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  Table of Contents    
REVIEW ARTICLE  
Year : 2012  |  Volume : 55  |  Issue : 1  |  Page : 1-16
Lymphomas of the gastro-intestinal tract - Pathophysiology, pathology, and differential diagnosis


Department of Pathology, Duke University Medical Center, Durham, NC, USA

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Date of Web Publication11-Apr-2012
 

   Abstract 

The gastrointestinal tract (GIT) is the most commonly involved site of extranodal lymphomas. The close association between chronic inflammation and specific GIT lymphomas not only provide interesting insights into the pathobiology of lymphomas but also poses unique diagnostic challenges. A clear understanding of marginal zone and mucosa associated lymphoid tissue (MALT) in health and disease is helpful to place GIT lymphomas in proper context. A wide variety of lymphomas besides MALT lymphomas occur in various parts of the GIT. The characteristic pathological, immunophenotypic, and genetic features of different GIT lymphomas categorized according to World Health Organization (WHO) classification are presented. The epidemiological, clinical, and pathological features of lymphomas occurring in each part of the GIT are summarized and the key points regarding lymphomas at each site are emphasized. A tabular summary of the important differential diagnostic considerations at each site is given and suggestions for a minimal diagnostic work up are provided.

Keywords: Celiac disease, extra-nodal, gastro-intestinal, lymphoma, mucosa associated lymphoid tissue

How to cite this article:
Cardona DM, Layne A, Lagoo AS. Lymphomas of the gastro-intestinal tract - Pathophysiology, pathology, and differential diagnosis. Indian J Pathol Microbiol 2012;55:1-16

How to cite this URL:
Cardona DM, Layne A, Lagoo AS. Lymphomas of the gastro-intestinal tract - Pathophysiology, pathology, and differential diagnosis. Indian J Pathol Microbiol [serial online] 2012 [cited 2014 Dec 22];55:1-16. Available from: http://www.ijpmonline.org/text.asp?2012/55/1/1/94847



   Introduction Top


The incidence of lymphoma has more than doubled in the past four decades and continues to increase. [1] Primary extranodal lymphomas constitute up to one third of all lymphomas, [2] and the gastrointestinal tract (GIT) is the commonest extranodal site of involvement by non-Hodgkin lymphomas in immunocompetent persons [3] and second only to central nervous system (CNS) lymphomas in human immunodeficiency virus-acquired immune deficiency syndrome (HIV-AIDS) patients. [4] GIT lymphomas together constitute 10-15% of all non-Hodgkin lymphomas and 30-40% of all extranodal lymphomas. [3],[5] Since the introduction of the revised European and American Lymphoma (REAL) classification [6] and its successor, the World Health Organization (WHO) classification of lymphomas, [7] it is widely accepted that different lymphomas are not merely morphological variations of one disease but constitute individual diseases with diverse clinical behaviors. [8] The modern lymphoma classification is based on morphological, immunophenotypic, genetic, and clinical features. Making the correct diagnosis, according to the WHO classification, is critical because treatments can vary widely from a simple "wait and watch" approach to local radiation or surgery to high dose chemotherapy with or without stem cell transplantation.

Fiberoptic endoscopy of the GIT has dramatically increased the number and variety of biopsies submitted for pathological examination of suspected lymphoma, but surgically removed specimens are also received, usually when the diagnosis of lymphoma is not suspected preoperatively. GIT lymphomas can be associated with chronic inflammation, which can pose diagnostic difficulties but also forms the basis of our understanding of mucosa associated lymphoid tissue (MALT) lymphomas. [9],[10] While chronic gastritis due to Helicobacter pylori is the best studied precursor of MALT lymphoma, other parts of the GIT demonstrate precursor inflammatory lesions that lead to specific types of lymphoma. While MALT lymphomas are most common, nearly all types of lymphomas described in the current WHO classification system [11] may occur in the GIT. The diagnostic difficulties for GIT lymphomas are compounded by the fact that often only small biopsies are available for examination and the morphology of a particular type of lymphoma may differ in the GIT compared to the lymph node. Several large series describing the epidemiological and clinicopathological features of primary GIT lymphomas have been published, [12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22] including a recent retrospective study from India. [23] The advent of wireless capsule endoscopy and double balloon enteroscopy have made previously inaccessible portions of GITs visible and changed our perceptions about some types of GIT lymphomas. [24] Finally, the increasing number of immunosuppressed patients (either due to HIV or iatrogenic) is associated with increasing incidence of some types of GIT lymphomas which were very rarely seen before. [25],[26],[27],[28],[29]

