polypoid, granulonodular, erythematous, edematous, and infiltrated folds ( Fig. 21-1 ). Most commonly, MALT lymphomas of the stomach are seen as an ulcerative lesion either alone or in combination with the other morphologies. MALT lymphomas are more commonly diffusely infiltrative than high-grade lymphoma. The differentiation between lymphomas and adenocarcinomas may not be easy; however, lymphomas tend to produce larger tumors than adenocarcinomas and may be multifocal as well. Gastric lymphomas more frequently involve the antrum and corpus. Rarely, the neoplasm may occupy the entire stomach.

Gross appearance of mucosa-associated lymphoid tissue (MALT) lymphoma. In this example, prominent polypoid and nodular effacement of the gastric mucosa is seen.

Microscopic findings

MALT lymphomas are derived from marginal zone B-cells, which they resemble cytologically, phenotypically, and genotypically. MALT lymphomas comprise both reactive (B-cell follicles and plasma cells) and neoplastic (marginal zone B-cells) components. At low magnification, the lamina propria is expanded with small uniform cells that infiltrate the muscularis mucosa ( Fig. 21-2 A). These neoplastic cells invade the surrounding gastric gland epithelium to form “lymphoepithelial lesions” (see Fig. 21-2 B). Lymphoepithelial lesions are the defining characteristics of MALT lymphomas but may not be seen in every case, particularly when the biopsy is small. They are clusters of B-cells within the epithelium, typically distorting or destroying the gland architecture. High-power assessment of the lymphoid infiltrate reveals cells similar to follicle-center centrocytes admixed with small lymphocytes referred to as monocytoid B-cells, which have eccentric small nuclei, abundant clear cytoplasm, and well-defined cell borders. Plasma cell differentiation may be seen, typically toward the luminal surface but also within the bulk of the tumor. Light chain restriction may be used to differentiate the clonal plasma cells from reactive plasma cells that are present as part of the inflammatory background. Often the background is scattered with larger transformed lymphoma cells, some of which have a “halo” around them. When these larger cells comprise greater than 5% of the cells, this may signify slightly worse prognosis. Sheets of large cells indicate high-grade transformation and should be diagnosed as large B-cell lymphoma.

Mucosa-associated lymphoid tissue (MALT) lymphoma. A, At low magnification, the lamina propria is markedly expanded by small lymphocytes. Residual oxyntic glands are present within the neoplastic infiltrate. B, The infiltrate is composed of monomorphic, monocytoid lymphocytes with eccentric small nuclei, abundant clear cytoplasm, and well-defined cell borders. The lymphocytes invade the gastric glandular epithelium to form lymphoepithelial lesions.

MALT LYMPHOMA—PATHOLOGIC FEATURES

Gross findings

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  Ulcerated, polypoid, granulonodular, or edematous and infiltrated mucosal folds

  
  
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  Single or multiple masses

  
  
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  Most commonly found in gastric body and prepyloric area

Microscopic findings

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  Monotonous infiltrate of monocytoid cells mixed with immunoblasts and plasmacytoid cells

  
  
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  Lymphoepithelial lesions

  
  
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  Infiltrate expands interfollicular space and effaces normal architecture

  
  
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  Reactive follicles often present

  
  
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  Presence of moderate nuclear atypia, Dutcher bodies, and prominent lymphoepithelial lesions are features highly suggestive of lymphoma

Immunohistochemistry

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  CD20+, CD5−, CD10− and low Ki-67 proliferation index, CD43+ especially in gastric

Genetic abnormalities

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  Translocations t(11;18)(q21;q21)

  
  
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  Trisomy of chromosomes 3, 12, and 18

Differential diagnosis

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  Reactive lymphoid hyperplasia

  
  
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  Mantle cell lymphoma

  
  
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  Follicular lymphoma

  
  
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  Diffuse large B-cell lymphoma

Ancillary studies

Immunohistochemistry can aid in establishing the diagnosis of MALT lymphoma ( Fig. 21-3 ). The neoplastic B-cells, similar to marginal zone B-cells, are CD20-positive and negative for CD10, CD5, and CD23. CD43 is aberrantly expressed in approximately one half of gastric MALT lymphomas. In a gastric biopsy showing a dense, monotonous lymphocytic infiltrate, an initial immunophenotyping panel of CD3, CD20, and CD43 can be performed. If the infiltrate is composed predominantly of CD20+ B-cells with coexpression of CD43, the diagnosis of MALT lymphoma can be rendered. Because admixed reactive T-cells and plasma cells are strongly positive for CD43, care must be taken in interpreting CD43 coexpression by the B-cells. Similarly, normal mantle zone B-cells and many T-cells are BCL2 positive, so only the putative tumor cell population should be interpreted. When there is high suspicion for a MALT lymphoma, but CD43 coexpression cannot be demonstrated, IgH rearrangement studies by PCR may be pursued. In the small intestine where normal B-cells can coexpress CD43, IgH rearrangement studies are often necessary to establish the diagnosis. When the lymphoid infiltrate is markedly nodular due to the presence of reactive follicles, follicular lymphoma should be excluded with CD10 and BCL6 immunohistochemical staining. Light chain stains are generally not useful because of low-density staining or high background.

