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. Patients have epigastric pain or dyspepsia; nausea and vomiting, bleeding, and weight loss may occur but are unusual. The symptoms often suggest gastritis or peptic ulcer disease rather than lymphoma.

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. Lymphomas usually involve one portion of the stomach, but the tumor may be multifocal and widespread. Multifocal, widespread, or ill-defined lymphomas may be associated with positive resection margins in gastrectomy specimens. A discrete, localized, polypoid tumor or an exophytic lesion mimicking carcinoma 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.

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 ).

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. 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). In addition, the frequency of H. pylori positivity varies among studies. Although some series report that 80% to 100% of patients harbor H. pylori , in other studies it is only a minority.

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.

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. The appearance is indistinguishable from that of nodal MZL ( Fig. 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.

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. Translocation t(11;18)(q21;q21) is the most common cytogenetic abnormality in gastric MZL, although its frequency varies widely, 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. 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. 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. 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 pathogenesis 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. 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. Rare cases show a t(14;18) involving the genes IGH@ and MALT1 . 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). Trisomy 3 and trisomy 18 are found in a subset of cases.

Staging, Treatment, and Outcome

Staging reveals disease confined to the stomach in an estimated 63% to 88% of cases ; regional lymph nodes are involved in the remaining cases, and in a few, there is more widespread disease. 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. The lymphoma is indolent and may remain localized for years, even without specific therapy.

In 1993, Wotherspoon and colleagues described their remarkable observation of regression of MZL after eradication of H. pylori using antibiotics. Since then, many other medical centers have reported the same phenomenon, with response rates typically ranging from 60% to 90%. The interval to histologic regression can be prolonged, with a range of 1 to 35 months and a median of 3 to 10 months. 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)]. 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 ; regression appears more likely to occur when the lymphoma is superficial (i.e., confined to the mucosa or submucosa) on endoscopic ultrasound.

A minority of patients experience relapse of lymphoma; in some cases, this is precipitated by H. pylori reinfection. 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. Microdissection studies suggest that the clonal cells reside in basal lymphoid aggregates. 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.

If the lymphoma does not respond, or relapses, after H. pylori eradication, other modalities (e.g., surgery, radiation, chemotherapy) may be used, and cure can usually be obtained. The 5-year survival rate of patients with gastric B-cell MZL is at least 90%, and the 10-year survival rate is between 80% and 90%. 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.

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, CDKN2A (gene for p16 ^Ink4A ) deletion, and MYC translocation, 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. 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. Also, in some cases, there is no evidence of H. pylori infection, even in patients studied by histology, immunohistochemistry, urease test, serology, or a combination of these methods. 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.

Differential Diagnosis

Clinical Features

Intestinal MZL is the second most common type of lymphoma to arise in the intestines (after DLBCL); it accounts for approximately 10% to 18% of all primary intestinal lymphomas. Almost all patients are middle-aged adults or older. Both men and women may be affected. This type of lymphoma may be located in any portion of the small or large intestine, but a disproportionately large number arise in the rectum. In most cases, disease is localized to the bowel, with or without regional lymph node involvement. A few patients have serum M components.

The prognosis of intestinal MZL is favorable but generally less favorable than that of gastric MZL. However, MZL is reported to have a better prognosis than any other type of intestinal lymphoma. In one study, 80% of patients with MZL were alive and well at last follow-up. In another study of intestinal lymphoma, patients with low-grade B-cell lymphoma had a 5-year survival rate of 94% and a 10-year survival rate of 82%; most of the lymphomas were MZLs, and this type of lymphoma showed a better outcome than the other low-grade lymphomas. In one additional study in which follow-up was available for 45 patients, only 1 patient died of lymphoma. The 5-year overall survival rate for intestinal MZL in one large series was 88%.

Rare patients with intestinal MZL respond to antibiotic therapy, suggesting that H. pylori or some other organism plays a role in the pathogenesis of at least a subset of these lymphomas.

Pathologic Features

On gross examination, these lymphomas form raised or polypoid masses, sometimes with ulceration, or, infrequently, they have the appearance of multiple, small, slightly raised lesions with erosion and erythema, akin to early gastric MZL. Most are single lesions, but occasionally they are multiple. In some series, most of the cases are transmurally invasive, but in others, the lymphomas are only superficially invasive. In a few cases, the lymphoma has an appearance of multiple lymphomatous polyposis (see Mantle Cell Lymphoma ).

The histologic features of MZL of the intestine are similar to those seen in the stomach. Rarely, there is associated amyloid deposition, without evidence of systemic amyloidosis. The immunophenotypic and genetic features are also similar to those of gastric MZL. The t(11;18) resulting in the API2-MALT1 fusion is found in 12% to 42% of cases in different series. In one series, the presence of t(11;18) was associated with MZLs that were larger and higher stage and more often affected men. As for gastric MZL, trisomy 3 and trisomy 18 are relatively common, and t(1;14) (involving the BCL10 and IGH@ genes) and t(14;18) (involving the IGH@ and MALT1 genes) are rare or absent (see Table 31.2 ).

A substantial number of MZLs involving the intestine are secondary; in these cases, the stomach is the most common primary site. Secondary intestinal MZLs have an even higher proportion of cases with t(11;18), correlating with the tendency of this translocation to be associated with higher-stage disease.

