Hematolymphoid Tumors of the Gastrointestinal Tract, Hepatobiliary Tract, and Pancreas

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Chapter 31

Hematolymphoid Tumors of the Gastrointestinal Tract, Hepatobiliary Tract, and Pancreas

Judith A. Ferry

Introduction

The gastrointestinal (GI) tract is the most common primary site of extranodal lymphomas. Between 4% and 20% of all non-Hodgkin lymphomas arise in this organ system. The stomach is most often involved, followed by the ileocecal region, the small intestine, and the colon.¹^–⁴ In a small proportion of cases, multiple portions of the GI tract are involved.²^,⁵ Lymphoma also occasionally arises in the hepatobiliary tract, and, rarely, in the pancreas. The types of lymphomas encountered differ to some extent from those encountered in lymph nodes (Tables 31.1 and 31.2). Although lymphomas arising in lymph nodes and in some extranodal sites are largely idiopathic, in the GI tract there are many clues to the pathogenesis of distinct types of lymphoma. Predisposing factors include infection (especially by Helicobacter pylori), celiac disease, inflammatory bowel disease (IBD), and a variety of immunodeficiency syndromes. Thus, the development of different types of lymphoma appears to be related to chronic antigenic stimulation, inadequate immune regulation, or a combination of these factors.

Table 31.1

Lymphomas of the Gastrointestinal Tract and Hepatobiliary Tree, Including Rare Types

Stomach*	Small Intestine	Colon	Anus	Appendix	Liver	Gallbladder	Pancreas
MZL	DLBCL	DLBCL	DLBCL	DLBCL	DLBCL	DLBCL	DLBCL
DLBCL	MZL (subtype: IPSID)	MZL		Burkitt	Burkitt	MZL	Burkitt ALCL
Burkitt	Burkitt	Mantle cell		MZL	MZL	Follicular	MZL
Mantle cell	EATL	Follicular			HSγδTCL HSαβTCL
Follicular	Mantle cell	Burkitt
PTCL	Follicular	PTCL
Hodgkin	PTCL NOS NK/T-cell, nasal type Hodgkin	Hodgkin

^* The types of lymphoma are listed according to frequency, with the most common at the top.

ALCL, Anaplastic large-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; EATL, enteropathy-associated T-cell lymphoma; HSαβTCL, hepatosplenic α/β T-cell lymphoma; HSγδTCL, hepatosplenic γ/δ T-cell lymphoma; IPSID, immunoproliferative small-intestinal disease; MZL, extranodal marginal-zone lymphoma; NK, natural killer; NOS, not otherwise specified; PTCL, peripheral T-cell lymphoma.

