Gastrointestinal Lymphoma

Clinical Features

The most common primary low-grade B-cell lymphoma of the GI tract is extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma). This lymphoma can develop in either primary or secondary MALT. Extranodal marginal zone lymphomas primarily occur in the stomach with decreasing incidences in the small bowel and colon. Approximately 75% to 85% of MALT lymphomas of the GI tract involve the gastric mucosa with the remaining involving the small bowel and colon.

Compared with the distal GI tract, the stomach is normally devoid of primary lymphoid tissue, and any lymphoid tissue present is secondary to inflammatory, infections, or autoimmune causes. So, it should not be surprising that the majority of gastric MALT lymphomas are associated with Helicobacter pylori infection. The inflammatory response to the infection leads to the formation of secondary lymphoid tissue in which the lymphoma develops.

In other sites in the GI tract, the extranodal marginal zone lymphoma can develop in the normal primary lymphoid tissue, especially in the distal small bowel and the colon. Although extranodal marginal zone lymphoma of MALT occurs less often in the small bowel, there is a unique form of MALT lymphoma that is primarily seen in patients from the Mediterranean and Middle Eastern areas that is referred to as immunoproliferative small intestinal disease (IPSID), which is discussed separately in this chapter.

Pathologic Features

Microscopic Findings

As the name implies, the neoplastic cells are derived from the marginal zone of the germinal centers and have a centrocyte to “monocytoid” appearance. They demonstrate abundant pale to clear cytoplasm with slightly irregular nuclei and inconspicuous nucleoli. Although the neoplastic cells are B cells, the lesions can contain a prominent T cells, or plasma cell infiltrate. Typically in GI MALT lymphomas, the lamina propria is expanded by the neoplastic lymphocytes that infiltrate through the muscularis mucosa as well as into the glandular epithelium with destructive lymphoepithelial lesions ( Fig. 19.1A and B ). Lymphoepithelial lesions consist of at least three neoplastic B cells infiltrating the glands with distortion or destruction of the glands (see Fig. 19.1B ). Actual lymphoepithelial lesions are typically thought to be pathognomonic for marginal zone lymphoma. However, lymphoepithelial-like lesions can be seen in multiple etiologies and in these cases, they consist of the epithelium infiltrated by T cells.

The lymphoepithelial lesions are more prominent in the stomach than the small bowel and colon, where they can be quite rare. Unfortunately, MALT lymphoma of the small bowel and colon can resemble expanded reactive MALT and Peyer’s patches. The marginal zone lymphoma cells expand from the marginal zone but can also infiltrate and colonize the reactive germinal centers ( Fig. 19.1F and G ). Reportedly, up to one-third of gastric cases demonstrates a component of plasma cell differentiation. These can also lead to amyloid deposition and light chain accumulation. There can be scattered larger atypical cells, which are admixed with the smaller neoplastic cells; however, if there are diffuse sheets of the larger neoplastic cells, the diagnosis would be DLBCL. In the evaluation of cases for MALT lymphoma, one can use the Wotherspoon criteria ( Table 19.2 ) as a useful framework to separate reactive gastritis (Wotherspoon 1 and 2) from suspicious lesions (Wotherspoon 3 and 4) from MALT lymphoma (Wotherspoon 5).

Table 19.2

Histological Differential Scoring of Lymphoid Infiltrations in the Stomach According to Wotherspoon et al. (1993)

Adapted from Wotherspoon A, Doglioni C, Diss T, et al. Regression of primary low-grade B-cell gastric lymphoma of mucosa-associated lymphoid tissue type after eradication of Helicobacter pylori. Lancet . 342:575-577, 1993.