Clinical Features

Most patients are young adults (median age, 25 years), ranging from adolescence to middle age. Males and females are equally affected. IPSID tends to be associated with lower socioeconomic status. Presenting symptoms include abdominal pain, malabsorption, diarrhea, and weight loss of months’ to years’ duration. Many patients also have digital clubbing. Obstruction, bleeding, and perforation are uncommon, in contrast to other types of small-intestinal lymphoma. At laparotomy, patients may have one or more recognizable intestinal masses, diffuse mural thickening and/or luminal dilation, or normal-appearing bowel. The abnormalities may involve the proximal small intestine, the entire small intestine, or, rarely, just the ileum; the stomach or colon may also be involved. Mesenteric lymph nodes are often enlarged. In the early phase of the disease, as with gastric MZL, the lymphoma may respond to broad-spectrum antibiotics such as tetracycline. Nonresponders may be treated with chemotherapy. Later in the course of disease, when muscle invasion or transformation to a high-grade lymphoma has occurred, the lymphoma behaves in an aggressive manner. For resectable stage Ie or IIe1 disease, the 5-year survival rate is 40% to 47%. For higher-stage, unresectable disease, the 5-year survival rate has been reported to be from 0% to 25%. However, patients treated with anthracycline-containing combination chemotherapy have a better outlook, with a complete remission rate of approximately 60%.

In approximately half of cases, there is a highly characteristic laboratory abnormality: the serum contains free α heavy chains without associated light chains. Free α heavy chain may also be found in body fluids, such as intestinal fluid, urine, and saliva. Secreted α heavy chain is more likely to be found in early stages of IPSID. Cases with this abnormality have been called α heavy-chain disease. Closer analysis of this paraprotein reveals that it is a truncated α ₁ heavy chain lacking the variable region and the first constant region, without associated light chain. The corresponding messenger RNA (mRNA) shows an internal deletion of domains V _H and C _H 1. It has been suggested that IPSID develops in patients with recurrent or persistent intestinal infection, which leads to chronic antigenic stimulation of IgA-secreting lymphoid tissue in this site; the resultant clonal population acquires mutations, leading to the production of α heavy chain with the internal deletion described earlier.

Pathologic Features

IPSID is typically characterized by a dense, continuous, bandlike mucosal lymphoid or lymphoplasmacytic infiltrate that is uninterrupted along the length of the small intestine. The mucosa also shows broad villi, although the intestinal epithelial cells usually remain intact. The extent of the infiltrate explains the pathogenesis of the malabsorption that affects patients. The histologic features are similar to those of B-cell MZLs in other extranodal sites, except that in IPSID there consistently is marked plasmacytic differentiation. The following staging system has been proposed to subclassify the infiltrate in IPSID.

Stage A

In stage A, lymphoma is confined to the small intestinal mucosa and mesenteric lymph nodes. The infiltrate consists predominantly of plasma cells, with smaller numbers of marginal-zone cells. The B cells may be inconspicuous. An immunostain for CD20 can help with recognition of B cells and also of lymphoepithelial lesions. There is variable villous atrophy ( Fig. 31.4 ).

Immunoproliferative small-intestinal disease, stage A. A, The lamina propria is filled and expanded by a dense cellular infiltrate. B, Higher-power view shows numerous plasma cells, one with a Dutcher body, and scattered small lymphoid cells. C, Despite the intensity of the cellular infiltrate, the surface epithelium is well preserved.

Differential Diagnosis

IPSID and celiac sprue are both characterized by lymphoplasmacytic infiltrates and villous atrophy. Patient demographic data should provide a strong clue to the diagnosis, because patients with celiac disease are predominantly of northwestern European descent and improve on a gluten-free diet, in contrast to IPSID patients. Histologic features in favor of a diagnosis of celiac disease include total villous atrophy (in contrast to the villous broadening seen in early-stage IPSID); hyperplastic, elongated crypts; intraepithelial lymphocytosis; and surface epithelial damage. High-grade lymphomas may be found in association with either disease, but the lymphoma that complicates celiac disease is a T-cell lymphoma prone to cause multifocal perforation.

It can be difficult to distinguish nonspecific chronic inflammation from early-stage IPSID, particularly on a small biopsy sample. In favor of a diagnosis of IPSID is a dense, predominantly plasmacytic infiltrate that distorts the mucosal architecture in a patient with clinical features compatible with IPSID. Immunohistochemical stains that show plasma cells expressing only α heavy chain help establish the diagnosis.

Clinical Features

Gastric DLBCL is mainly a disease of older adults, with a median age in the seventh decade; younger adults are affected only occasionally. There is a slight male preponderance. Patients may have a palpable mass on physical examination. Some cases arise in association with MZL, consistent with large-cell transformation of the low-grade lymphoma, whereas other large B-cell lymphomas appear to arise de novo; the proportion of cases in the two categories varies among series.

Pathologic Features

On gross examination, the lymphomas are usually single, but occasionally one may encounter multiple large, ulcerated or exophytic lesions that are usually transmurally invasive and may invade adjacent viscera. Any portion of the stomach (upper, middle, or lower third) can be involved, and occasionally more than one portion is involved. Microscopic examination reveals a diffuse proliferation of large cells with round, oval, irregular, or lobated nuclei, distinct nucleoli, and a narrow but distinct rim of cytoplasm ( Fig. 31.5 ).

Gastric diffuse large B-cell lymphoma. The biopsy shows an infiltrate of centroblasts and immunoblasts with oval, vesicular nuclei, prominent nucleoli, and scant cytoplasm, with occasional mitotic figures and interspersed cellular debris.

Immunophenotyping reveals CD20+ B cells expressing monotypic sIg and occasionally cIg and coexpressing CD43 in approximately half of cases. In contrast to MZL, the large-cell lymphomas that arise from them may be Bcl2− and often express Bcl6, although they remain CD10−. A minority of gastric DLBCLs are CD10+, approximately half are MUM1+, and a variable proportion are Bcl6+. On immunophenotyping, one third or fewer are shown to be of the germinal center B-cell (GCB) type (CD10+ or CD10−, Bcl6+, MUM1−), and the majority are non–germinal center B-cell/activated B-cell (non-GCB) type (either CD10−, Bcl6+, MUM1+ or CD10−, Bcl6−) (see Table 31.2 ).