In this review, we first briefly outline the normal components of lymphoid tissue in the GIT, clarify the relationship between normal and abnormal MALT and between marginal zone lymphomas and MALT lymphomas. The identifying features of the major types of GIT lymphomas are summarized. Next, we describe the epidemiological and clinicopathological features of lymphomas in different parts of the GIT. Differential diagnoses of lymphoid proliferations involving each part of GIT are also presented and the morphological and immunohistochemical features useful in distinguishing reactive from malignant infiltrates are emphasized.


   Mucosa Associate Lymphoid Tissue in The Git Top


The amount and nature of lymphoid tissue varies greatly within the GIT, thus influencing the type of lymphomas developing in each part. The character of these lymphoid tissues is determined by innate genetic factors and acquired immune stimulation, often directed by exposure to the innumerable dietary and microbial antigens and inflammatory responses. [30],[31],[32],[33] The normal esophagus essentially has no lymphoid tissue associated with the mucosa. [34] Likewise, B-lymphocytes, plasma cells, and granulocytes are almost completely absent in the stomach. A few CD8+ T-cells are present in intraepithelial locations and CD4+ T-cells are localized mainly in the lamina propria of stomach, accompanied by macrophages and very few CD1-positive Langerhans' cells. [35] In contrast, the intestines contain a large amount of lymphoid tissue, concentrated in the mucosa and submucosa, which is collectively referred to as mucosa associated lymphoid tissue or MALT. MALT, depending on the anatomical site, is called GALT (GIT associated lymphoid tissue), BALT (Bronchus), NALT (Nasopharyngeal), etc.

Intestinal MALT is the primary site for eliciting adaptive immune responses towards mucosal antigens and can be divided into three components. Most well-known among these are the organized lymphoid aggregates called Peyer's patches, which first appear during 19 th week of gestation on the antimesenteric border of the entire small intestine starting at the upper jejunum. Their numbers appear to be predetermined but their size steadily increases until puberty, followed by gradual involution in old age. They resemble miniature lymph nodes and contain both B- and T-cells, segregated in the follicles and interfollicular areas, respectively. Lacking afferent lymphatics, luminal antigens are carried to the Peyer's patches through specialized epithelial cells called M cells, present in the intestinal lining covering the dome region of the patch, and at least three types of dendritic cells. Structures closely related to Peyer's patches but containing only an isolated lymphoid follicle (ILF) develop after exposure to intestinal commensals and are particularly numerous in the colon, which lacks Peyer's patches. [33] Efferent lymphatics from the Peyer's patches carry memory B-cells and plasma cells to mesenteric lymph nodes and hematogenous lymphocytes traffic through MALT by virtue of specific adhesion molecules called addressins.

Two components of intestinal MALT are present more diffusely in the mucosa. Firstly, lamina propria immune cells are a heterogeneous collection of antigen presenting macrophages and dendritic cells, antibody producing plasma cells and helper T-cells. Few eosinophils and mast cells are also present, particularly in the small intestine. [36] Secondly, intra-epithelial lymphocytes are predominantly cytotoxic T-cells, present diffusely in low numbers throughout the intestines, with somewhat higher proportions in small intestines. [37],[38],[39] Distinct types of lymphomas arise from the three components of intestinal MALT and recapitulate the structure and function of the cells of origin to a variable degree.

"MALT" and Marginal Zone in Health and Disease

The unifying category of "extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)" was proposed over two decades ago. [40],[41],[42] It has helped to correctly classify and study the biology of extranodal lymphomas in diverse sites. The marginal zone is typically most prominent within mesenteric lymph nodes and the spleen, depicted as a rim of pale staining B-cells that lie outside the dark staining mantle zone of the lymphoid follicles. These "monocytoid" B-cells have abundant weakly eosinophilic or clear cytoplasm and a small, slightly cleaved nucleus. The marginal zone cells are predominantly post-germinal center, memory B-cells. [43] Chronic inflammation in mucosal sites or glandular tissue often shows features resembling normal marginal zone around reactive follicles. This "induced" MALT may further evolve into a MALT lymphoma. [44],[45] Thus, paradoxically MALT lymphomas occur more commonly in organs which do not normally show prominent MALT.