Table 31.2

Gastrointestinal Lymphomas: Pathologic Features

Type of Lymphoma	Composition	Usual Immunophenotype	Genetic Features
B-Cell Lymphomas
Extranodal marginal-zone lymphoma, MALT type	Small lymphocytes, marginal zone B cells, plasma cells, reactive follicles, lymphoepithelial lesions	Monotypic sIg+, cIg+/− (IgM > IgG or IgA), CD20+, CD5−, CD10−, Bcl6−, Bcl2+, CD43−/+, cyclin D1−	Immunoglobulin heavy chain clonally rearranged; t(11;18) (API2-MALT1) in some gastric and intestinal cases; trisomy 18 or trisomy 3 in some cases; t(14;18) (IGH@-MALT1) in some hepatic cases
DLBCL	Large centrocytes, and centroblasts; immunoblastic and anaplastic large B cells	Monotypic sIg+, CD20+, Bcl6+/−, CD10−/+, CD43+/−	IGH@ clonally rearranged; BCL6 abnormalities are common; t(8;14) (MYC-IGH@) sometimes found; t(14;18) (IGH@-BCL2) uncommon
Burkitt lymphoma	Medium-sized atypical lymphoid cells with round nuclei, basophilic cytoplasm, tingible body macrophages	Monotypic sIgM+, CD20+, CD10+, Bcl6+, Bcl2−, Ki67 ≈ 100%	IGH@ clonally rearranged; t(8;14), t(2;8) or (8;22) (MYC); endemic cases and minority of sporadic cases EBV+
Mantle cell lymphoma	Small to medium-sized, slightly irregular cells with scant cytoplasm	Monotypic sIgMD+, CD20+, CD5+, CD10−, CD43+, cyclin D1+	IGH@ clonally rearranged; t(11;14) (BCL1-IGH@)
Follicular lymphoma	Mixture of centrocytes and centroblasts, follicular dendritic cells	Monotypic sIg+, CD20+, CD10+, Bcl6+, Bcl2+, CD5−, CD43−, cyclin D1−	IGH@ clonally rearranged, t(14;18) (IGH@-BCL2) usually found
Plasmablastic lymphoma (DLBCL, plasmablastic type)	Plasmablasts, sometimes with more mature plasmacytoid cells, high mitotic rate	CD20−, MUM1+, CD79a+, CD138+, cIg−/+, Ki67 high	EBV+, most cases; MYC rearrangement common
T/NK Cell Lymphomas
EATL type I	Medium-sized and/or large, sometimes bizarre cells, many admixed reactive cells	CD3+, CD4−/CD8− > CD8+, granzyme+, perforin+	TCR genes clonally rearranged
EATL type II	Small to medium-sized cells, few admixed reactive cells	CD3+, CD8+, CD56+, granzyme+, perforin+, TCRγδ±	TCR genes clonally rearranged
Extranodal NK/T-cell lymphoma, nasal type	Small, medium-sized, and/or large atypical lymphoid cells, necrosis, vascular damage	cCD3+, CD2+, CD5−, CD56+, granzyme+, perforin+	TCR genes germline; EBV+
Hepatosplenic T-cell lymphoma	Medium-sized cells with clear cytoplasm in hepatic sinusoids and splenic red pulp	CD2+, CD3+, CD5−/+, CD4−, CD8−/+, TIA-1+	TCR genes clonally rearranged, isochromosome 7q and trisomy 8 common; EBV−
Hodgkin Lymphoma
Classic Hodgkin lymphoma	Reed-Sternberg cells and variants in a reactive background	CD15+/−, CD30+, CD20−/+, Pax5+, CD3−	EBV usually +, especially in abnormal immune states

cCD3, Cytoplasmic CD3; cIg, cytoplasmic immunoglobulin; DLBCL, diffuse large B-cell lymphoma; EATL, enteropathy-associated T-cell lymphoma; EBV, Epstein-Barr virus; IGH@, immunoglobulin heavy-chain gene; MALT1, mucosa-associated lymphoid tissue lymphoma translocation gene 1; NK, natural killer; sIg, surface immunoglobulin; TCR, T-cell receptor.

In 55% to 75% of GI lymphomas, the stomach is the primary site. Lymphoma accounts for 1% to 7% of all gastric malignancies.¹^,² The most common types in the stomach are diffuse large B-cell lymphoma (DLBCL) and extranodal marginal-zone lymphoma (MZL) of mucosa-associated lymphoid tissue (MALT), which is also known as MALT lymphoma. Some series have more of the former and others more of the latter. Other types of lymphoma are uncommon, but follicular lymphoma, Burkitt lymphoma, mantle cell lymphoma, and peripheral T-cell lymphoma (PTCL) may occasionally arise in the stomach (see Table 31.1). The proportion of gastric T-cell lymphomas appears to be higher in Asian countries than in Western countries, although DLBCL is still more common than T-cell lymphomas.⁶

In 15% to 35% of GI lymphomas, the small intestine or the ileocecal region is the presenting site.¹^,²^,⁷^,⁸ Within the intestines, the ileocecal region is the most common site for lymphoma, accounting for almost 40% of cases.³^,⁴ Lymphoma accounts for approximately 25% of small-intestinal neoplasms.¹ The proportions of different types of lymphomas vary from one series to another, depending on the age and ethnic background of patients studied and the part of the world in which the study was performed. The most common type in the small intestine is DLBCL, followed by MZL (including immunoproliferative small-intestinal disease), Burkitt lymphoma, various T-cell lymphomas, mantle cell lymphoma, and follicular lymphoma.¹^,⁵^,⁸^–¹⁰ The ileum is more commonly affected than the duodenum or jejunum. Lymphomas that arise in the ileocecal region are almost all diffuse, high-grade B-cell types (DLBCL or Burkitt lymphoma) (see Table 31.1).³^,⁵^,¹¹