Most DLBCLs arising in the GI tract would be subclassified as DLBCL, not otherwise specified (NOS) according to the World Health Organization (WHO) tumor classification system. The WHO has defined a number of “diffuse large B-cell lymphoma subtypes” and “other lymphomas of large B cells,” and some of these may involve the GI tract. One of the subtypes is Epstein-Barr virus (EBV)-positive DLBCL of the elderly, which is defined as an EBV+ clonal B-cell lymphoproliferation occurring in patients older than 50 years of age with no known immunodeficiency or prior lymphoma. The pathogenesis is thought to be related to the deterioration of immunity that occurs over time. This lymphoma can involve a variety of extranodal sites (as well as lymph nodes), but the GI tract is among the more common sites. The composition may be monomorphous, with a predominance of large, atypical lymphoid cells that may have the appearance of immunoblasts or Reed-Sternberg–like cells and variants. In some cases, the composition is more polymorphous, with B cells in a range of stages of maturation, including large atypical cells and also reactive cells such as histiocytes, small lymphocytes, and plasma cells. Necrosis is common. Tumor cells are usually CD20+ and/or CD79a+ and often CD30+ and MUM1/IRF4+, but negative for CD15. By definition, EBV is present in tumor cells.

Among the “other lymphomas of large B cells” is anaplastic lymphoma kinase (ALK)-positive DLBCL; a case of this type of lymphoma arising in the stomach of a 21-year-old man has been reported. Also in this category are plasmablastic lymphoma and human herpesvirus 8 (HHV8)-positive large B-cell lymphoma. Both of these rare types of lymphoma may be encountered in the GI tract. Because they occur most often in human immunodeficiency virus (HIV)-infected individuals, they are discussed later (see GI Lymphoproliferative Disorders in Abnormal Immune States ).

Molecular Features

Immunoglobulin heavy and light chains are clonally rearranged. Complex cytogenetic abnormalities are common. In contrast to lymph nodal DLBCL, BCL2 gene rearrangement is rare and MYC rearrangement is common in gastric DLBCL. Abnormalities of the BCL6 gene are more common in gastric than in nodal DLBCL. BCL6 abnormalities include both translocation and somatic hypermutation. In one study, gastric lymphomas with germline BCL6 had advanced-stage disease more often and showed a trend toward decreased chance of complete remission and worse survival. Another study documented frequent (42% of cases) loss of heterozygosity (LOH) on chromosome 6q in sites of putative tumor suppressor genes, as well as a smaller number of cases with LOH of tumor suppressor genes, including TP53 and APC . Amplification of genomic material in the BCL6 locus, the MLL (mixed-lineage leukemia) gene, and others were also found. There was a significant asso­ciation between MLL amplification and LOH of TP53 . Homozygous deletion of CDKN2A , encoding p16 ^Ink4A , has also been described in high-grade gastric lymphoma.

Activation of the NFκB pathway is important in the pathogenesis of lymphomas of a variety of types. Recently, mutations in A20 (official symbol TNFAIP3 ), in CARD11 , and in ABIN1 ( TNIP1 ) and ABIN2 ( TNIP2 )—A20-binding inhibitors of NFκB that are likely to contribute to activation of the NFκB pathway—have been documented in DLBCLs of the GI tract. Mutations of A20 were associated more often with DLBCLs having the non-GCB phenotype (according to the Hans algorithm, described earlier) and with significantly worse overall survival and event-free survival.

Unless a component of low-grade lymphoma is identified, it may not be possible to distinguish between de novo DLBCL and DLBCL arising from histologic progression of MZL (or other low-grade lymphoma). Genetic and cytogenetic features may be helpful. Despite the high frequency of t(11;18) and trisomy 3 in gastric B-cell MZLs, they are uncommon in gastric DLBCL, suggesting that they are not important in transformation of MZL to large B-cell lymphoma. One report suggests that trisomies (most often involving chromosomes 12 and 18) are more common in large-cell lymphomas that have arisen through transformation of MZL than in de novo large B-cell lymphomas.

A variety of mechanisms may lead to transformation of MALT lymphoma to DLBCL, including TP53 mutation, alterations in BCL6 , and aberrant DNA hypermethylation. Translocations involving BCL6 and MYC may play a role in progression of gastric MZL to DLBCL, and may be involved in the pathogenesis of de novo DLBCL as well. Recently, overexpression of Myc was shown to alter the microRNA signature in gastric lymphomas. In the setting of Myc-repressed microRNAs normally showing tumor suppressive activity, FoxP1 was overexpressed, theoretically promoting lymphomagenesis and large cell transformation. Accordingly, MALT lymphomas are typically negative for Myc and FoxP1 by immunohistochemistry; whereas, DLBCLs are often positive.

Staging and Outcome

In most of the cases, patients have stage I or II disease at presentation; patients with stage II disease usually outnumber those with stage I, and stage IIe1 is more frequent than IIe2. Patients may be treated with surgery, radiation, chemotherapy, or a combination of these modalities. The 5-year survival rate is estimated to be 65%. Some studies have documented pathologic features that have an impact on prognosis. In one study, the 5-year survival rate was 92% for large B-cell lymphoma associated with MZL, 89% for CD10+ large B-cell lymphoma, and only 30% for CD10− large B-cell lymphoma without a low-grade component. In another study, large B-cell lymphoma associated with a component of MZL or with lymphoepithelial lesions formed by small cells had a 5-year cause-specific survival rate of 84%, compared with 64% for de novo large B-cell lymphoma. Lymphoepithelial lesions formed by large cells were not associated with a favorable prognosis. In one study with immunophenotyping to subclassify gastric DLBCL as GCB or non-GCB type, patients with GCB type had a significantly better outcome.