Score	Diagnosis	Histologic Features
0	Normal	Scattered plasma cells in lamina propria; no lymphoid follicles
1	Chronic active gastritis	Small clusters of lymphocytes in lamina propria; no lymphoid follicles; no lymphoepithelial lesions
2	Chronic active gastritis with florid lymphoid follicle formation	Prominent lymphoid follicles with surrounding mantle zone and plasma cells; no lymphoepithelial lesions
3	Suspicious lymphoid infiltrate, probably reactive	Lymphoid follicles surrounded by small lymphocytes that infiltrate diffusely in lamina propria and occasionally into epithelium
4	Suspicious lymphoid infiltrate, probably lymphoma	Lymphoid follicles surrounded by marginal zone cells that infiltrate diffusely in lamina propria and into epithelium in small groups
5	MALT lymphoma	Presence of dense infiltrate of marginal zone cells in lamina propria with prominent lymphoepithelial lesions

MALT , Mucosa-associated lymphoid tissue.

Ancillary Studies

Immunohistochemical stains are often an essential part of rendering the diagnosis of MALT lymphoma. However, unfortunately, unlike most other low-grade B-cell lymphomas, only a proportion of cases will have an aberrant immunophenotype. The neoplastic cells are B cells and express B-cell lineage markers, CD20, PAX5, and CD79a. Additionally, because they are derived from marginal zone B cells, they also express BCL-2 but are negative for germinal center markers CD10, BCL6, and LMO2. The germinal center markers can highlight the residual germinal centers and helps accentuate follicular colonization by the lymphoma cells. There is no aberrant coexpression of CD5, cyclin D1, LEF1, SOX11, or CD23 on the neoplastic cells. Marginal zone lymphomas can demonstrate aberrant coexpression of CD43 ( Fig. 19.1C, D , and E ) but generally only in a minority of cases (up to 25% of gastric cases and 30%–40% of the colon or small bowel cases). In cases with prominent plasma cell differentiation, immunohistochemistry (IHC) or in situ hybridization for κ and λ light chains can be used to differentiate the clonal plasma cells from reactive plasma cells that are present as part of the inflammatory background. Additionally, the presence or absence of Helicobacter organisms should be documented in all gastric lymphoma or carcinoma cases either by hematoxylin and eosin (H&E), Giemsa, or immunohistochemical stains ( Fig. 19.1H ).

In borderline cases (e.g., Wotherspoon 3 and 4), when CD43 coexpression cannot be demonstrated, B-cell gene rearrangement studies by polymerase chain reaction (PCR) may be helpful. In the distal small intestine where normal B cells can coexpress CD43, B-cell gene rearrangement studies are often necessary to establish or confirm the diagnosis. Of note, B-cell clonality studies have a use in the initial diagnosis but should not be used as a means to determine therapy response. Specifically, B-cell clones may persist for an extended time after morphologic resolution, and their presence does not affect outcomes. We typically utilize the Groupe d' Etude des Lymphomes de l’Adulte (GELA) histologic scoring system by Copie-Bergman et al. (2013) ( Table 19.3 ) as a way of reporting treatment effect. One should note that even in the absence of lymphoma that treated Helicobacter gastritis takes months to more than 1 year for histology to become “normal.”

Several cytogenetic abnormalities have been associated with MALT lymphoma. There are four recurrent chromosomal translocations associated with MALT lymphoma, and they vary in their prominence at various anatomic sites. These include 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)/ FOXP1-IGH. Only two are associated with GI MALT lymphoma, t(11;18) and t(1;14). The t(11;18) translocation has been reportedly seen in 6% to 16% of gastric and 12% to 56% of intestinal MALT lymphomas. Only rare gastric (0%–5%) or intestinal (0%–13%) MALT lymphoma cases have the t(1;14). The most common genetic abnormalities in MALT lymphoma are trisomies involving chromosomes 3 and 18. Interestingly, although t(11;18) (API2/MALT1) lymphomas tend to be less responsive to Helicobacter eradication therapy, they also have little to no potential to progress to DLBCL.

Differential Diagnosis

Often the most challenging differential diagnosis is between chronic active Helicobacter gastritis versus MALT lymphoma. The infection leads to a reactive lymphoid infiltrate, creating acquired MALT with reactive germinal centers and surrounding mantle and marginal zones. During the transition from gastritis to lymphoma, both the number of Helicobacter organisms and the amount of acute inflammation typically decreases. Of note, although the neoplastic B cells are not Helicobacter antigen dependent, the reactive T cells appear to be Helicobacter antigen driven. These activated T cells active or stimulate B cells (both neoplastic and non-neoplastic) via CD40-CD40L interaction.