The large intestine is the primary site in 3% to 20% of GI lymphomas²^,⁷^,¹²^,¹³ and in 21%³ to 35%⁴ of all intestinal lymphomas. Lymphoma accounts for only approximately 0.5% of malignant neoplasms of this site.¹^,¹⁴ The most common type of lymphoma in the large intestine is DLBCL, followed by MZL, mantle cell lymphoma, and rare cases of follicular lymphoma, Burkitt lymphoma, and PTCL. The cecum is the most common site of involvement in the large intestine, followed by the rectum; other portions of the colon are only rarely affected.¹^,¹¹^,¹⁵ Anal lymphomas are very rare; they are usually DLBCLs (see Table 31.1).¹⁶

A variety of lymphomas can manifest with multifocal GI involvement, including mantle cell lymphoma, follicular lymphoma, enteropathy-associated T-cell lymphoma (EATL), MZL, and DLBCL.⁵^,¹¹

The most common presenting findings associated with GI lymphomas are abdominal pain, anorexia or weight loss, obstruction, palpable mass, diarrhea, nausea or vomiting, fever, perforation, and bleeding. Intussusception may be seen with bulky lymphomas in the ileocecal region. In a few cases, the lymphoma is discovered as an incidental finding.²^–⁵^,⁷^–⁹^,¹⁴^,¹⁷^–¹⁹

Symptoms distinctive for various types of lymphoma are described in this chapter. The more common types of lymphoma, based on pathologic subclassification, are discussed individually. Lymphoma of the appendix is also discussed separately.

Gastric MALT Lymphoma

Clinical Features

The stomach is the most common site for the development of MZL. Gastric MZL (MALT lymphoma) affects similar numbers of men and women, with a slight male preponderance in some series. Most patients are older adults, with a median age in the sixth or seventh decade. Infrequently, young adults and even adolescents are affected.²⁰^–²⁸ Patients have epigastric pain or dyspepsia; nausea and vomiting, bleeding, and weight loss may occur but are unusual.²⁹ The symptoms often suggest gastritis or peptic ulcer disease rather than lymphoma.³⁰

Pathologic Features

On endoscopy or on gross examination of a gastrectomy specimen, this type of lymphoma often consists of erosions, shallow ulcers, mucosal granularity, or thickened mucosal folds; alternatively, it may appear as a diffusely infiltrative, ill-defined lesion. Superficial lesions are more common than large masses. The appearance can mimic gastritis.²⁰^,²³^,²⁹^–³¹ Lymphomas usually involve one portion of the stomach, but the tumor may be multifocal and widespread. ²³^,³⁰^–³² Multifocal, widespread, or ill-defined lymphomas may be associated with positive resection margins in gastrectomy specimens.¹⁰^,²⁷ A discrete, localized, polypoid tumor¹⁰ or an exophytic lesion mimicking carcinoma³³ may be found, but this is much less common. Most lymphomas are confined to the mucosa or submucosa. Lymph node involvement is unusual with superficially invasive lymphomas, but it is common when there is invasion into the muscularis propria.²⁷

Microscopic examination reveals a diffuse or vaguely nodular infiltrate of marginal-zone cells, small or medium-sized cells with slightly irregular nuclei, and a distinct rim of clear cytoplasm. In approximately one third of cases, there is prominent plasmacytic differentiation in the form of a bandlike infiltrate of plasma cells in the most superficial portion of the lymphoma. The plasma cells may have the appearance of normal, mature plasma cells, or they may have cytoplasm with crystalline inclusions or nuclei with Dutcher bodies. Small clusters of neoplastic cells often infiltrate and disrupt gastric glands to form lymphoepithelial lesions. It is usually possible to identify reactive lymphoid follicles in the lymphoma, often with infiltration and replacement by neoplastic cells (follicular colonization). The cells that colonize the follicles are most commonly marginal-zone–type cells, but plasma cells or large lymphoid cells may also be found. Even when follicles cannot be seen on routinely stained sections, evidence of preexisting follicles can usually be found using antibodies to follicular dendritic cells (FDCs), such as CD21 or CD23. A few large cells can often be found scattered among the marginal-zone cells (Fig. 31.1).¹⁰^,³⁰