Three types of marginal zone lymphomas (MZLs) are described in the WHO classification - Nodal, Splenic, and extranodal MALT type. [46],[47],[48] In all three types of MZL, the monocytoid B-cells initially surround, and later colonize and replace, reactive follicles. Variable numbers of large transformed cells, plasmacytoid cells and plasma cells are seen. Except a few cases of nodal and splenic MZL in which the lymphoma cells may have CD5 and/ or CD23 expression, in almost all cases of MZL, the lymphoma cells are negative for CD5, CD10, CD23, CD103, and Cyclin D1, thus ruling out mantle cell lymphoma, small lymphocytic lymphoma, follicular lymphoma, and hairy cell leukemia. In spite of these similarities, response to treatment and prognosis vary: Splenic MZL responds well to splenectomy and MALT lymphomas (at least in initial stages) to local surgical or radiation therapy with long term survival. Nodal MZL behaves as an indolent lymphoma that is essentially incurable with standard chemotherapy.

At an early stage of development of MALT lymphoma, oligoclonal B-cell populations can be detected by molecular methods of immunoglobulin heavy chain analysis. [49] Eventually, one of these clones become dominant and subsequently become independent of the antigenic stimulation. [50] However, even after the detection of a monoclonal population, eradication of the inciting inflammatory stimulus can lead to complete regression of the "lymphoma" in a large proportion of cases. [51],[52]

MALT lymphomas were first described as a consequence of chronic gastritis due to Helicobacter pylori infection. [9],[44],[45] Worldwide, H. pylori infection is common, and up to 20% of infected individuals have symptoms of gastritis, but only a very small fraction, probably less than 0.1%, develop gastric carcinoma or lymphoma. [53] MALT lymphomas associated with chronic autoimmune thyroiditis and chronic sialadenitis represent examples of non-infectious chronic inflammatory etiology of these lymphomas. MALT lymphomas have been described in practically every site of the body, often without an underlying chronic inflammatory process. Many of these conditions were previously referred to as "pseudolymphomas" or "lymphoid pseudotumors" due to the polymorphous nature of the infiltrate and the indolent nature of the process. More recently, specific cytogenetic abnormalities have been documented in MALT lymphomas [54],[55],[56] and generally indicate further evolution of the disease in which eradicating the underlying inflammatory etiology is no longer curative. [51],[52],[55],[56],[57],[58],[59]


   Who Classification of Lymphomas Top


Like all earlier classifications, the WHO classification recognizes the fundamental distinction between Hodgkin lymphomas and Non-Hodgkin lymphomas (NHL) [11] with basic differences in the biology of these diseases. [60] Hodgkin lymphoma in extranodal sites, including GIT, is exceedingly rare. Non-Hodgkin Lymphomas comprise several entities broadly classified as B-cell or T-cell processes, with each group being further sub-classified as precursor cell or mature cell lymphomas. Many lymphoid neoplasms can present either as a mass lesion (lymphoma) or as circulating cells (leukemia) in different patients or in the same patient over the course of the disease. In the context of primary GIT disease, a mass lesion ("lymphoma") will be expected. B-cell lymphomas constitute the vast majority of lymphomas in the Western hemisphere (>80%) and at a lower frequency in the far East (about 60%), with Indian incidence being intermediate. [61] B-cell lymphomas generally respond better to current chemotherapy than T-cell lymphomas and have a better prognosis. [62],[63] The precursor B-cell or T-cell lymphoblastic lymphomas, Burkitt lymphoma, and large B-cell lymphomas are aggressive and highly proliferative while those with small cells are usually indolent. There are, however, important exceptions such as mantle cell lymphoma (MCL) and T-cell lymphomas, in which the behavior does not correlate with the cell size. In addition to characteristic cell morphology, many lymphomas also demonstrate fairly typical architectural features which are useful in diagnosis. Specific cytogenetic abnormalities are seen in many lymphomas and appear to influence their behavior to a great extent. The distinguishing clinicopathological features of the major types of lymphomas occurring in the GIT are summarized in [Table 1].
Table 1: Morphology, immunophenotype, cytogenetics, and clinical behavior of major WHO subtypes of lymphomas seen in the GIT

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   Lymphomas and Lymphoma Mimics in Different Parts of Git Top


