LYMPHOMAS OF THE GASTROINTESTINAL TRACT

Patrick A. Treseler, M.D., Ph.D.

Division of Surgical Pathology

Department of Pathology

University of California, San Francisco

NOTE: The following monograph is the property of the author and has been provided as a service to the medical community. No part of it may be reproduced without the written consent of the author.

The gastrointestinal tract is the most common site for involvement by extranodal lymphomas, with about 30% of such tumors presenting as GI primaries. While virtually any type of lymphoma may involve the GI tract, certain tumor types and clinical settings are associated with the highest rates of gastrointestinal involvement, and these will form the focus of this presentation. Overall, the stomach is the most common site of involvement in primary gastrointestinal lymphomas, followed by the small intestine (except in the Middle East, where small intestinal tumors are the most common). Lymphomas of the esophagus are rare. While the most common type of GI lymphoma in essentially all sites is a diffuse large B-cell lymphoma, other forms (particularly low grade lymphomas of mucosa-associated lymphoid tissue (MALT) type) have generated the most interest in recent years.

I. B-CELL LYMPHOMAS

A. Low grade B-cell lymphoma of MALT type.

B-cell lymphomas of MALT type (also known as MALT lymphomas or, more colloquially, as MALTomas) are so named because of their histologic resemblance to either native or acquired MALT, which can be found in the GI tract and elsewhere. There is morphologic, immunologic, and genotypic evidence to support their derivation from post-germinal center marginal zone B-cells, and as such they appear related to the node-based lymphoma known as monocytoid B-cell lymphoma. In the REAL classification, these two entities are united under common heading of marginal zone B-cell lymphomas.

Low grade MALT lymphomas occur most frequently in the stomach. Gastric low grade MALT lymphomas display unusually indolent behavior, remaining localized to their site of origin for long periods of time (often many years) without disseminating, a feature which has made them uniquely amenable, among the small cell lymphomas, to cure by local therapy such as surgical excision with or without radiation therapy. Such indolent behavior has led to speculation that perhaps these are benign lymphoid neoplasms, however many features have convinced most authorities that these are tumors are true malignancies. Such features of low grade MALT lymphomas include: their clonal nature, frequent associated clonal cytogenetic abnormalities (the most common being trisomy 3, present in 30% of cases), destructive local infiltration of gastric epithelium, and frequent nodal metastases (present in 30% of even "early" cases, where gastric tumor appears localized to the mucosa or submucosa). Another intriguing feature of gastric low grade MALT lymphomas is their close and possibly etiologic association with the Helicobacter pylori organisms associated with many cases of clinical gastritis. H. pylori organisms are found in the stomach in up to 90% of individuals with low grade gastric MALT lymphomas (a rate much higher than the general population), and evidence suggests that the "acquired MALT" which develops in H. pylori gastritis forms the lymphoid background from which gastric MALTomas arise. In vitro assays have forged a further link between H. pylori and MALT lymphoma by demonstrating that the neoplastic B-cells proliferate in response to H. pylori antigens in a strain-specific fashion, suggesting that gastric MALTomas may be antigen-dependent B-cell proliferations (at least in early stages), which may also in part explain their tendency to remain localized to the stomach. Interestingly, it appears to be the helper T-cells which are specific for the H. pylori antigens; the neoplastic B-cells themselves appear to produce antibodies reactive with a variety of autoantigens (such as gastric parietal cell, follicular dendritic cell, or basement membrane antigens). Preliminary clinical studies have shown success in treating low-grade gastric MALT lymphomas by eradication of the H. pylori organisms with antibiotics, though it remains to be proven whether such remissions are durable (some patients have quickly relapsed following re-infection with H. pylori) and whether such therapy is effective in treating MALTomas which have spread beyond the gastric submucosa. In addition, some patients demonstrate persistence of clonal B-cell neoplasm using sensitive techniques such as PCR despite histologic evidence of remission; the significance of such findings remains uncertain at present.