Immunohistochemical features of mucosa-associated lymphoid tissue (MALT) lymphoma. Immunohistochemical staining highlights a dense B-cell infiltrate highlighted by CD20 (A) with aberrant coexpression of CD43 (B), while CD3 highlights the scattered reactive T-cells in the background.

The presence or absence of Helicobacter organisms should be documented, for clinical management of the patient and further substantiation of the process leading to MALT development.

Four recurrent chromosomal translocations are recognized in MALT lymphomas: t(11;18)(q21;q21)/API2-MALT1, t(1;14)(p22;q32)/IgH-BCL10, t(14;18)(q34;q21)/IgH-MALT1, and t(3;14)(p14.1;q32). H. pylori -related gastric MALT lymphoma is most commonly associated with t(11;18) translocation. It is suspected that early low-grade forms of MALT carry trisomy of chromosomes 3, 12, and 18, leading to the subsequent emergence of a higher-grade B-cell clone.

Differential diagnosis

The differential diagnosis of MALT lymphomas in the stomach includes a reactive lymphoid process and lymphocytic gastritis. Reactive lymphoid aggregates can be distinguished from MALT lymphomas by their normal cytologic features and normal immunophenotype, as described. In lymphocytic gastritis, despite a prominent inflammatory infiltrate, the absence of lymphoepithelial lesions and cytologic features of the infiltrate should reliably distinguish this lesion from lymphoma. Additionally, the infiltrate of lymphocytic gastritis is T-cell rich (CD3 and CD5 positive), unlike the B-cell infiltrate in MALT (CD20 positive). Gene rearrangement analysis may be needed to diagnose difficult cases.

Prognosis and therapy

Long-term remissions can be induced in low-grade MALT lymphomas in 70% to 80% of cases. The lymphomas that are most likely to respond to H. pylori eradication by antibiotics are those that are located superficially within the gastric mucosa. Certain genetic abnormalities, such as t(11;18) and BCL-10 mutation, may be associated with lack of response to this therapy. Recurrences of low-grade lymphoma are encountered in patients treated by H. pylori eradication, but these appear to be infrequent and may be self-limiting and regress spontaneously without further therapy. Transformation to diffuse large B-cell lymphoma may occur.

Clinical features

Diffuse large B-cell lymphoma (DLBCL) of the GI tract is most frequent in the stomach. No good survey data are available on the incidence of DLBCL. Some cases show histologic evidence of coincident low-grade B-cell lymphoma; the WHO classification indicates that the two should be diagnosed separately and discourages use of the term high-grade MALT lymphoma . One study reported that primary gastric lymphomas, including many DLBCL, were more often symptomatic than secondary lymphomas. However, low-grade and high-grade lymphomas do not differ significantly in the type of symptoms or clinical presentation. Helicobacter infection undoubtedly plays a role in DLBCL arising from indolent MALT lymphoma, but whether it is directly involved in the transformation process or whether H. pylori is involved in de novo gastric DLBCL is unclear.

Pathologic features

Microscopic findings

The definitional feature of DLBCL in the GI tract does not differ from disease in other sites (e.g., sheets of B-cell immunoblasts or centroblasts) ( Fig. 21-4 ). The extent of the clusters of large cells varies, with some cases exhibiting only a few fields of large cell lymphoma and others showing massive infiltration and destruction of the bowel wall. There may or may not be lymphoepithelial lesions. Gastric DLBCL, in particular, may show coincident low-grade MALT lymphoma. In most cases examined, these two entities are clonally related, both by light chain restriction and at the DNA sequence level. As with systemic DLBCL, the immunologic profile may suggest either a follicle center origin (CD10 or BCL-6 positive) or a non-follicle center origin. The absence of CD5, CD10, and BCL-6 raises the possibility of origin from a MALT lymphoma.

Diffuse large B-cell lymphoma. A, At low magnification, a dense lymphoid infiltrate with a pushing border is noted. B, The infiltrate is composed of sheets of pleomorphic large cells with prominent nucleoli and moderate amounts of cytoplasm. C, Immunohistochemical stain for CD20 shows a membranous staining pattern of the B-cells and emphasizes the pleomorphic nature of the cells.