[Table 2] lists the major epidemiological, clinical, and pathological features of primary lymphomas occurring in different GIT sites. [12],[14],[15],[16],[17],[18],[19],[20],[21],[22],[64],[65],[66] Primary lymphomas of the stomach are the commonest among all GIT sites, followed by the small and large intestines. Because epithelial malignancies are rare in the small intestine, lymphomas constitute a high proportion of all malignancies at this GIT site. Ileocecal junction is commonly involved by intestinal lymphomas and involvement of the appendix and anorectum is not uncommon, but the esophagus is rarely involved. [14],[67] The two most important determinants of prognosis in GIT lymphomas are the specific type of lymphoma and stage of disease. Staging of GIT lymphomas is performed either according to the Ann Arbor staging System or the Paris (TNM) staging system. [Table 3] gives the definition of each stage in the two systems. The important differential diagnoses for lesions resembling lymphomas in various GIT sites are given in [Table 4]. [68],[69],[70],[71],[72],[73],[74],[75],[76],[77],[78],[79],[80],[81],[82],[83],[84],[85],[86] Some key points concerning lymphomas from different GIT sites are briefly discussed below.
Table 2: Clinicopathological features of lymphomas of occurring in different sites in the GIT

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Table 3: Staging systems for gastrointestinal lymphomas[93]

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Table 4: Differential diagnoses by site

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Esophagus

Most esophageal lymphomas are due to secondary involvement from other sites and <50 cases of primary esophageal lymphomas have been reported in the literature. [64],[87],[88],[89],[90] Non-lymphoid malignancy [Figure 1] or systemic lymphoma should be ruled out before making a diagnosis of primary esophageal lymphoma. Patients may present with dysphagia, weight loss, or even hoarseness of voice. Esophageal perforation or tracheoesophageal fistula has been noted, primarily in cases of secondary involvement. Lymphomas are not distinguishable by endoscopy from esophageal carcinoma as both can produce ulcers, submucosal raised plaques, or polypoid or circumferential lesions, and biopsy is essential for correct diagnosis. Primary esophageal lymphomas are overwhelmingly B-cell neoplasms, with MALT lymphomas and diffuse large B-cell lymphoma (DLBCL) being most common, but T-cell lymphomas and primary esophageal Hodgkin lymphomas have also been reported. [87],[91] About 11% of lymphomas involving the esophagus secondary to spread from other sites are Hodgkin lymphomas. [67] These reported patients with primary esophageal lymphomas were in their forties through eighties and most were successfully treated by radiation and/or chemotherapy, except those cases occurring in HIV positive patients who had a rapidly fatal outcome. [92]
Figure 1: Mimic of DLBCL- High grade neuroendocrine carcinoma of the esophagus. (a) Epithelioid, discohesive cells with moderate cytoplasm, uniform cytology and a background of lymphocytic inflammation. Scattered areas of increased mitotic activity are seen. H and E, ×20; (b) and (c) Immunohistochemical staining revealed this monotonous population was pancytokeratin negative (not shown), CD45 negative but strong and diffusely synaptophysin and CD56 (not shown) positive. (b - ×20, C - ×20)

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Stomach

This is the most common GIT site involved by lymphoma, with two types accounting for >85% of primary gastric lymphomas- Marginal zone lymphoma of MALT type (MALT lymphoma), and DLBCL. Two points need special attention - (1) Differentiating chronic gastritis and MALT lymphoma in cases with a dense lymphoid infiltrate of small to medium sized cells; and (2) Evaluating the significance of large cells in gastric B-cell lymphomas.