This differential between gastritis and lymphoma can at times be extremely challenging. Although strict adherence and application of the Wotherspoon criteria are not typically required, it does provide a useful framework for classifying reactive gastritis from cases that are suspicious for or diagnostic for MALT lymphoma. A differentiating point is the presence of epithelial invasion and glandular destruction by a B-cell process. As outlined earlier, aberrant CD43 expression and detection of a clonal B cell process are useful in the differentiation between a reactive inflammatory process and lymphoma.

The other primary differential includes the other mature B-cell lymphomas. Both mantle cell lymphoma (MCL) and FL are discussed in further detail later. Briefly, MCL demonstrates an abnormal phenotype with aberrant expression of CD5, CD43, cyclin D1, and SOX11 by the neoplastic B cells. MALT lymphomas can have a nodular appearance overlapping with that of low-grade FL. However, FL has a distinctive immunophenotype with an expression of germinal center markers CD10, BCL6, LMO2 with aberrance coexpression for BCL2. FL is negative for CD43. Another mature B-cell lymphoma that can mimic MALT lymphoma is SLL or CLL. These can also have similar cytomorphologic appearance (although typically with less cytoplasm). SLL and CLL lymphoma cells are typically B cell markers CD19, CD20, PAX5, and CD79a as well as aberrant expression of CD43, CD5, CD23, and CD200. SLL and CLL also demonstrate aberrant coexpression of LEF1 in the neoplastic B cells. The expression of LEF1 is typically seen in T cells and can be seen in aggressive B-cell lymphomas.

Prognosis and Therapy

Long-term remission is generally the rule, not the exception, in low-grade MALT lymphomas, especially the gastric subtype. The continued proliferation of gastric MALT lymphoma cells in patients with H. pylori is dependent on the presence of H. pylori –specific T cells and not caused by antigen and direct B-cell receptor interactions. The majority of patients respond to Helicobacter eradication antibiotic therapy with long-term remissions seen in up to 70% to 80% of cases. Certain features are associated with failure of Helicobacter eradiation therapy. Specifically, the presence of either the t(11;18) and t(1;14) translocation is associated with BCL10 expression, and these patients are more likely to fail Helicobacter eradication therapy. Approximately, 6 weeks after Helicobacter eradication therapy, patients should be tested for the continued presence of the organisms (either by biopsy or another method, such H. pylori fecal antigen test). Specifically, with the rise in clarithromycin as well as metronidazole and levofloxacin antibiotic-resistant strains, more than 20% of patients need a second round of antibiotic therapy to eliminate the infection.

Additionally, when the lymphoma has extended beyond the submucosa, the lesion tends to be more resistant to conservative therapy. Generally, MALT lymphomas are sensitive to radiation therapy with an excellent response rate. Additionally, some patients may be managed with single-agent rituximab or rituximab with additional chemotherapy. Transformation to DLBCL may occur but typically in fewer than 10% of cases. Interestingly, DLBCL cases that are associated with Helicobacter may also respond to Helicobacter eradication therapy only.

Clinical Features

Immunoproliferative small intestinal disease typically affects adolescent and younger adults with a median age of 25 years. Patients typically present with abdominal pain with chronic diarrhea and malabsorption (often severe), resulting in malnutrition and weight loss. In these patients, the malnutrition can lead to peripheral edema, muscle spasms, and digital clubbing. GI tract obstruction, bleeding, and perforation is uncommon. However, these patients can also present with enteroenteric fistula as well as lactose intolerance, hypocalcemia, and organomegaly. Common risk factors for IPSID include low socioeconomic status, poor sanitation, endemic parasitic infestation, and history of infantile infectious enteritis. Importantly, in areas with improving sanitary conditions, the frequency of the disease is decreasing. Similar to the association of H. pylori infection and gastric marginal zone lymphoma, IPSID is thought to be associated with an infectious etiology. Specifically, Campylobacter jejuni has been shown to be associated with IPSID, although other possible infectious agents have also been suggested. As mentioned earlier, patients with IPSID produce an altered α heavy chain that can be secreted and then detected in body fluids. Up to 70% of patients can have an α heavy chain paraprotein, which typically is at its highest levels early in the disease course and may diminish as the disease progresses.