DIFFUSE LARGE B-CELL LYMPHOMA—PATHOLOGIC FEATURES

Gross findings

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  Ulcerative or mass-forming lesion

Microscopic findings

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  Diffuse infiltration by large lymphoid cells

  
  
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  Most commonly have oval to round vesicular nuclei with multiple nucleoli and scant to moderate cytoplasm

  
  
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  Effacement of normal structures

Immunohistochemical

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  CD20+ B-cells with a Ki-67 proliferation index greater than 40% to 50%

  
  
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  Variable coexpression of CD10, BCL-6, BCL-2, and MUM-1

Differential diagnosis

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  Burkitt and Burkitt-like lymphoma

  
  
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  Poorly differentiate carcinomas

Ancillary studies

Gene rearrangement analysis, with or without microdissection, may reveal genetic identity of a DLBCL with an underlying MALT lymphoma. However, this is not clinically important because there is no difference in behavior of de novo DLBCL and large cell lymphoma transformed from MALT lymphoma. As with other low-grade lymphomas that transform, a minority of GI tract DLBCL carry mutations or loss of p53 and p16. Classic cytogenetics and array-based analysis suggest that there are at least two pathways to lymphomagenesis in the stomach, with t(11;18) (API2/MALT1) lymphomas remaining low grade and tumors with chromosomal instability and no t(11;18) having the potential to progress to DLBCL.

Differential diagnosis

It is most important to distinguish primary DLBCL from secondary lymphoma. Immunohistochemistry can provide some assistance if the tumor cells have a follicle center phenotype, but this is primarily a clinical and radiographic distinction. The occasional case with a particularly cohesive appearance or an infiltrative pattern may raise the differential of carcinoma, but this is easily excluded by immunohistochemistry.

Prognosis and therapy

Standard therapy for GI tract DLBCL tracks the approach in nodal DLBCL: chemotherapy with rituximab and CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). This may be followed by radiation therapy. Surgery—in the past a common therapeutic approach—has generally fallen out of favor except for rare cases with extensive hemorrhage or perforation. The role of antibiotic therapy in aggressive large cell lymphoma of the stomach has not been extensively studied, but several groups report lasting regression of DLBCL with MALT lymphoma after antibiotic therapy alone (albeit not as often as in pure MALT lymphoma).

Clinical features

IPSID typically afflicts young adults and is slightly more common in males. It is seen almost exclusively in the Middle East and Mediterranean regions. Common risk factors include low socioeconomic status, endemic parasitic infestation, poor sanitation, and infantile infectious enteritis. Campylobacter jejuni has been proposed as an infectious trigger to IPSID, analogous to Helicobacter and gastric MALT, but there is not agreement on this. Some genetic factors have also been implicated. Presentation is typically severe malabsorption with chronic severe intermittent diarrhea and weight loss. Nearly half of patients experience peripheral edema, tetany, and clubbing of fingers. Alpha heavy chain paraproteinemia (α heavy chain without associated light chain) is present in up to 70% of IPSID cases, which are at their highest levels early in the course and may diminish with progression of disease.

Pathologic features

Microscopic findings

IPSID demonstrates a histologic spectrum ranging from low- to high-grade histology, divided into stages A through C. All stages exhibit at least some features typical of other MALT lymphomas, but they tend to have more marked plasma cell differentiation.

Stage A is characterized by a lymphoplasmacytic infiltrate with features of a typical MALT lymphoma (reactive follicles with parafollicular clusters of clear cells and lymphoepithelial lesions) that is confined to the mucosa and expands the lamina propria, causing broad villi ( Fig. 21-5 ). Mesenteric lymph nodes may be involved. In stage B disease, the infiltrate becomes nodular and extends beyond the mucosa into the submucosa. The macroscopic appearance at this stage is typically abnormal, with thickened mucosal folds. Stage C is characterized by the presence of large masses and transformation to large cell lymphoma.

Immunoproliferative small intestinal disease (IPSID). Small intestinal villi are thickened by the small lymphocytic infiltrate, which extensively involves the mucosa.

Lymph node involvement is initially seen as mature plasma cells that fill the sinuses and then progresses to infiltration of the marginal zone and colonization of follicle centers.

IMMUNOPROLIFERATIVE SMALL INTESTINAL DISEASE (IPSID)—PATHOLOGIC FEATURES

Gross findings

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  Early-stage disease has normal macroscopic appearance

  
  
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  Advanced lesions have mucosal fold thickening and may have mucosal cobblestoning

  
  
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  Large masses are present in advanced disease

  
  
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  Involves any part of small intestine with predilection for the proximal small intestine

  
  
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  Mesenteric lymph node involvement is common even in early disease

  
  
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  Direct extension into adjacent structures is a feature of advanced disease

Microscopic findings

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  Stage A: lymphoplasmacytic infiltrate with features of a typical MALT lymphoma, confined to the mucosa, may involve mesenteric lymph nodes

  
  
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  Stage B: nodular infiltrate with follicular colonization, extends into submucosa and mild cytologic atypia

  
  
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  Stage C: large masses and transformation to large cell lymphoma (numerous centroblasts and immunoblasts), plasmacytoid differentiation may still be evident

Immunohistochemistry

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  CD20+, CD5−, CD10−, and CD23−

  
  
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  α-Immunoglobulin heavy chains in the cytoplasm of the infiltrating plasma cells, centrocytes, and transformed blast cells

Differential diagnosis

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  Low-stage disease: reactive lymphoid hyperplasia, mantle cell lymphoma, and follicular lymphoma

  
  
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  High-stage disease: large B-cell lymphoma, melanoma, and other poorly differentiated malignancies

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