FIGURE 31.1 Gastric marginal-zone lymphoma. A, Low-power view shows a diffuse infiltrate of marginal-zone B cells with a reactive follicle (upper left). B, Marginal-zone cells infiltrate and disrupt gastric glands, forming lymphoepithelial lesions. C, A follicle has been replaced by neoplastic cells (“follicular colonization”). D, High-power view shows that the “colonizing” cells are plasma cells, some with Dutcher bodies.

Biopsies of the gastric mucosa also frequently show evidence of infection with H. pylori, detectable on routinely stained sections in some cases, or with special stains such as the thiazine or Steiner stain, or by immunohistochemistry. Alternatively, evidence of H. pylori infection can be detected by use of the rapid urease test, the urea breath test, tissue culture, or serology.²⁰ The likelihood of finding H. pylori is greater with lymphomas that are superficial (i.e., confined to the mucosa or submucosa) and those that are entirely low grade (rather than having areas of progression to a diffuse large B-cell type).³⁴ In addition, the frequency of H. pylori positivity varies among studies. Although some series report that 80% to 100% of patients harbor H. pylori,⁶^,²⁸ in other studies it is only a minority.³²

After therapy to eradicate H. pylori, complete histologic regression of lymphoma is characterized by a lamina propria with a distinctive empty appearance, basal aggregates of small lymphocytes, and scattered plasma cells (Fig. 31.2). Partial regression shows areas of empty lamina propria with foci of atypical lymphoid cells or lymphoepithelial lesions, or both.³⁵

FIGURE 31.2 Gastric mucosa after regression of marginal-zone lymphoma. A, Low-power view shows a pale, hypocellular lamina propria. B, The lamina propria contains loose connective tissue, fibroblasts, and rare lymphocytes.

Early involvement of lymph nodes often takes the form of bands of marginal-zone cells along sinuses, sometimes with parafollicular aggregates with a marginal-zone pattern, progressing to confluent sheets of marginal-zone cells with or without monocytoid B cells and follicular colonization.³⁰^,³⁶ The appearance is indistinguishable from that of nodal MZL (Fig. 31.3).

FIGURE 31.3 Perigastric lymph node involved by marginal-zone lymphoma. A, Large aggregates of neoplastic cells replace much of the lymph node, surrounding and invading a reactive follicle. B, Monocytoid B cells with abundant pale cytoplasm encroach on a germinal center.

Immunohistochemistry

Immunophenotyping shows that these lymphomas are positive for CD20 and negative for CD5, CD10, Bcl6, and cyclin D1; they have monotypic surface immunoglobulin (sIg)-positive B cells and plasma cells expressing polytypic or monotypic cytoplasmic immunoglobulin (cIg). The immunoglobulin is most often IgM, but in some cases it is IgA or IgG. The neoplastic cells are Bcl2+, although Bcl2 may be lost in colonized follicles. CD43 is coexpressed in up to one third of cases. An immunostain for cytokeratin can be helpful for highlighting lymphoepithelial lesions. The proliferation fraction, as measured with Ki67, is low, although it is characteristically high in residual reactive germinal centers.²⁷^,³⁰^,³¹^,³⁷