Stage is also prognostically important. Patients with stage Ie or IIe1 have a better outcome than those with stage IIe2 or higher. In one study of high-grade gastric lymphoma, four features—age older than 60 years, male sex, high lactate dehydrogenase (LDH) level, and ascites—were each identified as an independent factor associated with poor outcome. Survival was worse with an increasing number of these factors.

Differential Diagnosis

Poorly differentiated carcinoma may be composed of dyshesive-appearing cells that form few or no glands and therefore may be difficult to distinguish from DLBCL. Lymphoid cells may show artifactual vacuolar change and mimic signet ring cells, but mucin stains and immunohistochemical stains are helpful in distinguishing between lymphoma and carcinoma.

Clinical Features

DLBCL is the most common type of intestinal lymphoma, accounting for as much as two thirds of cases. Most patients with intestinal DLBCL are middle-aged to older adults. Few cases occur in younger adults or children. There is a slight male preponderance among adults, whereas affected children are almost exclusively male. DLBCL in children is found almost always in the ileocecal area. In most patients, regional lymph nodes are involved. In most cases, the lymphoma is confined to the bowel with or without regional lymph node involvement; in the remainder, disease is more widespread.

This type of lymphoma is relatively aggressive but potentially curable. In one report, de novo large B-cell lymphoma had a less favorable outcome than large B-cell lymphoma that arose in association with MZL.

Pathologic Features

On gross examination, the tumors are similar to, or larger than, low-grade lymphomas. They are elevated or infiltrative, ulcerated lesions that are usually transmurally invasive. A subset show evidence of perforation. Most are composed of centroblasts, often with an admixture of immunoblasts or multilobated large lymphoid cells; a minority are composed almost exclusively of immunoblasts ( Fig. 31.6 ).

Diffuse large B-cell lymphoma arising in the cecum of a human immunodeficiency virus-positive patient. A, A diffuse infiltrate of lymphoid cells obliterates much of the bowel wall. B, The tumor cells are large, atypical lymphoid cells with oval or irregular nuclei and prominent nucleoli. Their appearance is consistent with that of centroblasts.

In some cases, a component of MZL is found, which is consistent with large-cell transformation of a low-grade lymphoma. The proportion of cases with an underlying low-grade lymphoma varies greatly in different series, from 10% to more than 50% of large B-cell lymphomas. The immunophenotypic features overlap with those found in gastric DLBCL. In contrast to gastric DLBCL, in which most cases have a non-GCB immunophenotype (either CD10−, Bcl6+, MUM1+ or CD10−, Bcl6−) most de novo intestinal DLBCLs have a GCB immunophenotype (CD10+ or CD10−, Bcl6+, MUM1−).

Intestinal DLBCL is genetically heterogeneous. In one study of 14 cases, 3 had a t(14;18) translocation involving genes IGH@ and BCL2 , 1 had a t(8;14) translocation involving IGH@ and MYC , 5 had a BCL6 rearrangement, and 1 had a t(11;18) translocation involving API2 and MALT1 . Although the t(11;18) characteristic of a subset of MZLs is generally considered to prevent histologic progression to DLBCL, rare cases of intestinal DLBCL harbor t(11;18). This suggests that large-cell transformation of an underlying MZL with this translocation may occur (see Table 31.2 ).

Differential Diagnosis

The differential diagnosis for intestinal DLBCL is similar to that for gastric DLBCL. In addition, floridly reactive lymphoid tissue in the intestine occasionally raises the question of lymphoma. The bowel normally harbors hyperplastic lymphoid tissue in the terminal ileum (Peyer patches), but hyperplastic lymphoid tissue in other portions of the intestine, if prominent, may suggest lymphoma. This problem may arise with lymphoid polyps, polypoid lesions composed of reactive lymphoid tissue that may be found in the colon. Large collections of hyperplastic lymphoid tissue may develop in the rectum; these have been referred to as rectal tonsils . These are large, discrete nodules of organized lymphoid tissue with reactive follicles, often showing florid hyperplasia, located in the lamina propria or submucosa. Rectal tonsils may be accompanied by overlying cryptitis, mild architectural distortion, intraepithelial lymphocytes (IELs), and lymphoepithelial lesions, typically without crypt obliteration. In lymphoid follicular proctitis, a condition characterized by congested, nodular mucosa and often associated with rectal bleeding, reactive lymphoid tissue, including lymphoid follicles, is found in the distal portion of the GI tract. Familiarity with these entities and appreciation of the follicular architecture, with large B cells mostly confined to follicles, can help the clinician to avoid overdiagnosis as lymphoma.

Clinical Features

Among lymphomas with involvement of the GI tract at presentation, mantle cell lymphoma is uncommon. Mantle cell lymphoma affects middle-aged or older adults, with a male preponderance. Almost all patients are 50 years of age or older. Mantle cell lymphoma usually manifests with widespread disease with involvement of lymph nodes and a variety of extranodal sites, and GI involvement is common. Any portion of the GI tract may be affected, and frequently the lymphoma affects multiple sites (stomach, small intestine, colon, and, on occasion, the esophagus). Presenting symptoms include abdominal pain, diarrhea, bloody stool, and weight loss. This type of lymphoma often takes the form of innumerable polyps, which is termed multiple lymphomatous polyposis ; this pattern is particularly prevalent in the intestines. The ileocecal region tends to contain the largest polyps. In some cases, particularly when mantle cell lymphoma involves the stomach, it takes the form of a smaller number of protruded, ulcerated, or fold-thickening lesions. Mesenteric lymph nodes are usually involved by lymphoma. Staging frequently reveals widespread disease away from the GI tract. Although there is usually a positive response to chemotherapy, relapses are common, and survival time is typically only 3 to 5 years. Predisposing factors for the development of mantle cell lymphoma are currently unknown.