In gastric resection specimens, low grade MALT lymphomas typically display a number of characteristic histopathologic features. Residual reactive lymphoid follicles with germinal centers are almost always present, reflecting a pre-existent follicular gastritis. The interfollicular areas are expanded, however, by a dense lymphoid infiltrate which is often polymorphous, but generally includes significant numbers of centrocyte-like cells (small cleaved cells), which may sometimes appear surrounded by moderate amounts of clear cytoplasm yielding a "monocytoid" appearance. Groups of three of more lymphoid cells invading the overlying epithelium form so-called lymphoepithelial lesions, which are typically conspicuous and associated with expansion and distortion of glandular structures and degenerative changes in the epithelial cells, most commonly an eosinophilic metaplasia of the cytoplasm. About one-third of cases will show significant plasma cell differentiation, with numerous plasma cells or plasmacytoid lymphocytes in the superficial mucosa. The lymphomatous infiltrate may be localized to the superficial mucosa or submucosa, or may invade quite deeply through the gastric wall. Neoplastic lymphoid cells may also invade reactive follicles, a process termed follicular colonization, to produce a nodular low power appearance which may mimic follicular lymphoma, although in gastric MALT lymphomas such nodules are generally restricted to the mucosa and/or superficial submucosa. Gastric MALT lymphomas are often multifocal in resection specimens, making assessment of resection margins difficult.

It should be emphasized that essentially none of the above described histopathologic features is seen in every case of low-grade gastric MALT lymphoma, and virtually every one can be seen in other neoplasms or even benign reactive conditions. Even prominent lymphoepithelial lesions, often regarded as among the features most suggestive of MALT lymphoma, can be seen in florid follicular gastritis as well as non-MALT lymphomas. Thus, the histologic diagnosis of gastric MALT lymphoma is based on analysis of the gestalt of features present, rather than on the presence of any individual feature. These difficulties are magnified in small mucosal biopsies, where limited sampling and crush artifact can further limit assessment. In general, it has been suggested that an unequivocal diagnosis of low grade MALT lymphoma be made on the basis of histologic analysis of small gastric mucosal biopsies only if all three of the following features are present in full flower: 1) a dense, extensive, interfollicular lymphoid infiltrate (sometimes defined as occupying at least half of a low-power field using a 4X objective); 2) the predominance within the infiltrate of atypical centrocyte-like cells, with or without clear cytoplasm, and 3) prominent lymphoepithelial lesions, generally associated with expansion and distortion of glandular structures, and eosinophilic degeneration of the epithelial cytoplasm. Specimens showing lesser degrees of atypia should be termed "suspicious lymphoid infiltrates"; in such cases repeat biopsies to provide material for immunophenotyping and lymphoid antigen receptor gene rearrangement studies could be helpful if warranted clinically. The histologic scoring system initially described by Wotherspoon et al. (1993) for assessment of post-therapy biopsies (but equally applicable to initial diagnostic specimens) is reproduced here, and can be useful in categorizing suspicious lymphoid infiltrates.

Grade
Description
Histological Features
0
Normal
Scattered plasma cells in LP. No LFs
1
Chronic active gastritis
Small clusters of lymphocytes in LP. No LFs. No LELs.
2
Chronic active gastritis with florid LF formation
Prominent LFs with surrounding MZ and plasma cells. No LELs.
3
Suspicious lymphoid infiltrate in LP, probably reactive
LFs surrounded by small lymphocytes that infiltrate diffusely in LP and occasionally into epithelium
4
Suspicious lymphoid infiltrate in LP, probably lymphoma
LFs surrounded by CCL cells that infiltrate diffusely in LP and into epithelium in small groups
5
Low-grade B-cell lymphoma of MALT
Presence of dense diffuse infiltrate of CCL cells in LP with prominent LELs

LP = Lamina Propria, LF = lymphoid follicle, LEL = lymphoepithelial lesion, MZ = mantle zone, CCL = centrocyte-like, MALT = mucosa associated lymphoid tissue

Table adapted from Wotherspoon et al. Lancet 1993; 342: 575-77. Reprinted with permission.