Molecular Features

Molecular genetic studies show clonally rearranged immunoglobulin heavy- and light-chain genes. Analysis of heavy-chain genes shows somatic hypermutation, consistent with neoplastic cells at a postgerminal center stage of development. The BCL1 (cyclin D1, official symbol CCND1) and BCL2 genes are germline.¹⁰^,³⁰ Translocation t(11;18)(q21;q21) is the most common cytogenetic abnormality in gastric MZL,³⁸ although its frequency varies widely,³⁸^–⁴⁰ from 5% to 50% of cases in different series. This translocation involves the API2 gene (official symbol BIRC3) on chromosome 11 and the MALT1 gene on chromosome 18; it results in a chimeric transcript that can be detected by reverse transcriptase polymerase chain reaction (RT-PCR). The fusion is believed to confer a survival advantage to the neoplastic cells. This translocation is found almost exclusively in extranodal MZL.⁴¹ The t(11;18) is associated with a number of clinical and pathologic correlates. MZLs that fail to regress with anti–H. pylori therapy may harbor the t(11;18), whereas t(11;18) is consistently absent in cases that do regress with such therapy. This translocation tends to be associated with higher-stage disease.⁴²^,⁴³ In patients with H. pylori infection, the translocation shows a tendency to be more frequent when the H. pylori strain is positive for the bacterial cytotoxin-associated gene A (cagA). cagA-positive strains are associated with a more prominent neutrophilic infiltrate and therefore with more reactive oxygen species capable of causing DNA damage, predisposing to the acquisition of translocations.⁴⁴ A higher proportion of H. pylori–negative gastric MZLs is also associated with t(11;18)(q21;q21); this could be related to a different pathogenesis⁴³ or to the tendency of lymphomas with this translocation to manifest at an advanced stage, when the lymphoma is able to grow independently of the presence of the bacteria. The t(11;18) is only very rarely found in cases of large B-cell lymphoma, suggesting that MZLs with this translocation are very unlikely to undergo large-cell transformation. In general, the proportion of European gastric MZLs that are positive for t(11;18) has been higher than in Asia or North America. The reason for this variation is uncertain, but possibilities include host factors related to genetic makeup; the prevalence of different strains of H. pylori; study of resection specimens as opposed to biopsies—because larger, more deeply invasive tumors more often harbor the t(11;18); inclusion of MZLs in some series secondarily involving stomach; and possibly the techniques used (RT-PCR versus fluorescent in situ hybridization [FISH]) (see Table 31.2).

Another cytogenetic abnormality associated with gastric MZL, although less commonly, is t(1;14) (p22;q32), which involves the genes BCL10 and IGH@ (immunoglobulin heavy chain). This change results in deregulation of the BCL10 gene, with resultant loss of its normal pro-apoptotic activity and acquisition of oncogenic potential.⁴² The t(1;14) is also associated with failure of lymphoma to regress with antibiotics. The t(1;14) is associated with strong nuclear expression of Bcl10 protein; the t(11;18) is associated with moderate nuclear expression of Bcl10. Some cases lacking both translocations demonstrate moderate Bcl10 expression, so the protein expression is not specific for a certain cytogenetic change.⁴⁴ Rare cases show a t(14;18) involving the genes IGH@ and MALT1.³⁸^,⁴⁰ The three translocations—t(11;18), t(1;14), and t(14;18)—are mutually exclusive. All three are believed to contribute to lymphomagenesis via activation of nuclear factorκB (NFκB).⁴⁴^–⁴⁸ Trisomy 3 and trisomy 18 are found in a subset of cases.³⁹^,⁴⁰^,⁴⁹

Staging, Treatment, and Outcome

Staging reveals disease confined to the stomach in an estimated 63% to 88% of cases²⁰^,²⁶^,³¹^,³²^,⁵⁰; regional lymph nodes are involved in the remaining cases, and in a few, there is more widespread disease.²⁶^,³¹^,⁵⁰ Patients with widespread disease may have involvement of another MALT site, most commonly the small intestine or colon, but also the lung, kidney, salivary gland, thyroid, ocular adnexa, and others; a few have bone marrow involvement.²^,¹⁰^,³¹^,³²^,³⁸^,⁵¹ The lymphoma is indolent and may remain localized for years, even without specific therapy.¹⁰