MALT Lymphoma and Chronic Gastritis

A recent consensus report by the European Gastrointestinal Lymphoma study group provides important guidelines for the histologic diagnosis and utility of ancillary studies such as PCR and FISH [93] and a practical approach to diagnosis is presented in a recent review. [94] Histologically and biologically, there is a continuum from acute to chronic gastritis to gastric MALT lymphoma. During diagnostic endoscopy, at least 10 biopsies from grossly visible lesions and from uninvolved mucosa should be obtained. The histological criteria proposed by Wotherspoon et al[95] have been used to grade the lymphoid infiltrate on a scale from 0 to 5 [Table 5]. In practice, grades 2, 3, and 4 lesions may not be easy to distinguish from each other and from MALT lymphoma. Reactive lymphoid follicles are present in chronic gastritis [Figure 2], but the presence of a dense, ill-defined infiltrate of monotonous B-cells (seen on immunohistochemical stain such as CD20) extending away from lymphoid follicles [Figure 3], the presence of cytological atypia, the finding of Dutcher bodies in the plasma cells and the presence of lymphoepithelial lesions favor a diagnosis of MALT lymphoma over chronic gastritis. Positive immunoreactivity for CD43 is seen in about half of MALT lymphomas but not in benign/reactive processes. However, other small B-cell lymphomas (SLL, mantle cell lymphoma) may also express CD43. Additional immunostains (at a minimum CD10, CD5, and Cyclin D1) are invaluable to allow this clinically important distinction. Demonstration of clonal B-cells by molecular methods may be helpful in doubtful cases, but in otherwise typical cases it is not a prerequisite for diagnosis. On the other hand, staining for H. pylori (histochemical or immunohistochemical) and FISH for t(11;18) abnormality involving the API/MALT-1 loci is recommended at diagnosis. Irrespective of the presence or absence of demonstrable H. pylori organisms in the lesions, all cases of gastric MALT lymphoma can be initially treated with antibiotics but staging must be completed before starting antibiotic therapy. Overall, about 75% respond to antibiotics alone compared with <20% response rate in H. pylori negative cases and in those with t(11;18). Only patients whose lymphomas do not regress after complete H. pylori eradication require either radiation or systemic chemotherapy. Surgery is restricted to the treatment of rare complications such as perforation or uncontrolled bleeding. Endoscopic follow-up with biopsies and histological examination is mandatory. PCR based studies for B-cell clonality should not be repeated on the post treatment biopsies if there is clinical and histological evidence of lymphoma regression, because positive PCR results are seen in a high proportion of lymphoma free patients.
Figure 2: Chronic active gastritis with prominent secondary follicle formation. The lymphoid aggregate is still relatively small and appears contained to the mucosa. There is no lymphoepithelial lesion or significant architectural distortion associated with the inflammation. H and E, ×10. H. pylori organisms are seen on IHC (inset, ×40)

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Figure 3: MALT Lymphoma of Stomach: Compared to chronic gastritis, the lymphoid infiltrate in MALT lymphoma extends deeper into the lamina propria (a, H and E, ×20). Immunohistochemistry for CD20 shows many B-cells (b, ×10), and contains lymphoepithelial lesions in which neoplastic B-cells infiltrate and eventually overrun epithelial structures (c, CD20, ×40)

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Table 5: Wotherspoon / WHO histological scoring for diagnosis of gastric MALT lymphoma

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Large Cells in Gastric B-cell Lymphomas

In hematopathology, a large lymphoid cell is by definition larger than the nucleus of a histiocyte. This "internal yardstick" is helpful to avoid incorrect assessment due to swelling of cells. MALT lymphomas typically contain a mixture of large and small lymphoid cells, but presence of up to 10% large cells dispersed throughout does not change the outcome. [96] The WHO classification does not recommend categorization as "high grade MALT lymphoma" for cases with higher number of large cells mixed with small cells. However, when large cells are present in confluent sheets or clusters with other areas showing typical MALT lymphoma morphology, the diagnosis should be "DLBCL associated with MALT lymphoma [Figure 4]. [97] In stage I or II gastric lymphomas, DLBCL with associated low grade MALT component appear to have a better outcome than DLBCL without associated MALT component, [96] prolonging the event free survival but not necessarily the overall survival. [20] De novo DLBCL is also not uncommon in the stomach.
Figure 4: Diffuse Large B-cell Lymphoma, Stomach: (a, b) - Confluent collections of large cells indicate a large cell lymphoma. Evidence of an underlying MALT lymphoma is seen in this case as lymphoepithelial lesions (c, arrows) and presence of a polymorphous infiltrate including plasma cells (d arrows). H and E, A - ×4, B-D - ×40.

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Small Intestine

As described in an earlier section, small intestine has abundant mucosal lymphoid tissue which contains both B- and T-cells and lymphomas of both cell types occur in this location. Reactive lymphohistiocytic infiltrate due to infections can occur and mimic Hodgkin lymphoma in immunocompromised patients [Figure 5]. The commonest lymphoma in adults is DLBCL, but in children Burkitt lymphoma is the commonest type. Some lymphomas are rather unique to the small intestine or have unique features when they occur in this GIT site.
Figure 5: Mycobacterium avium-intracellulare (MAI) infection. The lamina propria is expanded by a predominantly lymphohistiocytic infiltrate. There is mild villous blunting and minimal intraepithelial lymphocytes. No significant crypt injury/destruction is present. (H and E, ×10). Acid Fast stain highlights the numerous microorganisms (inset; ×40)