Immunophenotyping and molecular studies for lymphoid antigen receptor gene rearrangements can be useful adjuncts in diagnosis, but should never take the place of routine histology, which remains the "gold standard" in diagnosis. The demonstration of a clonal B-cell population (either by immunoglobulin light chain restriction or clonal gene rearrangements) obviously supports the diagnosis of a B-cell neoplasm. Like monocytoid B-cell lymphomas, B-cell MALT lymphomas show a "B-cell, NOS" phenotype, with expression of pan B-cell markers and light chain restriction, but in general a lack of any distinctive aberrant antigen expression which might specifically suggest a MALToma. Pertinent negative findings are helpful in excluding other B-cell neoplasms, however. For example, CD5 negativity largely excludes both B-cell CLL/SLL and mantle cell lymphoma (>90% of which express CD5), and CD10 negativity argues against follicular lymphoma (a majority of which are CD10 positive). Other less sophisticated uses of immunophenotyping in paraffin sections can also be helpful. Stains for cytokeratins can help highlight lymphoepithelial lesions. And, since most interfollicular lymphoid cells in follicular gastritis are T-cells, the presence of a dense interfollicular B-cell infiltrate in gastric biopsies argues for a B-cell lymphoma, even if clonality cannot be proven. In the final analysis, these ancillary studies can only be seen as an adjunct to the diagnosis. The significance of a clonal B-cell population in the absence of histologic features of lymphoma remains unknown at the present.

Although less common than gastric primaries, low grade MALT lymphomas also not infrequently present in the intestines. Most involve the small intestine; colorectal tumors are rare. The most common form of intestinal MALT lymphoma histopathologically and immunophenotypically resembles gastric MALToma, and is diagnosed in the same manner. It apparently shows a somewhat less favorable prognosis than gastric primaries, however. Despite its occurrence throughout the world, this form is termed the "Western type" of intestinal MALT lymphoma, largely to distinguish it from a form endemic to the Mediterranean and Middle East, previously referred to a "Mediterranean lymphoma", but now more commonly referred to as immunoproliferative small intestinal disease (IPSID). IPSID typically presents in young adults as a malabsorption syndrome. Pathologically, it can be thought of a low grade B-cell MALT lymphoma with marked plasma cell differentiation, showing a dense lymphoplasmacytic infiltrate which expands and blunts the intestinal villi. The diagnosis is otherwise made in a manner similar to other forms of MALT lymphoma. The neoplastic cells of IPSID show a characteristic production of alpha immunoglobulin heavy chains without light chain, which occurs as a paraprotein in the serum, leading to its alternate designation as alpha-chain disease. The disease follows a variable course, but in its early phases may respond to broad spectrum antibiotics, suggesting the possibility of an infectious etiology although no specific agent has been identified.

B. High grade B-cell lymphoma of MALT type.

High grade B-cell MALT lymphomas are simply low grade MALTomas which have transformed to a diffuse large B-cell lymphoma. There is usually nothing specific about the appearance or immunophenotype of the large cell lymphoma itself to suggest MALT origin, but rather it is the existence of a prior or coexistent low grade MALT lymphoma which permits the inference that a particular large B-cell lymphoma is derived from MALT. Since many gastrointestinal large B-cell lymphomas are discovered without any known previous or coexistent low grade MALToma, this raises the interesting (and currently unanswerable) question of whether all gastrointestinal diffuse large B-cell lymphomas are of MALT origin, although a case can be made that most are of MALT origin given a common pattern of oncogene expression in gastric low grade MALTomas and large cell lymphomas compared with node-based tumors. Current research suggests that the transformation from low grade to high grade MALT lymphoma may involve decreased expression of bcl-2 and acquisition of increased p53 abnormalities resulting in overexpression of the p53 protein product.

Any gastrointestinal low grade MALT lymphoma can transform to a high grade MALToma. Since varying numbers of large transformed lymphoid cells are often and indeed usually present in the polymorphous interfollicular infiltrate of a low grade MALT lymphoma, this raises the question of what defines transformation to a high grade tumor. Most authorities currently suggest that high-grade MALT lymphoma be diagnosed when large lymphoid cells with distinct nucleoli are present in compact clusters, confluent aggregates, or sheets (not counting large cells confined to apparent colonized follicles), although if the high grade tumor is a minor component within a larger low grade MALT lymphoma, it should be so noted. If the tumor is predominantly of large cell type, there is no significant difference in behavior if a low grade component can be identified, although again it is suggested that the presence of the minor component be noted. Shrinkage artifact in poorly fixed specimens can sometimes obscure the recognition of large cells, which may be difficult to tell from the surrounding centrocyte-like cells, which may have somewhat open chromatin and small nucleoli. It has been suggested that large cells be counted as such only if they show distinct nucleoli and a rim of amphophilic cytoplasm. Given the focality of the large cell component in some tumors, failure to detect a high grade large cell component in mucosal biopsies does not exclude the possibility of transformation, and a re-biopsy should be suggested in cases where the clinical suspicion is high (e.g., a significant clinical mass lesion, or failure to respond to antibiotic therapy).