In 1993, Wotherspoon and colleagues described their remarkable observation of regression of MZL after eradication of H. pylori using antibiotics.⁵² Since then, many other medical centers have reported the same phenomenon, with response rates typically ranging from 60% to 90%.²⁰^–²²^,²⁹^,³⁵ The interval to histologic regression can be prolonged, with a range of 1 to 35 months and a median of 3 to 10 months.²⁴^,²⁸^,³¹^,³⁵ Features associated with failure of regression include invasion beyond the submucosa, spread beyond the stomach, absence of H. pylori, and presence of certain chromosomal abnormalities [t(11;18) and t(1;14)].¹⁰^,²⁸^,³¹^,³³^,⁴² A component of DLBCL also decreases the chance of regression. In some cases of DLBCL arising in association with MZL confined to the stomach, complete regression with antibiotic therapy alone has been described ⁵³^–⁵⁷; regression appears more likely to occur when the lymphoma is superficial (i.e., confined to the mucosa or submucosa) on endoscopic ultrasound.⁵³^,⁵⁵^–⁵⁷

A minority of patients experience relapse of lymphoma; in some cases, this is precipitated by H. pylori reinfection.²² In patients who are histologically negative for lymphoma after H. pylori eradication, clonal B cells can be detected by PCR even months to years later.¹⁰^,²¹^,³¹^,³⁵ Microdissection studies suggest that the clonal cells reside in basal lymphoid aggregates.³⁵ Clonal B cells can be detected by PCR at presentation in endoscopically normal mucosa in a subset of cases; this finding may predict a longer time needed to achieve histologic remission.²⁴

If the lymphoma does not respond, or relapses, after H. pylori eradication, other modalities (e.g., surgery, radiation, chemotherapy) may be used,²⁰^,²⁸^,³¹^–³³^,³⁵ and cure can usually be obtained. The 5-year survival rate of patients with gastric B-cell MZL is at least 90%,¹⁰^,²⁵^,²⁶^,²⁸^,⁵⁰ and the 10-year survival rate is between 80% and 90%.²⁰^,³³ Of note, patients with H. pylori infection with or without MALT lymphoma appear to be at increased risk for gastric carcinoma. Follow-up of MALT lymphoma patients reveals development of gastric carcinoma in some cases. The carcinomas may occur in a background of atrophy with intestinal metaplasia, in the same site previously involved by lymphoma.²⁸

Pathogenesis

Most gastric MZLs are believed to arise from a background of gastritis with a component of acquired MALT induced by H. pylori infection. Persistent infection with chronic antigenic stimulation leads to the appearance of a clonal population of B cells. Surprisingly, the B cells do not have specificity for H. pylori; instead, they produce antibodies that may be reactive with a variety of autoantigens. It is the T cells in the infiltrate that have strain-specific reactivity for H. pylori. In the early phase of the disease, the B cells require H. pylori and the T cells to proliferate. Accordingly, in this phase, the lymphoma remains localized and may respond to antibiotic therapy directed against H. pylori. With time, the clonal B cells acquire genetic abnormalities associated with autonomous growth, leading to a histologically low-grade lymphoma that does not regress with H. pylori eradication and that may spread beyond the stomach. Additional genetic abnormalities, such as TP53 inactivation and allelic loss,¹⁰ CDKN2A (gene for p16^Ink4A) deletion,⁵⁸ and MYC translocation,³⁰^,⁵⁸^,⁵⁹ may occur and may lead to large-cell transformation.

Important pathogenetic questions remain. MZL develops in a small proportion of individuals with H. pylori gastritis. It is possible that host factors and environmental factors play a role in the pathogenesis of this type of lymphoma. One study suggested that certain polymorphisms in the T-cell regulatory gene CTLA4 (cytotoxic T-lymphocyte antigen 4) may be associated with an increased or decreased risk for MZL.⁶⁰ Others have described an increased risk of gastric MZL with certain polymorphisms of genes involved in inflammatory response and antioxidative capacity, with those individuals with a stronger inflammatory response to H. pylori and diminished antioxidative capacity more likely to develop gastric MZL.⁶¹ Also, in some cases, there is no evidence of H. pylori infection,³² even in patients studied by histology, immunohistochemistry, urease test, serology, or a combination of these methods.⁴³ In such cases, it is not clear whether infection was present previously and resolved at a stage after the lymphoma attained autonomous growth or whether there are other, as yet unrecognized, etiologic agents for gastric MZL. A few H. pylori–negative MZLs (as well as a small proportion of cases of chronic gastritis) may be caused by non–H. pylori species, such as Helicobacter heilmannii. H. heilmannii is detectable on histologic examination as long, thin, spiral bacilli adjacent to the surface epithelium.⁶²^,⁶³