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Lymphomas associated with chronic antigenic stimulation: The biology of these lymphomas in the small intestine is more complex than H. pylori associated gastric MALT lymphoma. Both B- and T-cell lymphomas can be "induced" under appropriate conditions of antigenic stimulation. Immunoproliferative small intestinal disease (IPSID) or alpha chain disease belongs to the same group of lymphomas as H. pylori associated gastric MALT lymphoma but there are important differences. [98],[99] IPSID is quite rare compared to gastric MALT lymphoma and its etiological connection to infection with Campylobactor jenuni is not completely clear. IPSID is a disease of young adult males which tends to occur in geographically restricted regions around the Mediterranean sea but may be seen elsewhere, including India. [23] Most patients present with abdominal pain and diarrhea and endoscopic examination shows involvement of duodenum by polypoid or flat lesions. Histopathologic findings include blunting or flattening of villi with a predominance of atypical plasma cells in the lamina propria. Molecular studies show production of abnormal alpha chains which cannot assemble the complete Ig molecule with light chains due to deletions in V H1 or C H region. Some patients in the early stages may respond completely to antibiotic therapy but others progress to DLBCL, which often has a fatal outcome.

A rare T-cell lymphoma called enteropathy associated T-cell lymphoma (EATL) occurs either as a late complication of chronic celiac disease or de novo. It accounts for 1.4% of all lymphomas [100] and 5.4% of peripheral T cell lymphomas. [101] Two types are recognized, type I and II [Figure 6]. The abnormal T-cells in both types of EATL have identical immunophenotype (CD3+, CD5-, CD7+, CD103+, CD4-, CD8-/+, CD56+, cytotoxic molecules+), but the T-cells are more pleomorphic and larger in type I and uniform and small in type II. Type I is more frequent than type II and is more often associated with chronic celiac disease. The median age at diagnosis is about 60 years in both types and males are affected more frequently. Early diagnosis of type I disease is challenging because 90% occur in jejunum and ileum, which is not accessible by routine endoscopy. [101] All biopsies from suspected or established celiac disease patients should be carefully examined to exclude development of lymphoma [Figure 7]. Once established, the prognosis in both types of EATL is dismal. Fortunately, the risk of EATL type I can be substantially reduced by eliminating all exposure to the offending antigen (gluten) in patients with celiac disease. If the celiac disease reaches a refractory stage (defined as persistent or recurrent symptoms, positive celiac disease-specific serology, villous atrophy after 6 to 12 months on a gluten free diet and exclusion of other etiologies, [75] clonal T-cells may be detected even when overt mass lesions of lymphoma are not seen. In EATL type II, it may be impossible to reach the correct diagnosis without appropriate immunohistochemical stains, because the morphology closely resembles mantle cell lymphoma.
Figure 6: Enteropathy associated T-cell Lymphoma (EATL) type II: The Uniform small cells in this lymphoma closely mimic cells of mantle cell lymphoma. (a, b - HandE, ×4 and ×40, respectively). Immunohistochemistry shows the lymphoma cells are positive for CD3+ (c, ×20), but negative for CD5 (d, ×20). They are CD7 positive (not shown), CD8 positive (e, ×20) and show cytoplasmic granular staining for Granzyme B (F, ×40)

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Figure 7: Celiac Disease with marked villous blunting, mild crypt hyperplasia and numerous IELs (inset). The lamina propria inflammation is predominantly plasmacytic in nature with scattered eosinophils. No crypt injury/destruction or significant distortion of the normal gland distribution is noted. (H and E, ×20 and inset ×40)

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Intestinal Follicular Lymphoma

This entity is recognized as a variant of follicular lymphoma in the 2008 edition of WHO classification. A comprehensive recent review [24] and single center case series [102] show that this lymphoma is similar to node based follicular lymphoma with regard to morphology and immunophenotype (CD10+, BCL6+, BCL2+), but has a superior prognosis compared to nodal disease. It is often detected as an incidental polyp or plaque in the duodenum [Figure 8] or terminal ileum during endoscopy, but more advanced technics such as double balloon endoscopy or capsule endoscopy shows multifocal involvement of the entire small intestine in many cases. Nevertheless, a majority of patients may not require specific treatment.
Figure 8: Follicular Lymphoma - Duodenum was considered the usual site of involvement by follicular lympoma, but may occur anywhere along the GIT. The follicular architecture is variably prominent on HandE staining (a, H and E). Immunohistochemical stains show the follicle centers are positive for CD10 (b) and BCL6 (c), which confirm the follicular center origin of the lymphoma. In addition BCL2 positive staining (not shown) confirms the malignant nature of the follicles. (Note: Reactive follicles in MALT lymphoma are negative for BCL2, unless colonized by the lymphoma cells. However, in this case the lymphoma cells are CD10-, BCL6 ± ). (A-C, ×10)