  1. Mantle cell lymphoma

Small cell lymphomas other than low grade MALT lymphomas can involve the GI tract, including CLL/SLL, follicular lymphoma, and, most notably mantle cell lymphoma. Mantle cell lymphoma may involve virtually any portion of the gastrointestinal tract, which is the most common site of extranodal involvement by this tumor. Overall, between 20% and 30% of mantle cell lymphoma cases involve the GI tract, not uncommonly as the primary site of involvement. A particularly characteristic form of GI tract involvement is the presence of multiple polypoid lesions, most commonly in the ileocecal region (where regional lymph nodes are also frequently involved), a condition termed lymphomatous polyposis. Lymphomatous polyposis has been regarded as synonymous with mantle cell lymphoma in the past, but it is now clear that other forms of non-Hodgkin’s lymphoma, especially follicular lymphoma, may on occasion present in an identical fashion, so attention to pertinent diagnostic cytoarchitectural features is important (see below). In other cases, GI mantle cell lymphomas may present clinically as discrete masses, ulcers, and mucosal thickenings which may more closely mimic other lymphomas.

Because of its worse prognosis (median survival 2-3 years) compared with other small cell lymphomas, it is important to distinguish mantle cell lymphoma of the GI tract from its histologic imitators, particularly the much more indolent low grade MALT lymphomas. The histologic features of mantle cell lymphoma include a monomorphic population of small lymphocytes, typically resembling small cleaved cells, but with nuclei which may range from round to frankly convoluted. In contrast to MALToma, there is a paucity of other admixed cell types such as large non-cleaved lymphocytes. The tumor cells are usually present in diffuse sheets, although a mantle zone pattern, with tumor cells surrounding naked germinal centers, may provide a clue in some cases. A nodular pattern has also been reported on occasion. An increased mitotic rate may be seen, particularly in the blastic variant. Unlike low grade MALT lymphomas, lymphoepithelial lesions are uncommon.

Mantle cell lymphoma shows a variety of immunophenotypic characteristics which can be quite useful in arriving at the correct diagnosis. By frozen section or flow immunophenotyping, the cells appear as B-cells with immunoglobulin light chain restriction which are CD5(+) and CD23(-), an immunophenotype virtually diagnostic of mantle cell lymphoma, given that the only other common CD5(+) small cell lymphoma, CLL/SLL, is characteristically CD23(+). Even if only paraffin-embedded material is available, immunophenotyping is still helpful, as CD43 coexpression is usually seen, which, while not specific for mantle cell lymphoma, does suggest a B-cell neoplasm. In addition, cyclin D1 overexpression can be detected by antibodies which work well in paraffin sections. This overexpression, which represents activation of the PRAD1/CCND1 gene at the bcl-1 locus at 11q13 by the characteristic t(11;14) translocation found in most mantle cell lymphomas, appears to date to be quite specific for mantle cell lymphoma.