Pathologic Features

Ancillary Studies

The neoplastic cells are positive for B-cell markers CD20, PAX5, and CD79a as well as BCL2. They can also aberrantly express CD43 but are negative for germinal center markers CD10, BCL6, and LMO2. Additionally, the neoplastic cells are negative for aberrant coexpression of CD5, cyclin D1, LEF1, and CD23. The plasmacytic component can be highlighted by plasma cell marker CD138.

One of the distinctive features of IPSID is the presence of an aberrant α heavy-chain protein in which the Ig lacks the variable heavy chain domain as well as the first constant domain producing a truncated Ig that cannot bind to the light chain. This protein can be detected in the plasma or serum. Additionally, the α Ig heavy chains can be demonstrated in the cytoplasm of the infiltrating B cells, plasma cells, and transformed large cells. The Ig heavy chain is clonally arranged. However, other recurrent genetic abnormalities have not been described. Specifically, the t(11;18) translocation described in other MALT lymphomas has not been demonstrated in IPSID.

Differential Diagnosis

The differential diagnosis for IPSID depends on the stage of the disease. As described earlier, one of the most challenging differentials is between lymphoma and reactive lymphoid process. In stage A, the initial consideration is often that of gluten-sensitive enteropathy (GSE) or celiac disease. However, in GSE, the intraepithelial lymphocytes are significantly increased with associated villous atrophy. Typically, patients with GSE are from northern European ancestry and respond to a gluten-free diet. Also, the infiltrate in GSE is CD3+ T cells, whereas IPSID is populated by CD20+ B cells. Additionally, other intestinal T-cell lymphomas often present with a similar diffuse infiltrate like IPSID; however, these are easily differentiated by CD3 and CD20 immunostains.

The nodular lymphoid aggregates of stage B disease can mimic reactive lymphoid hyperplasia as well as FL and MCL. Reactive follicular hyperplasia is common in the distal small bowel, but lymphoid aggregates in the proximal small bowel necessitate additional work up. The reactive processes also lack prominent lymphoepithelial lesions that are typical of MALT-lymphoma or IPSID. Compared with other low-grade lymphomas, IPSID demonstrates a prominent plasma cell or plasmacytoid differentiation with lymphoepithelial lesions. The neoplastic cells are not as monotonous as is typical of MCL and do not demonstrate aberrant expression of cyclin D1 or SOX11. FL consists of centrocytes with germinal center differentiation and aberrant BCL2 expression.

The differential diagnosis of stage C disease is that of high-grade malignancies, including EATL, DLBCL malignancies, plasmablastic lymphoma (PBL), and even poorly differentiated carcinoma or melanoma. Often among and between the pleomorphic neoplastic cells are residual low-grade neoplastic cells that can help with these differentials

Prognosis and Therapy

There are no treatment guidelines for patients with IPSID; however, in patients with early-stage disease, the use of broad-spectrum antibiotic therapy has led to remission, similar to Helicobacter eradication for gastric MALT lymphoma. In more advanced cases with visible tumor masses, chemotherapy with rituximab (e.g., R-CHOP [rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone]) is typically used, with reported remission and long-term survival rate of up to 70%. Ultimately, in situations with obstructing tumors, treatment with radiation, surgery, or both may be required.

Pathologic Features

Microscopic Findings

The neoplastic cells are composed of two B-cell types that are found in follicle or germinal centers, centrocytes, and centroblasts. The centrocytes are small and have angulated and cleaved nuclei with inconspicuous nucleoli. The centroblasts are larger cells that have round to oval nuclei that can occasionally appear indented or cleaved. Centroblasts have one to three nucleoli, and the cells are typically greater than three times the size of normal lymphocytes. The number of these large centroblasts in a high-power field (hpf) determines the grade of the tumor with up to 5 centroblasts being grade 1, 6 to 15 being grade 2, and greater than 15 being grade 3. The current WHO combines grade 1 and 2 into a low-grade category. There are two growth patterns, a nodular and a diffuse growth pattern. The diffuse pattern can have a prominent sclerotic component and on biopsies can lack any nodular architecture.