Pathologic Features

On gross examination, multiple lymphomatous polyposis has the appearance of multiple, fleshy-white nodules, 0.5 to 2 cm in greatest dimension, involving the mucosa but sometimes with superficial submucosal involvement ( Fig. 31.7 ). Less commonly, mantle cell lymphoma takes the form of a discrete mass or an ulcerated lesion.

Multiple lymphomatous polyposis. Gross examination reveals marked expansion of mucosal folds, producing multiple serpiginous and polypoid masses. Microscopic examination showed mantle cell lymphoma.

Microscopic examination shows a bandlike infiltrate, or multiple ill-defined nodules, of atypical, monotonous lymphoid cells that are slightly larger and more irregular than normal lymphocytes, with scant cytoplasm and without conspicuous nucleoli. Single epithelioid histiocytes may be scattered among the neoplastic cells. Remnants of reactive follicle centers may be identified in some nodules. The lymphoma tends to displace and obliterate intestinal glands, but formation of true lymphoepithelial lesions is not a feature ( Fig. 31.8 ).

Multiple lymphomatous polyposis. A, Low-power view. B, High-power view shows small, slightly irregular lymphoid cells with scant cytoplasm and few interspersed single epithelioid histiocytes. C, With antibody to cyclin D1, there is staining of the nuclei of many of the atypical cells, confirming a diagnosis of mantle cell lymphoma.

Immunophenotyping typically shows CD20+, CD5+, CD43+, CD10−, CD23−, and nuclear cyclin D1+ B cells expressing monotypic immunoglobulin, IgMD type, with λ being more frequent than κ light chain. With antibodies to FDCs such as CD21, a loose, expanded dendritic network is seen. This lymphoma is associated with t(11;14), a translocation that involves BCL1 and the IGH @ (see Table 31.2 ). Rare cases of mantle cell lymphoma are negative for cyclin D1. Nuclear expression of Sox11 has been demonstrated in more than 90% of cases of mantle cell lymphoma ; expression of Sox11 can be helpful in identifying the rare cyclin D1–negative cases.

Expression of α ₄ β ₇ , the mucosal homing receptor, by mantle cell lymphoma is highly associated with GI involvement.

Differential Diagnosis

On occasion, lymphomas other than mantle cell type have the endoscopic or gross appearance of lymphomatous polyposis. In addition, as stated earlier, not all mantle cell lymphomas take the form of lymphomatous polyposis. Follicular lymphoma, MZL, and even T-cell lymphoma can have the appearance of lymphomatous polyposis. Mantle cell lymphoma without the classic polyposis appearance can be mistaken for other small B-cell lymphomas. The problem can be resolved readily in most cases with careful study of hematoxylin and eosin (H&E)-stained slides augmented by immunohistochemistry. The distinction is important, because mantle cell lymphomas have a poor outlook compared with other low-grade lymphomas.

A minority of cases of mantle cell lymphoma are characterized by histologic features suggesting more aggressive behavior; these “aggressive variants” include blastoid and pleomorphic variants. In the blastoid variant, neoplastic cells have finely dispersed chromatin, and the mitotic rate is high (usually >20 mitoses/10 high-power fields), so that the appearance is reminiscent of lymphoblastic lymphoma. In the pleomorphic variant, neoplastic cells are larger and more pleomorphic than in the usual mantle cell lymphoma, and, in contrast to typical mantle cell lymphoma, nucleoli are often prominent in at least some of the neoplastic cells. The appearance may mimic DLBCL. In the blastoid variant, occurrence in an older adult is a clue that lymphoblastic lymphoma is unlikely, and the immunophenotype (CD20+, CD5+, cyclin D1+, monotypic sIg+) confirms a diagnosis of mantle cell lymphoma and excludes lymphoblastic lymphoma. In the pleomorphic variant, even though there are many large pleomorphic neoplastic cells, there is often an admixture of medium-sized cells more closely resembling those seen in mantle cell lymphoma. Cyclin D1 expression by neoplastic cells confirms a diagnosis of mantle cell lymphoma.

Clinical Features

Burkitt lymphoma is a highly aggressive, rapidly growing B-cell lymphoma with distinctive pathologic features, including the presence of a translocation involving MYC . In the WHO classification of tumors of the hemato­poietic and lymphoid tissues, three clinical variants of Burkitt lymphoma are described: endemic, sporadic, and immunodeficiency-associated. Endemic Burkitt lymphoma occurs mainly in young children in sub-Saharan Africa. A complex interplay of environmental and host-related factors—climate, malaria, EBV infection, age, and developmental stage of the patient—appear to play a role in the development of this subset of Burkitt lymphoma. Most patients with immunodeficiency-associated Burkitt lymphoma are HIV+, and a few have an underlying iatrogenic or congenital immunodeficiency. Patients with sporadic Burkitt lymphoma are those who are not immunodeficient but do not fit the epidemiology for endemic Burkitt lymphoma. Sporadic Burkitt lymphoma is rare, although it accounts for 30% to 50% of all cases among children in whom lymphoma develops.