  1. AIDS-Related lymphomas.

Non-Hodgkin’s lymphomas represent the most common malignancy in AIDS patients after Kaposi’s sarcoma, and unlike KS, occur with increased frequency in all AIDS risk groups. About 30% of AIDS-related non-Hodgkin’s lymphomas involve the GI tract at presentation, with the stomach and small intestine representing the most common sites of involvement. Pain, ulceration with bleeding, obstruction, and constitutional symptoms are all seen as presenting complaints. The vast majority of AIDS-related lymphomas have been reported to correspond to one of three "diffuse aggressive" histologic types of the Working Formulation: large cell, immunoblastic, and small non-cleaved cells type (and would thus be considered large cell, Burkitt’s, or high grade Burkitt’s-like lymphomas in the REAL classification). Frequently, it is difficult to precisely sub-classify AIDS-related lymphomas, as many display histopathologic features which vary significantly within the tumor. Precise histologic sub-classification may be of largely semantic interest, however, since in AIDS patients, essentially all of these lymphomas behave in an aggressive, high-grade fashion (despite the characterization of diffuse large cell lymphoma as an "intermediate grade" lymphoma in the Working Formulation), with reported median survivals of 5 to 11 months in most series. Histologically, all tend to show a high mitotic rate with significant necrosis. Virtually all are B-cell lymphomas, and are generally thought to develop secondary to the impaired immunosurveillance which occurs in AIDS. Many cases (including a majority of the immunoblastic lymphomas) show evidence of EBV infection, and most show evidence of c-myc proto-oncogene activation which may be etiologic. High grade Burkitt’s and Burkitt’s-like lymphomas also commonly involve the GI tract in non-AIDS patients, particularly among pediatric and young adult patients.

  1. Post-transplant lymphoproliferative disorders (PTLDs).

Transplant patients receiving immunosuppressive drugs constitute the other major class of immunocompromised hosts to experience high rates of non-Hodgkin’s lymphomas. As in AIDS, most are EBV-driven B-cell proliferations, but in contrast to AIDS, these proliferations are a heterogeneous group which range from benign hyperplasias to frankly malignant high grade lymphomas. Most patients with PTLDs have extranodal involvement, with the GI tract being the principal site of clinical presentation. Overall, the GI tract is involved in about 35% of PTLD cases, with the small bowel being the most common site. In many cases, it is difficult to determine from routine histopathologic examination whether the lesions are benign or malignant, leading to use of the more general term PTLD. A variety of classification schemes for PTLDs have been proposed over the years. Most recently, Harris et al. (1997) reported the results of a Society for Hematopathology workshop which proposed five categories for PTLDs: 1) "early lesions", which generally resemble benign hyperplasias, and appear polyclonal; 2) polymorphic PTLDs, which resemble "mixed small and large cell lymphoma with plasmacytoid differentiation" morphologically, and which may be either polyclonal or monoclonal; 3) monomorphic PTLDs, which resemble diffuse large cell lymphoma, morphologically, and are usually monoclonal; 4) plasmacytoma-like lesions, which resemble plasmacytoma, and are usually monoclonal; and 5) T-cell-rich/HD-like PTLD, which resemble T-cell-rich B-cell lymphoma or Hodgkin’s disease morphologically, and show a monoclonal B-cell population by immunophenotyping or genotyping. The latter two categories of PTLD appear to be uncommon. The most perplexing category appears to be that of polymorphic PTLD, where clinical aggressiveness cannot be reliably predicted by either histopathology or studies of clonality. Fortunately, since clinical management usually involves a trial of reduction of immunosuppression in all but overtly malignant cases, this distinction does not need to be made by the pathologist in all cases.

  1. T-CELL LYMPHOMAS

A. Enteropathy-associated T-cell lymphoma (EATL).

While virtually any T-cell lymphoma can affect the GI tract, EATL is perhaps the most distinctive. Most cases occur in elderly individuals, many of whom have histories of malabsorption syndromes, particularly celiac disease. Clinically, the jejunum is most frequently involved, often as multiple well-circumscribed ulcers without a clinical mass lesion. Biopsies or resection specimens show lymphoid infiltrates which typically resemble a large cell lymphoma, but which may vary considerably, even within a given patient, with other areas resembling small cell lymphomas or even Hodgkin’s disease. Tumor cells commonly invade the overlying epithelium, sometimes in aggregates resembling lymphoepithelial lesions. The presence of numerous associated eosinophils, eosinophils, and other inflammatory cells related to the ulceration, together with the often polymorphous nature of the infiltrate, may mask the neoplastic nature of this disorder, which should nonetheless be suspected in this clinical setting. Most cases previously described in the literature as "ulcerative jejunitis" are now suspected of being EATLs, given some studies which have found clonal T-cell receptor gene rearrangements by PCR. Most cases have a characteristic CD3(+), CD7(+), CD4(-), CD8(-) immunophenotype. As this is also the typical immunophenotype for intestinal intraepithelial T-cells, an origin from native intraepithelial T-cells has been proposed. The tumor tends to follow an aggressive clinical course, with frequent dissemination to multiple body sites.