Typically, FL presents as nodules composed primarily of centrocytes. Compared with normal germinal centers, the neoplastic nodules lack tangible body macrophages and significant mitotic figures ( Fig. 19.2A and B ). Occasionally, only the diffuse portion is biopsied, which can mimic the other low-grade B-cell lymphomas. DTFL almost exclusively consists of centrocytes in a predominantly follicular pattern ( Fig. 19.2A ) and is limited to the mucosa or submucosa. If the lymphoma demonstrates high-grade features, has extensive diffuse growth pattern, extends into or beyond the muscularis propria, or demonstrates extensive lymph node involvement, it be consistent with systemic FL involvement of the GI lymphoma and should not be considered a DTFL.

Ancillary Studies

The neoplastic cells are positive for B-cell markers CD19, CD20, PAX5, and CD79a ( Fig. 19.2C ). The neoplastic cells are derived from the germinal center and as such are typically positive for CD10, BCL6, and LMO2 ( Fig. 19.2E and F ). However, in some cases, CD10 can be weak or lost. The neoplastic cells demonstrate aberrant coexpression of BCL2 ( Fig. 19.2G ). Most FLs will be positive for the standard BCL2 (clone 124); however, because mutations can occur in the BCL2 gene, the use of an alternative BCL2 clone (clone EP36/E17) is sometimes necessary to confirm the diagnosis. The neoplastic cells are negative of CD3, CD43 ( Fig. 19.2D ), CD5, Cyclin D1, Sox-11, and Lef1. Typically, whereas neoplastic follicles in low-grade lymphomas have a Ki-67 labeling index of less than 10%, normal reactive germinal centers have an elevated Ki-67 (>90%) labeling index. The dendritic cell networks are highlighted by immunostains for CD21, CD23, and CD35. Compared with the nodal and extranodal types, the DTFLs tend to have to a diminished follicular dendritic cell network, often resulting in a “hollowed-out” appearance with the stain restricted to the periphery ( Fig. 19.2H ). Additionally, unlike the systemic forms, the duodenal-type variant often express IgA as well as the mucosal homing receptor α-β7.

Follicular lymphomas demonstrate clonal rearrangements of the Ig heavy chain and light chains. Additionally, almost all FLs have cytogenetic abnormalities with the most common involving translocation of the BCL2 gene, which can be identified in up to 90% of low-grade FLs. The most common is the translocation involving the BCL2 and IGH genes, t(14;18)(q32;q21), with rare cases involving the BCL2 and light chain gene t(2;18)(p12;q21). The majority of DTFLs tested to date only have a BCL2/IGH translocation. Outside of this variant, only 10% of cases have only the t(14;18) with most demonstrating additional abnormalities. Other frequent abnormalities, which can be seen in non-DTFL forms, include BCL6 rearrangements or BCL6 5’ mutations, as well as +7, +12, +18, 17p deletion, and 6q23-36 abnormalities. A translocation involving IRF4 can rarely be seen in cases of grade 3 FLs. Interestingly, DTFL (compared with systemic) demonstrates elevated expression of CCL20 and MADCAM1 similar to marginal zone lymphoma.