Differential Diagnosis

Marginal-Zone Lymphoma versus Gastritis

On routinely stained sections, the presence of an expansile, destructive infiltrate with loss of glands; cytologic atypia of the infiltrating cells (having the appearance of marginal-zone rather than normal small lymphocytes); frequent lymphoepithelial lesions; and Dutcher bodies favors a diagnosis of lymphoma. Immunohistochemical studies are often of assistance. Demonstration of monotypic immunoglobulin light-chain expression confirms a diagnosis of lymphoma. A diffuse infiltrate of B cells and coexpression of CD43 by B cells favor a diagnosis of lymphoma. In selected cases, PCR can be useful to distinguish marked chronic gastritis from early involvement by MZL.⁶⁴

Marginal-Zone Lymphoma versus Other Low-Grade Lymphomas

In the stomach, MZL is much more common than either follicular lymphoma or mantle cell lymphoma. However, either of these can involve the stomach and mimic MZL. MZL is composed of CD5−, CD10− B cells with relatively abundant clear cytoplasm and may show plasmacytic differentiation and an admixture of a few large cells. Mantle cell lymphoma typically is composed of a monotonous population of small to medium-sized CD5+, cyclin D1+ B cells with scant cytoplasm, without a large-cell or plasmacytic component. However, in a small proportion of mantle cell lymphomas, the neoplastic cells have pale cytoplasm and resemble marginal-zone cells,⁶⁵ so relying on morphology alone may occasionally be misleading. Follicular lymphoma has a more distinct follicular architecture and is typically composed of CD10+, Bcl6+ B cells with nuclei that are usually more irregular, and cytoplasm that is usually more scant, compared with marginal-zone cells (see Table 31.2).

Transformation to Large B-Cell Lymphoma versus Marginal-Zone Lymphoma with Increased Large Cells

Sheets or confluent clusters of large, transformed cells found outside of follicles in a background of MZL represent large-cell transformation. Most authorities require clusters of at least 20 large cells for large-cell transformation²⁵^,⁵⁹ and report that diffusely scattered large cells representing 5% to 10%,²⁵ or even 20%,⁵⁰ of the total population are not associated with a worse prognosis as long as clusters of large cells are not seen. Before diagnosing focal large-cell transformation, it is important to exclude the possibility that the large cells are residual reactive germinal center cells or neoplastic large cells colonizing follicles. Immunohistochemical stains to demonstrate a follicular dendritic network can be helpful in resolving these uncertainties. The DLBCLs that arise in association with gastric MZLs are often positive for Bcl6, and immunostaining for Bcl6 may be helpful in highlighting possible areas of large cell transformation.⁶⁶ However, reactive germinal centers are also positive for Bcl6; stains for FDCs can be performed to investigate this as a possibility.

Poorly Preserved High-Grade Lymphoma versus Marginal-Zone Lymphoma

In a small biopsy with artifactual degenerative change in large B-cell lymphoma or Burkitt lymphoma, there may be cellular shrinkage and distortion leading to a false impression of low-grade lymphoma. The presence of apoptotic debris or mitotic figures suggests a higher-grade tumor. Staining with the proliferation marker Ki67 can be quite helpful in distinguishing low- from high-grade lymphomas. Clinical information, such as the endoscopic appearance of the tumor, can also provide a clue to the correct diagnosis.¹⁰

Plasmacytoma versus Marginal-Zone Lymphoma

Convincing cases of GI plasmacytoma are rare. Most reported cases are more likely MZLs with prominent plasmacytic differentiation. In favor of a diagnosis of lymphoma are the presence of a component of B lymphocytes, lymphoepithelial lesions, and IgM+ neoplastic cells (MZLs may express other heavy chains, but IgM expression by a plasma cell neoplasm would be very rare).