 

DIAGNOSTIC TROUBLE SPOTS IN GASTROINTESTINAL LYMPHOMAS

1. Distinguishing between reactive lymphoid hyperplasia and small cell lymphomas.

This has been largely discussed in the section on low grade MALT lymphoma above. While reactive lymphoid follicles can be present in virtual any gastrointestinal biopsy, the presence of an extensive dense interfollicular lymphoid infiltrate, a predominance of centrocyte-like cells (which may include monocytoid cells) in the infiltrate, deep extension of the infiltrate into the wall, and prominent destructive lymphoepithelial lesions should alert one to the possibility of a low grade MALT lymphoma. Rely on ancillary studies if available, but diagnose unequivocally only if most or all of the above features are present. Regard lesser degrees of atypical findings as suspicious for MALT lymphoma, as discussed above. A monomorphous dense lymphoid infiltrate should raise suspicion of a non-MALT lymphoma, such as mantle cell lymphoma, follicular lymphoma, or small lymphocytic lymphoma. Ancillary studies are recommended to support the diagnosis.

  1. Distinguishing between low grade MALT lymphoma and other small cell lymphomas.

This topic has also be discussed in the above sections on low grade MALT lymphoma and mantle cell lymphoma. In summary, if one is going to diagnose low grade MALToma by morphology alone, one must insist on seeing its diagnostic features in full flower. Rare or inconspicuous lymphoepithelial lesions and a cellular monomorphism in a GI lymphoma should suggest the possibility of other small cell non-Hodgkin’s lymphomas. Full immunophenotyping by frozen section immunoperoxidase or flow cytometry can be extremely useful in distinguishing these small cell lymphoproliferative disorders, given the characteristic expression of CD5 by CLL/SLL and mantle cell lymphoma, and the frequent expression of CD10 by follicular lymphoma, and may be worth a re-biopsy to obtain. Paraffin section staining can at least confirm the B-cell nature of the suspicious infiltrate, and positive staining for cyclin D1 indicates mantle cell lymphoma.

  1. Mistaking intermediate or large lymphoid cells for small cells due to poor fixation.

Poor fixation in biopsy or resection specimens can cause shrinkage artifact making intermediate size lymphoid cells (from Burkitt’s, Burkitt’s-like, and lymphoblastic lymphoma) and even large lymphoid cells appear relatively small with apparent condensed chromatin and scant cytoplasm, a situation which could lead to the mistaken diagnosis of a small cell lymphoma. Careful attention to the nuclear chromatin pattern, with comparison to the bona fide small reactive T-cells which can be found scattered in virtually all tissues, should alert one to this possibility. In addition, intermediate size and large cell lymphomas are generally aggressive neoplasm which display a higher mitotic rate and more frequent necrosis than seen in small cell lymphomas, thus the presence of frequent mitotic figures and apoptotic or karyorrhectic debris should also be taken as a warning that one is not dealing with a small cell lymphoma. The clinical setting may provide further diagnostic clues: indolent small cell lymphomas are uncommon in children and AIDS patients, while Burkitt’s lymphomas and other high grade tumors are much more commonly seen in these groups.