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Burkitt Lymphoma

The WHO criteria for Burkitt lymphoma include demonstration of a translocation involving MYC oncogene on chromosome 8 with one of the immunoglobulin genes (2, 14 or 22, involving kappa, IgH, and lambda, respectively) in small to medium, uniform B-cells which express CD10 and BCL6 and surface immunoglobulin but lack expression of BCL2 and TdT. The proliferation fraction, as measured by Ki67 immunostaining, is 99% or higher. The category of Burkitt-like lymphoma is usually defined as a lymphoma with features intermediate between Burkitt lymphoma and diffuse large B-cell lymphoma. The immunophenotype is similar to Burkitt lymphoma, but some cases are BCL2 positive and the cell morphology is less uniform and resembles DLBCL. Furthermore, the cytogenetic abnormalities may involve both MYC and BCL2 or BCL6 genes. These lymphomas are sometimes referred to as "Grey zone lymphoma" period is missing. In non-endemic areas, Burkitt lymphoma commonly affects the abdominal organs, with the ileocecal region being the most commonly affected GI site. In adults, abdominal lymph nodes may be affected more frequently and/ or more severely. The characteristic morphology (diffuse proliferation of uniform, small non-cleaved cells with cytoplasmic vacuoles and a starry sky appearance) must be accompanied by the translocation involving MYC and immunoglobulin gene for a diagnosis of BL. Because BL specific aggressive chemotherapy protocols offer a chance of cure, whereas routine chemotherapy such as CHOP used for DLBCL is usually associated with suboptimal response, every effort should be made to provide the accurate diagnosis.

Large Intestine

Almost all primary colorectal lymphomas reported from the West have B-cell lineage, but rare T-cell lymphomas are reported in the East. DLBCL is the single most common lymphoma in the large intestine, but other B-cell lymphomas, including mantle cell lymphoma [Figure 9], MALT lymphoma, and follicular lymhoma can be seen in the colon. While MALT lymphomas are relatively uncommon in large intestine, DLBCLs may show a low grade component in a minority of cases. [18],[65],[103] In immunocompetent patients the cecum is involved most often but in immunodeficient patients, the rectum (and anal canal) is likely to be involved.
Figure 9: Mantle Cell Lymphoma: (a) Involvement by mantle cell lymphoma is often multifocal and may be subtle as in this case or produce the better known "lymphomatoid polyposis; (b) Nuclear staining of variable intensity with Cyclin D1 is characteristic. Note, the normal pattern of Cyclin D1 staining in nuclei of lining epithelial cells. (a - ×20, b - ×40)

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Anorectum

Most lymphomas in this location are encountered in immunodeficient patients, particularly those suffering from HIV/AIDS. Some uncommon variants of large B-cell lymphoma are seen in this population. Their diagnosis may be challenging due to their atypical morphology and immunophenotype. Plasmablastic lymphomas and extra-cavitary variant of primary effusion lymphoma deserve special mention. The former is most commonly seen in the oral cavity of chronically HIV infected patients but can occur in other parts of the GIT including the ano-rectal region [26] and a majority of cases are associated with EBV [Figure 10]. On the other hand, primary effusion lymphoma is associated with HHV8 (or Kaposi Sarcoma herpes virus, KSHV) and often presents as pleural effusions but can occur as a solid tumor. [104],[105] KSHV may be seen in a relatively high proportion of aggressive B-cell lymphomas in HIV patients [106] and all morphological and immunophenotypic characteristics should be considered for appropriate diagnosis. A plasmacytoid morphology or an immunophenotype that is closer to plasma cells than to B-cells is observed in these lymphomas as both lymphomas often lack expression of pan B-cell antigen CD20 and PAX5, but often express CD79a and always express MUM1, CD38 and CD138. Distinction of these lymphomas from plasmablastic myeloma may be difficult, but is important for correct treatment. Marked reactive lymphoid hyperplasia may produce localized masses referred to as "Anorectal Tonsils" [Figure 11] and must be distinguished from low grade lymphomas.
Figure 10: Plasmablastic Lymphoma: This aggressive variant of diffuse large B-cell lymphoma usually occurs in the oral cavity of HIV positive patients, but can also be seen in patients with iatrogenic immunosuppression, such as in post transplant patients. Anorectal location has been noted, but other parts of the GIT such as the small intestine, as in this case, can be involved. (HandE. a - ×10, b - ×60). The immunophenotype can be perplexing. The lymphoma cells do not express CD20 (c) or CD79a, but are CD45+, CD138+ (d), and cytoplasmic light chain+. EBV early RNA is strongly expressed (e), but EBV LMP and EBNA2 immunostains are typically negative (not shown). (c - ×40, d, E - ×20)