Differential Diagnosis

The differential diagnosis includes benign reactive lymphoid proliferation, such as follicular hyperplasia and rectal tonsil, as well as other low-grade B-cell lymphomas. Specifically, many conditions in the GI tract can lead to nodular lymphoid hyperplasia, and the distal small bowel usually demonstrates prominent lymphoid aggregates with well-defined germinal centers. Most reactive nodular FL hyperplasia can be differentiated from FL on histology evaluation. Reactive lymphoid hyperplasia demonstrates expanded polarized germinal centers with intact marginal and mantle zones. The germinal centers also demonstrate prominent mitotic activity with high Ki-67 labeling index and multiple tingible body macrophages. These reactive germinal centers express germinal center markers BCL6, CD10, and LMO2 but are negative for aberrant BCL2 expression. The reactive process typically demonstrates increased mitotic index with Ki-67 of greater than 90%; however, neoplastic follicles typically demonstrate less than 10% Ki-67 staining. Most of the other mature B cells lymphomas (marginal zone, mantle, and SLL) can have a nodular growth pattern, and immunohistochemical features are often vital in the differential. BCL2 expression helps differentiate FL from benign germinal centers, but most other mature B-cell lymphomas also expression the antiapoptotic protein BCL2.

Prognosis and Therapy

The prognosis of patients with FL can be variable depending on the grade and stage of the lesion. There is a specific prognostic system for FL (Follicular Lymphoma International Prognostic Index score), which includes age older than 60 years, serum lactate dehydrogenase, hemoglobin level, Ann Arbor stage, and number of involved nodal areas. Compared with a systemic variant of lymphoma, DTFL has a particular indolent course. Specifically, DTFL is a localized disease to the mucosa and submucosa with only rare cases demonstrating evidence of nodal disease, and none of these cases demonstrated high-grade transformation. Patients with asymptomatic DTFL can be treated with a watch-and-wait approach. In general, therapy for patients with low-grade FL is directed at symptom relief and includes resection or excision, single-agent chemotherapy (rituximab only), or radiation therapy. Low-grade FLs are typically considered noncurative and are a chronic disease with a median survival time of greater than 12 years. Follow-up is aimed at evaluation for high-grade transformation or progression to DLBCL or high-grade B-cell lymphoma (HGBL; double-hit lymphomas). Grade 3a lesions tend to have a more aggressive course than grade 1 and 2 lesions requiring therapy. However, those treated with doxorubicin-containing regiments demonstrate similar overall survival to grade 1 and 2 lesions.

Patients with FL grade 3B are treated like those with DLBCL.

Clinical Features

Mantle cell lymphoma is a small cell lymphoma that morphologically resembles a mature or low-grade B-lymphoma but typically has an aggressive clinical course. MCL is typically a disease of older adults (mean age, 60 years) with a male predominance (at least 2:1). Unfortunately, almost 70% to 80% of patients have advanced disease (stage IV) at the time of diagnosis. In some series, greater than 80% of these patients have GI tract involvement. Although any part of the GI tract can be involved, the small bowel, specifically the ileum, is the most common site. MCL was the first to be associated with lymphomatous polyposis. At the time of initial diagnosis of MCL in the GI tract, patients can be asymptomatic but may also present with abdominal pain, diarrhea, hematochezia, weight loss, and fatigue.

Pathologic Features

Microscopic Findings

Mantle cell lymphoma can grow in three architectural patterns, including mantle, nodular, and diffuse. In the GI tract, the lesions tend to be nodular or diffuse; however, mantle zone pattern and in situ disease can be seen. Typically, the lymphoma is centered in the mucosa and submucosa with a diffuse or nodular pattern. The infiltrate often displaces the glands, and although there can be glandular destruction, lymphoepithelial lesions are not typically seen.

The lymphomatous infiltrate is composed of small lymphocytes with scant cytoplasm and irregular nuclei. The classical variant cells are typically very monomorphic or monotonous compared with other mature or low-grade lymphomas or reactive conditions ( Fig. 19.3A and B ). In the background, there are often scattered epithelioid macrophages, which can give the section a “starry-sky” appearance. There are only rare larger cells, which tend to be follicular dendritic cells and not large neoplastic cells. Another classic finding is the presence of hyalinized small vessels throughout the lesion. Mitotic figures are easy to identify but are usually less than 1 to 2/hpf. There are two aggressive variants of MCL, the blastoid and the pleomorphic variants. The blastoid variant is typically monomorphic medium to large cells resembling lymphoblasts and can resemble cells of acute leukemia or lymphoma. This variant typically also contains tingible body macrophages and increased mitotic index of greater than 3 mitoses/hpf. As the name suggests, pleomorphic MCL demonstrates variable size from large anaplastic-looking cells to small lymphocytes seen in the classic variant. The proliferation index is between that of the blastoid variant and the classic variant. Often the morphologic features overlap and are challenging to differentiate from DLBCL.