  1. Mistaking large cell lymphomas with other large cell malignancies

Large cell lymphoma of the gastrointestinal may resemble poorly differentiated carcinomas, melanomas, and other non-lymphoid neoplasms in the gut to the extent that it may be considered prudent to perform at least a limited panel of paraffin section immunoperoxidase stains (such as cytokeratin, LCA, and S-100) to properly categorize poorly differentiated large cell malignancies unless there is unequivocal histologic evidence of differentiation (such as gland formation in adenocarcinoma). Combining AE1/AE3 and CAM 5.2 keratins produces a cocktail which will react with virtually all epithelial tumors, and combining CD45RB (leukocyte common antigen, or LCA) with a the pan-B cell marker CD20 and pan-T cell marker CD43 can similarly produce a cocktail capable of detecting even anaplastic lymphomas which may loose LCA expression. Keep in mind that CD43 is also a sensitive marker for myeloid differentiation, and consideration should be given to the possibility of an extramedullary myeloid tumor (granulocytic sarcoma) before diagnosing a T-cell lymphoma on the basis of CD43 expression alone. For poorly differentiated tumors with a "null cell" phenotype in initial screening with a panel such as keratin/LCA/S-100, consider anaplastic lymphoma (confirm with specific B and T cell markers), plasmacytoma/myeloma (confirm with plasma cell markers such as CD38 and CD56 as well as the B-cell marker CD79a, which stains most plasma cells), and extramedullary myeloid tumor (confirm with myeloperoxidase or CAE). Note that disaggregated gastric foveolar cells in gastric MALTomas may resemble infiltrating signet ring cells of a gastric adenocarcinoma, but can generally be distinguished by their lack of significant cytologic atypia, their occurrence only in areas of dense lymphoid infiltrate, their localization to the superficial lamina propria, and other diagnostic features of MALT lymphoma present elsewhere in the specimen. Immunoperoxidase markers must always be seen as an adjunct to diagnosis, however, and never as a substitute for adequate clinical history, good specimen fixation, and good routine H&E stains.

 

References

Recent General References and Review Articles

Chan, J.K.C. Gastrointestinal lymphomas: an overview with emphasis on new findings and diagnostic problems. Semin Diagn Pathol 13: 260-296; 1996.

Isaacson, P.G. Gastrointestinal lymphoma. Hum Pathol 25: 1020-1029; 1994.

Isaacson, P.G. Recent developments in our understanding of gastric lymphomas. Am J Surg Pathol 20(Suppl 1): S1-S7; 1996.

Isaacson, P.G. The MALT lymphoma concept updated. Ann Oncol 6: 319-320; 1995.

Isaacson, P.G., and Norton, A.J. Extranodal lymphomas. New York: Churchill Livingstone, 1994.

Harris, N.L., et al. A revised European-American classification of lymphoid neoplasms: a proposal from the international lymphoma study group. Blood 84: 1361-1392; 1994.

 

B cell MALT lymphoma

Zukerberg, L.R., Ferry, J.A., Southern, J.F., and Harris, N.L. Lymphoid infiltrates of the stomach: evaluation of histologic criteria for the diagnosis of low-grade gastric lymphoma on endoscopic biopsy specimens. Am J Surg Pathol 14: 1087-1099; 1990.

Zamboni, G, Franzin, G., Scarpa, A., Bonetti, F., Pea, M., Mariuzzi, G.M., and Menestrina, F. Carcinoma-like signet-ring cells in gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Am J Surg Pathol 20: 588-598; 1996.

Wotherspoon, A.C., Doglioni, C., Diss, T.C., Pan, L., Moschini, A., de Boni, M., and Isaacson, P.G. 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.

Savio, A., Franzin, G., Wotherspoon, A.C., Zamboni, G., Negrini, R., Buffoli, F., Diss, T.C., Pan, L., and Isaacson, P.G. Diagnosis and posttreatment follow-up of Helicobacter pylori-positive gastric lymphoma of mucosa-associated lymphoid tissue: histology, polymerase chain reaction, or both? Blood 87: 1255-1260; 1996.

Cammarota, G., Tursi, A., Montalto, M., Papa, A., Branca, G., Vecchio, F.M., Renzi, C., Verzi, A., Armuzzi, A., Pretolani, S., Fedeli, G., and Gasbarrini, G. Prevention and treatment of low-grade B-cell primary gastric lymphoma by anti-H. pylori therapy. J Clin Gastroenterol 21: 118-122; 1995.

Carlson, S.J., Yokoo, H., and Vanagunas, A. Progression of gastritis to monoclonal B-cell lymphoma with resolution and recurrence following eradication of Helicobacter pylori. JAMA 275: 937-939; 1996.

Bayerdorfer, E., Neubauer, A., Rudolph, B., Thiede, C., Lehn, N., Eidt, S., and Stolte, M. Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. Lancet 345: 1591-1594; 1995.

Torlakovic, E., Cherwitz, D.L., Jessurun, J., Scholes, J., and McGlennen, R. B-cell gene rearrangement in benign and malignant lymphoid proliferations of mucosa-associated lymphoid tissue and lymph nodes. Hum Pathol 28: 166-173; 1997.