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Figure 11: Anorectal tonsils with marked lymphoid hyperplasia. The epithelium is mildly distorted, but there is no significant glandular injury/ destruction or LELs. The lymphocytes are predominantly small in size (inset). Nodular areas suggestive of germinal centers and with tingible body macrophages are present. (H and E, ×4). By immunohistochemisttry, these follicle centers are CD20+ (b, ×4) and CD3 negative (c, ×4)

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   Diagnostic Approach for Suspected Git Lymphomas Top


In every case of GIT lymphoma, the goal is to provide a diagnosis according to the WHO classification so that the correct treatment can be given. Detailed algorithms or practical guide to diagnosis with relatively modest ancillary techniques have been published [36],[97] but must be adopted for the individual practice situation. A judicious use of immunohistochemistry can provide a great deal of information with relatively low cost. Generous sampling during endoscopy, prompt fixation, and optimal processing are required to produce consistently high quality H&E sections, which must form the basis for decisions about additional ancillary testing. In general, diffuse large B-cell lymphomas, which form the largest single type of GIT lymphomas, are unlikely to be mistaken for a benign process but may mimic non lymphoma entities. Immunohistochemical staining for CD20 may be sufficient to arrive at the correct diagnosis in most of these cases. Staining with CD45, CD138, pancytokeratin and S-100 antibodies is robust and usually reliable in cases of acute leukemia, plasma cell neoplasm, poorly differentiated carcinoma and melanoma, respectively. The infiltrates composed of small or mixed lymphoid cells prove most challenging as do the presence of lymphoid follicles. The pathologist should be familiar with the characteristics of reactive follicles (presence of zonation, tingible body macrophages, and complete mantle zones), but BCL2 immunohistochemistry may be required to make the distinction between reactive and neoplastic follicles and follicular colonization by mantle zone or marginal zone lymphoma cells. Non lymphoid processes such as systemic mastocytosis and Langerhans' histiocytosis can be distinguished with CD117 and CD1a immunostains, respectively.

The clinical context is extremely important in deciding which ancillary tests are required. Because most chronic gastritis and gastric MALT lymphoma patients are initially treated with antibiotics, the exact distinction may not be necessary. Demonstrating the proportion of B-cells with one or two immunostains may be adequate. On the other hand, distinction between mantle cell lymphoma, EATL type II and other reactive small lymphocytic infiltrates is crucial and Cyclin D1 staining should be included in any GIT lymphoma composed of small cells. Clinical correlation is essential in every case of suspected lymphoma and GIT lymphomas are no exception. In particular, the distinction between primary GIT lymphoma and secondary involvement of GIT by lymphoma cannot be performed on the basis of pathological examination alone. The prognosis for primary and secondary GIT lymphoma of the same WHO type may be entirely different. The presence of HIV infection or other causes of immunodeficiency (for example, post-transplant status) should be noted because of the possibility of unusual types of lymphomas and the vastly inferior prognosis in the usual types.

In summary, GIT lymphomas are common extranodal lymphomas occurring in all age groups. Accurate diagnosis of the type of lymphoma is vitally important for correct treatment and determining prognosis. The close connection between chronic inflammation in GIT and lymphoma has shed much light on the growth and natural history of thee lymphomas.[112]

 
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Correspondence Address:
Anand S Lagoo
Department of Pathology, Duke University Medical Center, Box 3712 DUMC, Durham, NC 27710
USA
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DOI: 10.4103/0377-4929.94847

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