Burkitt lymphoma accounts for approximately 5% of all intestinal lymphomas. Involvement of the ileocecal region is the most common manifestation of sporadic Burkitt lymphoma. Ileocecal disease is occasionally seen with endemic or immunodeficiency-associated Burkitt lymphoma, although presentation with disease outside the GI tract is more common. Infrequently, sites in the GI tract other than the ileocecal area, including the stomach and more distal portions of the colon, are involved. Only 1% of gastric B-cell lymphomas were Burkitt lymphomas in one large series. GI Burkitt lymphoma affects children and young adults, with a marked male preponderance. In some cases, staging reveals disease beyond the GI tract. Immunocompetent patients with Burkitt lymphoma who are treated with aggressive, high-intensity, short-duration chemotherapy have an excellent prognosis.

Pathologic Features

On gross inspection, the GI tumors are usually bulky exophytic lesions, sometimes with ulceration ( Figs. 31.10 and 31.11, A ). Microscopic examination typically reveals a diffuse infiltrate of densely packed, uniform, medium-sized cells with round nuclei, granular chromatin, three to four small nucleoli, and a distinct rim of deeply basophilic cytoplasm with minimal to absent intervening stromal elements. There are typically numerous tingible body macrophages that produce a “starry sky” pattern. The mitotic rate is usually very high. Occasionally, the nuclei of neoplastic cells show greater pleomorphism and the nucleoli are fewer in number but tend to be more prominent (see Fig. 31.11, B through D ). If the immunophenotype and genetic features in such cases are typical of Burkitt lymphoma, they are still acceptable as Burkitt lymphoma. In some instances, neoplastic cells have plasmacytoid differentiation, with eccentric basophilic cytoplasm and a single central nucleolus. Nuclei may be somewhat pleomorphic. This variant is found most often in immunodeficient patients.

Burkitt lymphoma. A large fleshy tumor arises in the ileocecal region.

Burkitt lymphoma. A, The appendix has been cross-sectioned to reveal that it is replaced by homogeneous white tumor. B, A dense, diffuse infiltrate of lymphoid cells involves the appendiceal wall. C, A “starry sky” pattern is prominent in many areas. D, Neoplastic cells are slightly pleomorphic and medium sized, with one or more nucleoli and a scant to moderate quantity of cytoplasm.

Immunophenotyping reveals monotypic IgM+, CD20+, CD10+, Bcl6+, CD5−, Bcl2−, TdT− B cells with a proliferation fraction of almost 100%. Cytogenetic analysis reveals t(8;14), t(2;8), or t(8;22), corresponding to translocations involving the MYC gene and either the IGH@ or the κ or λ light-chain gene. Translocations involving BCL2 or BCL6 are absent. Other than the translocation involving MYC , cytogenetic abnormalities are few or absent. EBV is found in approximately one third of sporadic Burkitt lymphomas and is typically present in endemic cases (see Table 31.2 ).

Differential Diagnosis

The differential diagnosis of Burkitt lymphoma mainly includes other high-grade B-cell lymphomas, such as DLBCL and the so-called “B-cell lymphomas” unclassifiable, which have features intermediate between those of DLBCL and Burkitt lymphoma. Careful attention to histologic and immunophenotypic features, supplemented by cytogenetic analysis, help one to avoid misdiagnosis. Some high-grade lymphomas that resemble Burkitt lymphoma also harbor a translocation involving BCL2 ; these are designated “double-hit” lymphomas. They are associated with a very poor prognosis. A clue to the diagnosis is that, in contrast to Burkitt lymphoma, double-hit lymphomas usually express Bcl2 protein. Double-hit lymphomas account for a subset of the B-cell lymphoma unclassifiable type.

On a small biopsy, a floridly hyperplastic germinal center could mimic Burkitt lymphoma. As in Burkitt lymphoma, reactive germinal center cells are CD20+, CD10+, Bcl6+, Bcl2−, with Ki67+ in almost 100% of cells. A lymphoid follicle should be associated with a follicular dendritic meshwork, so immunostains for CD21 or CD23 may be helpful; such meshworks are typically absent in Burkitt lymphoma. Clinical information regarding the presence or absence of a large mass is helpful as well.

Clinical Features

EATL type I (sometimes previously referred to as type A) occurs in adults within a wide age range (20 to 80 years, with a mean or median age in the 50s or 60s); there is a slight male preponderance. The development of this type of lymphoma is closely linked to celiac disease. It is more prevalent among individuals of European descent and, in particular, among those from the United Kingdom, especially Ireland and Wales. EATL type I accounts for approximately 80% of EATL in Europeans but is rare to absent among Asians. Patients often have a history of celiac disease, which may be of long or short duration. Strict adherence to a gluten-free diet reportedly diminishes, but does not eliminate, the risk for lymphoma, whereas poor compliance with a gluten-free diet is associated with an increased risk. In one large study, EATL developed in approximately 0.5% of 1757 individuals with celiac disease who were monitored for a mean of 18 years after diagnosis. A subset of patients with EATL have no prior history of celiac disease; in some of these cases, there is histologic evidence of enteropathy, suggesting that the patients had subclinical celiac disease. Even if enteropathy is not found, the presence of antibodies to gliadin or endomysium or of the human leukocyte antigen (HLA) genotype characteristic of celiac disease (HLA DQA1 * 0501 , DQB1 * 0201 ) may be found.