Hsi, E.D., Greenson, J.K., Singleton, T.P., Siddiqui, J., Schnitzer, B, and Ross, C.W. Detection of immunoglobulin heavy chain gene rearrangement by polymerase chain reaction in chronic active gastritis associated with Helicobacter pylori. Hum Pathol 27: 290-296; 1996.

Nakamura, S., Akazawa, K., Kinukawa, N., Takashi, Y, and Tsuneyoshi, M. Inverse correlation between the expression of bcl-2 and p53 proteins in primary gastric lymphoma. Hum Pathol 27: 225-233; 1996.

Eidt, S., Lorenzen, J., and Ortmann, M. Depth of infiltration of primary gastric B-cell lymphomas: correlations with proliferation, apoptosis and expression of p53 and bcl-2. Path Res Pract 192: 925-930; 1996.

Du, M., Peng, H., Singh, N., Isaacson, P.G., and Pan, L. The accumulation of p53 abnormalities is associated with progression on mucosa-associated lymphoid tissue lymphoma. Blood 86: 4587-4593; 1995.

Mantle cell lymphoma

Weisenburger, D.D., and Armitage, J.O. Mantle cell lymphoma: an entity comes of age. Blood 87: 4483-4494; 1996.

Moynihan, M.J., Bast, M.A., Chan, W.C., Delabie, J., Wickert, R.S., Wu, G., and Weisenberger, D.D. Lymphomatous polyposis: a neoplasm of either follicular mantle or germinal center cell origin. Am J Surg Pathol 20: 442-452; 1996.

Ruskone-Fourmestraux, A., Delmer, A., Lavergne, A., Molina, T., Brousse, N, Audouin, J., and Rambaud, J.C. Multiple lymphomatous polyposis of the gastrointestinal tract: prospective clinicopathologic study of 31 cases. Gastroenterology 112: 7-16; 1997.

Fisher, R.I., Dahlberg, S., Nathwani, B.N., Banks, P.M., Miller, T.P., and Grogan, T.M. A clinical analysis of two indolent lymphoma entities: mantle cell lymphoma and marginal zone lymphoma. Blood 85: 1075-1082; 1995.

Bosch, F., Jares, P., Campo, E., Lopez-Guillermo, A., Piris, M.A., Villamor, N., Tassies, D., Jaffe, E.S., Monserrat, E., Rozman, C., and Cardesa, A. PRAD-1/Cyclin D1 gene overexpression in chronic lymphoproliferative disorders: a highly specific marker of mantle cell lymphoma. Blood 84: 2726-2732; 1994.

Kumar, S., Krenacs, L., Otsuki, T., Kumar, D., Harris, C.A., Wellmann, A., Jaffe, E.S., and Raffeld, M. bcl-1 rearrangement and cyclin D1 protein expression in multiple lymphomatous polyposis. Am J Clin Pathol 105: 737-743; 1996.

AIDS-related lymphomas

Rotterdam, H., and Tsang, P. Gastrointestinal disease in the immunocompromised patient. Hum Pathol 25: 1123-1140; 1994.

Post-transplant lymphoproliferative disorders

Rotterdam, H., and Tsang, P. Gastrointestinal disease in the immunocompromised patient. Hum Pathol 25: 1123-1140; 1994.

Harris, N.L., Ferry, J.A., and Swerdlow, S.H. Posttransplant lymphoproliferative disorders: summary of Society for Hematopathology Workshop. Semin Diagn Pathol 14: 8-14; 1997.

Knowles, D.M., Cesarman, E., Chadburn, A., Frizzera, G., Chen, J., Rose, E.A., and Michler, R.E. Correlative morphologic and molecular genetic analysis demonstrates three distinct categories of posttransplantation lymphoproliferative disorders. Blood 85: 552-565; 1995.

Enteropathy-associated T-cell lympoma

Isaacson, P.G., O’Connor, N.T.J., and Spencer, J. Malignant histiocytosis of the intestine: a T-cell lymphoma. Lancet 2: 688-691; 1985.

Ashton-Key, M., Diss, T.C., and Isaacson, P.G. Analysis of shallow ulcers in ulcerative jejunitis and enteropathy associated T-cell lymphoma. Mod Pathol 9: 106A; 1996.