Ancillary Studies

The neoplastic cells are positive for B-cell markers CD20, CD19, CD79a, and PAX5 ( Fig. 19.3C ). Additionally, the neoplastic B cells aberrantly expression CD5 and CD43 and are negative for CD3 ( Fig. 19.3D and E ). There is normal expression for BCL-2; however, the cells typically lack expression of germinal center markers CD10, BCL6, and LMO2. The B cells are also typically negative for aberrant coexpression for LEF1 and CD23 ( Fig. 19.3H ). By flow cytometry, MCL is typically positive for the FMC7 (an epitope of CD20). MCL demonstrates nuclear expression of cyclin D1 (BCL1) in the vast majority of cases ( Fig. 19.3F ). Fortunately, SOX11 is expressed in most cases of cyclin D1 positive and negative cases as well as the blastoid and pleomorphic variants ( Fig. 19.3G ). There can be expression of MUM1/IRF4 in a minority of the lymphoma cells. Mantle cells typically express surface IgM or IgD heavy chain with a restricted surface light chain expression, typically lambda restricted.

Fluorescent in situ hybridization (FISH) and cytogenetic studies typically demonstrate the classic translocation associated with MCL, which is t(11;14)(q13;q32), involving the cyclin D1 gene and the IGH gene. The t(11;14) is seen in the vast majority of cases; however, there is a minor population of MCL that does not have the cyclin D1 translocation. In these cases, t(2;12) (p12;p13) translocation, fusing cyclin D2 to the κ light-chain gene locus, or a t(6;14)(p21;q32) translocation, fusing IGH and cyclin D3, have been identified. Additionally, several other cytogenetic alterations have been reported, including gains in 3q, 7p, 8q, 12q, and 18q and loss of 1p, 6q, 8p, 9p, 10p, 11q, 13, and 17p. Additionally, tetraploidy and complex karyotypes are more often associated with pleomorphic or blastoid variants. MYC (8q24) translocations can also be seen in blastoid MCL and tend to predict an aggressive clinical course.

Differential Diagnosis

The primary diagnostic considerations are other low-grade lymphomas such as marginal zone lymphoma, FL, and SLL. Specifically, lymphomatous polyposis can be caused by MCL, FL, or marginal zone lymphoma. From a cytomorphologic perspective, MCL cells are very monotonous appearing with slight nuclear irregularities, but they lack the typical cleaved morphology of FL cells and the monocytoid appearance of marginal zone lymphoma cells. Given that many of the biopsies suffer from extensive crush artifacts, increased importance is placed on immunohistochemical and cytogenetic findings. Specifically, although both FL and MCL are positive for pan-B-cell markers and BCL2, FL cell also expresses germinal center markers CD10, BCL6, and LMO2, which are negative in MCL. Conversely, MCL expresses CD5, cyclin D1, SOX11, and CD43, and patients typically have systemic disease as well. SLL or CLL can also be a systemic disease, and like MCL, expresses pan-B-cell markers, BCL-2, CD5 and CD43. However, SLL is typically positive for LEF1, but the MCL is positive for cyclin D1 and SOX11. A notable pitfall is that the proliferation centers of SLL or CLL can be cyclin D1 positive by immunohistochemical stains.

Prognosis and Therapy

Typically, at the time of diagnosis, the patient already has systemic disease. Surgery generally has limited utility unless there are obstructive type symptoms or if there was persistent hemorrhage. Survival is poor and worse in patients with blastoid or pleomorphic variants or classic type with a Ki-67 index of greater than 40% to 50%. The overall median survival period is 3 to 5 years from the time of diagnosis. Unfortunately, the majority of patients are not curable even with aggressive chemotherapy and newer therapeutic modalities.