Patients with EATL have abdominal pain, weight loss, diarrhea, vomiting, symptoms related to perforation or obstruction, fever, night sweats, or a combination of these findings. Among patients with a history of celiac disease, symptoms often result from an apparent worsening of the disease, with loss of response to a gluten-free diet. Only a small minority have a palpable mass on initial physical examination, and peripheral lymphadenopathy is very uncommon. Rarely, patients have symptoms related to distant spread of disease. Lymphoma is often confined to the small intestine at the time of presentation. In almost all cases, the lymphoma affects the jejunum (more frequently), the ileum, or both. The stomach and the colon are uncommonly involved. Mesenteric lymph nodes may be involved by lymphoma. Staging sometimes reveals spread to the liver and, rarely, to the bone marrow. In most cases, lymphoma is confined to the abdomen at the time of presentation. In one series of patients with EATL, the Ann Arbor stage was I in 19% of cases, II in 58%, and IV in 23%. Similar results were found in another series: 75% of patients had stage I or II disease.

Among intestinal lymphomas, EATL has the worst prognosis, with the possible exception of extranodal NK/T-cell lymphoma, nasal type (discussed later). Treatment is complicated by the severe malnutrition that characterizes many of these patients. Only approximately half of patients complete their planned chemotherapeutic regimens because of toxicity or disease progression. Chemotherapy may be complicated by perforation, GI bleeding, or sepsis. Most patients (84% in one series) die of lymphoma or of complications of therapy. Median survival time ranges from 3 to 10 months. However, a few patients treated with chemotherapy achieve remission and become long-term survivors, suggesting that chemotherapy is effective in a small subset of cases.

Overall, patients treated with surgery have a very poor prognosis. The addition of anthracycline-based chemo­therapy results in only a slightly improved prognosis. In an attempt to improve outcomes, newer agents or high-dose chemotherapy regimens followed by stem cell transplantation have been tested. In some studies, these more aggressive efforts have not proved to be efficacious, but a few studies have shown improved outcomes with 5-year survival rates of 50 to 60%. The perforation associated with intestinal involvement is the most common cause of death, but in some cases, dissemination of disease to lymph nodes and a wide variety of extranodal sites (liver, spleen, brain, heart, bone marrow, lungs, kidney, and thyroid) and toxicity resulting from therapy contribute to mortality.

EATL in a patient with no history of refractory celiac disease (RCD) is referred to as de novo EATL , and when there is such a history, it is designated secondary EATL . Patients with secondary EATL have had a slightly worse outcome than those with de novo EATL in some series.

Pathologic Features

EATL type I most commonly involves the jejunum or the ileum. Presentation with disease outside the small intestine is rare. Lesions may be single or multiple. They take the form of plaques, nodules, or strictures, with circumferential ulceration and often with perforation. Large masses are less common ( Fig. 31.12 ).

Enteropathy-associated T-cell lymphoma type I. A, The small intestine is dilated, and its serosal surface is covered by a fibrinopurulent exudate resulting from perforation. B, The bowel is opened to reveal multiple small ulcerated lesions, but no large, discrete mass. C, Higher-power view of one of the circumferentially oriented linear ulcers.

(Reproduced with permission from Case records of the Massachusetts General Hospital: weekly clinicopathological exercises. Case 53.1987: a 55-year-old woman with one year of malabsorption and the recent development of abdominal pain. N Engl J Med. 1987;317:1715-1728, Copyright © 1988 Massachusetts Medical Society. All rights reserved.)

Microscopic examination reveals a dense, diffuse infiltrate of atypical lymphoid cells associated with ulceration and a variable admixture of inflammatory cells. The neoplastic population usually consists of medium-sized or large, atypical lymphoid cells, or a mixture of both, that may be monotonous or pleomorphic, with round or irregular nuclei, prominent nucleoli, and a scant to moderate quantity of pale cytoplasm. Tumor cells may occasionally have the appearance of immunoblasts or may be large and bizarre, with an anaplastic appearance. There is often an admixture of histiocytes, eosinophils, small lymphocytes, and plasma cells. Occasionally, eosinophils are numerous; in such cases, there may be peripheral eosinophilia. Careful examination commonly reveals intravascular clusters of tumor cells. Changes of celiac disease are often seen in the mucosa away from the lymphoma, including increased numbers of IELs, villous atrophy, crypt hyperplasia, and a lymphoplasmacytic infiltrate in the lamina propria ( Figs. 31.13 and 31.14 ).

Enteropathy-associated T-cell lymphoma type I. High-power view shows large, bizarre pleomorphic cells. They were positive for CD30 (not shown).

Changes in the mucosa surrounding enteropathy-associated T cell lymphoma. A, The mucosa shows villous blunting. Tumor cells are seen in the lumen of a small vessel just deep to the muscularis mucosae. B, There are increased numbers of intraepithelial lymphocytes. The epithelium shows goblet cell loss.

Immunohistochemical Features

Immunohistochemistry shows that neoplastic cells usually express leukocyte common antigen (CD45), cytoplasmic CD3, and CD7, but they often lack CD2, usually lack CD5, and consistently lack CD1a, TdT, and CD57. CD8 is expressed in some cases, as noted earlier, and in rare cases CD4 expression is described, but usually CD4 and CD8 are both absent. The α/β T-cell receptor (TCR) is expressed in some cases, indicating origin from α/β T cells, and most cases are considered to be of α/β origin. CD30 is expressed by some lymphomas with anaplastic morphology, but epithelial membrane antigen (EMA) is expressed much less often; Alk1 should not be expressed. The neoplastic cells have a cytotoxic phenotype: They express cytotoxic granule proteins (T cell–restricted intracellular antigen 1 [TIA-1], granzyme B, and perforin). The cytotoxic nature of the neoplastic cells, and of the intraepithelial cells from which they arise, could be responsible for tissue damage, including the villous atrophy, ulceration, and necrosis seen with celiac disease and lymphoma. In most cases, CD103 (human mucosal lymphocyte antigen 1 [HML-1]), is expressed by intestinal IELs and by a subset of lamina propria lymphocytes. Among lymphomas, this antigen is characteristically expressed only in EATL and hairy cell leukemia.

Clinical Features

EATL type II (previously called type B) has clinical and pathologic features that distinguish it from EATL type I (also called classic type). In contrast to type I, it does not appear to be associated with celiac disease, nor with an increased frequency of HLA types associated with celiac disease. EATL type II accounts for approximately 20% of cases of EATL among whites. However, in Asian populations in which celiac disease is uncommon, EATL is reported to be predominantly or exclusively type II. Patients are middle-aged and older adults with a median age in the 50s or 60s; there is a male preponderance, with a male-to-female ratio of approximately 3 : 1. Patients with EATL type II have abdominal pain without a prior history of malabsorption, and perforation is common. The lymphoma often involves the small bowel, most commonly the jejunum. There may be concurrent involvement of the colon or stomach. In contrast to EATL type I, some cases of EATL type II are reported to involve the colon without small-intestinal involvement. The lymphoma is usually localized (stage I or II), but occasionally it may involve other intraabdominal structures, omentum, mesentery, and, less often, more distant sites such as bone marrow, inguinal lymph nodes, and brain. The clinical course and response to therapy are similar to those of EATL type I, and the prognosis is equally poor.

Pathologic Features

On gross examination, lymphomas may be unifocal or multifocal. They take the form of diffusely infiltrating lesions (or, less often, protruded lesions), usually accompanied by ulceration and often by perforation. Microscopic examination reveals a diffuse, often transmural infiltrate of relatively monotonous small or medium-sized lymphoid cells with dark to stippled chromatin, small to absent nucleoli, and scant to moderate quantity of pale cytoplasm without a conspicuous component of admixed reactive cells such as histiocytes and eosinophils and without conspicuous fibrosis. Most lymphomas show surface ulceration, but away from sites of ulceration and perforation, necrosis is typically absent. At the periphery of the lymphoma, tumor cells often involve the mucosa, with less involvement of deeper portions of the wall of the bowel. Examination of mucosa away from the lymphoma usually shows a marked increase in IELs. Villous blunting and crypt hyperplasia are often absent; if present, they are usually mild. The areas with increased IELs may be adjacent to or at a distance from the lymphoma ( Fig. 31.15 ).

Enteropathy-associated T-cell lymphoma type II. A, A diffuse infiltrate of lymphoid cells occupies the bowel wall. B, Higher-power view shows small and medium-sized atypical lymphoid cells. C, Neoplastic cells expressed CD3 (immunoperoxidase technique on paraffin section).

The most common immunophenotype of the neoplastic cells is CD3+, CD5−, CD4−, CD8+, CD56+, CD30−, and TIA-1+, although there is sometimes modest deviation with respect to one or more of these classic markers. In a few cases, aberrant coexpression of CD20 has been reported, although other B-cell markers are not expressed. Most cases express TCRγδ and therefore appear to be of γ/δ T-cell origin, although betaF1+ cases of α/β T-cell origin are also described. EBV is typically absent. The immunophenotype of the IELs is similar or identical to that of the neoplastic cells in the lymphoma. When the immunophenotype of the IELs deviates from that of the lymphoma, the most common differences involve expression of CD8 or CD56.

Compared with EATL type I, EATL type II is composed of a more monomorphic population of smaller cells. EATL type II more often expresses CD8 and CD56 and less often expresses CD30; has fewer admixed inflammatory cells, less necrosis, and less fibrosis; and less often has typical changes of celiac disease (i.e., prominent villous blunting, crypt hyperplasia) in the surrounding mucosa ( Table 31.3 , and see Table 31.2 ). EATL type II is also more often of γ/δ T-cell origin when compared with EATL type I.

Table 31.3

EATL and Associated Conditions

	Histology	Immunophenotype	T-Cell Clonality	Prognosis
Celiac disease (untreated)	Increased IELs, villous atrophy, crypt hyperplasia, lymphoplasmacytic infiltrate in lamina propria	IELs: predominance of CD3+, CD8+, CD103+, TIA-1+ T cells; rare CD4+ cells; rare CD56+ cells; few CD4−/CD8− γ/δ cells	Polyclonal	Good, with proper diet
Refractory sprue	As for celiac disease, sometimes with histologic changes of ulcerative jejunitis	IELs: Predominance of CD3+, CD4−/CD8−, TIA-1+ T cells Lamina propria: mixture of CD4+ and CD8+ T cells	Almost always monoclonal	Moderately poor; patients may die of malnutrition or lymphoma may develop with the same clonal rearrangement as prior refractory sprue
Ulcerative jejunitis	One or more mucosal ulcers with many inflammatory cells	IELs: Predominance of CD3+, CD4−/CD8−, TIA-1+ T cells Ulcer base: mixture of CD4+ and CD8+ T cells and other inflammatory cells	Monoclonal	Moderately poor; patients may die of malnutrition or perforation or lymphoma may develop with the same clonal rearrangement as prior ulcerative jejunitis
EATL type I	Lymphoma: medium-sized and large atypical cells or anaplastic large cells	Lymphoma: CD3+, CD4−, CD8−, CD103+/−, TIA-1+, CD30+/−	Monoclonal	Very poor
	Adjacent mucosa: as for celiac disease	IELs: as for refractory sprue and ulcerative jejunitis	Monoclonal; same clone as the EATL
EATL type II	Lymphoma: monomorphic medium-sized cells	Lymphoma: CD3+, CD4−, CD8+, CD56+, CD30−, CD103−, TIA-1+	Monoclonal	Very poor
	Adjacent mucosa: often shows increased IELs but without other changes of celiac disease	IELs: CD3+, CD4−, CD8+, CD56+ cells	Monoclonal; same clone as the EATL

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