Gastrointestinal lymphoma

Gastrointestinal Lymphoma PETER G. ISAACSON,

DM, DSc, FRCPATH

Primary gastrointestinal lymphoma comprises a group of distinctive clinicopathological entities, most of which are not included in current lymph node-based

lymphoma classifications. They may be of B- or

T-cell type, with primary gastrointestinal Hodgws tremely uncommon.

disease being ex-

Most low grade B-cell gastrointestinal lympho-

Middle arise in sch. In mas are

East most primary gastrointestinal lymphomas the small intestine, closely followed by the stonboth areas esophageal and colorectal lymphovery rare.

mas are of mucosa-associated lymphoid tissue (MALT) type, so called because they recapitulate the features of MALT rather than those of lymph nodes. Paradoxically, however, most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. These gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacterfylori

B-CELL GASTROINTESTINAL LYMPHOMA AND MUCOSA-ASSOCIATED LYMPHOID TISSUE: THE MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA CONCEPT

and their growth can be influenced by eradication of this organism from the stomach. Low grade MALT lymphomas, which usually have a very favorable clinical course, may undergo high grade transformation; high grade tumours also may arise de nova and these probably also belong to the MALT group. Immunoproliferative small intestinal disease (IPSlD) is a special form of MALT lymphoma with a restricted geographic distribution, which is characterized by synthesis of alpha heavy-chain hnmunoglobulin.

Other gastrointestinal B-cell lympho-

mas include mantle cell lymphoma, which presents as lymphomatous polyposis, and Burkitt’s or Burkitt-like lymphoma. Enteropathy (celiac disease)-associated

T-cell lymphoma

(EATL) is the most common

primary gastrointestinal T-cell lymphoma. This is a clinically aggressive tumor that arises from the intraepitbelial T-cell population, which is increased in celiac disease. HUM PATHOL 6 1994 by W.B. Saunders

25:1020-

1029. Copyright

Company

Gastrointestinal lymphomas, the most common exare almost exclusively of no11tranodal lymphomas,’ Hodgkin’s type, with primary gastrointestinal Hodgkin’s disease being extremely rare. There is marked geographic variation in the incidence of primary gastrointestinal lymphoma with a very high incidence in the Middle East’ and pockets of high incidence in western Europe.‘3 Because nodal lymphoma often involves the gastrointestinal tract,’ strict criteria for the diagnosis of primary gastrointestinal lymphoma are required. The criteria proposed by Dawson et al’ in 1961 require that the lymphoma is limited to the gastrointestinal tract and its contiguous lymph nodes but do JIOI take into account modern staging procedures that can detect small foci of disease elsewhere. Thus, a satisfactory operational definition is that the lymphoma has presented with the main bulk of disease in the gastrointestinal tract, necessitating direction of treatment to that site. The stomach is the most common site of primary gastrointestinal lymphoma in western countries, but in the From rhc I)epar-trrlcnt tlon

Medical

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HistopattlotcyI. UK.

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for- publication

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In the early 1SXOs Isaacson and Wright”,7 noted that the histology of certain low grade B-cell gastrointestinal lymphomas was unlike that of comparable low grade nodal lymphomas but, instead, was similar to that of mucosa-associated lymphoid tissue (MALT). The morphological and clinical homogeneity of these lymphomas was thought to reflect their origin from MALT. Unlike nodal low grade B-cell lymphomas, MALT lymphomas tend to remain localized and seldom involve the bone marrow. Low grade MAI,T lymphoma may undergo high grade transformation and residual low grade foci are often observed in apparently primary high grade MALT lymphomas. Paradoxically, there is normally no lymphoid tissue the most common site of MALT in the stomach,” lymphoma, and the other sites where MALT lymphomas arise, such as the salivarygland”and thyroid.“‘However, in the salivary gland and thyroid lymphoma always is preceded by myoepithelial sialadenitis (Sjogren’s syndrome) and Hashimoto’s thyroiditis, respectively.“’ The lymphoid tissue that accumulates in these two autoimmune conditions shows the features of MALT as typified by Peyer’s patches. In the stomach MAI.T accumulates after Hdicohnctm fylori infection,‘~” partly as a result of various autoimmune proct3ses, I” and it is from this socalled acquired MALT that lymphoma may arise.

THE CLASSIFICATION OF PRIMARY GASTROINTESTINAL LYMPHOMA Theoretically. with the exception of cutaneous cerehriform T-cell lymphoma, any of the lymphomas listed in current classifications of non-Hodgkin’s lymphomas may arise in the gastrointestinal tract. However, such cases are the exception and most primary gastrointestinal lymphomas are distinctive entities that do not feature in any current lymphoma classification. A classification of primary gastrointestinal lymphomas is shown in Table 1. B-cell lymphomas of MALT type are the most COIIImon lymphomas and may he high or low grade. When low grade MALT lymphomas transform to high grade tumors they lose most of their histological hallmarks and, unless there are residual foci of low grddr disease, it becomes problematic whether a high grade B-cell

GASTROINTESTINAL

LYMPHOMA

TABLE 1. Primary Gastrointestinal Non-Hodgkin’s Lymphoma

(Peter G. Isaacson)

ohserved in MALI” (Fig 1A). (iastric MAI,1’ lvmphomas arise from this acquired ~cIALT and, accordingly, I-f jqkri can he fomnd in almost all cases.” I,ow grade B-cell gastric lymphoma occurs predominantly in the elderly, but cases have heen reported in younger patients. The clinical presentahon suggests a diagnosis of gastritis or peptic ulcer disease rather than a neoplasm. Pathology

‘I‘ CC.11

lymphoma of the gut is of MAI.T type or not. However, there is accumulating evidence of immunophenotypic”’ and mol[ecular genetic’ ’ differences between high grade B-cell lymphomas of MALT and nodal types. Immunoproliferative small intestinal disease (IPSID) is a subtype of MALT lymphoma” distinguished by its epidemiology and the synthesis of an abnormal alpha l’eavy chain. Burkitt’s or Burkitt-like lymphoma is an especiall) common rimary small intestinal lymphoma P in the Middle East.” Although any of the nodal B-cell lymphomlas theoretically may occur as a primary gastrointestinal tumor, the only one that does so with any frequency is mantle cell lymphoma, which manifests in the gut as lymphomatous polyposis.” The increasingly importm~ group of B-cell lymphoproliferative condilions associated with immunodeficiency c.ommonly present in the gastrointestinal tract hut are more properly considered in the context of immunodeficiencyrelated l;mphoproliferative conditions as a whole. Gastrointestmal T-cell lymphomas are much less common and incl’udr the entity of enteropathy-associated T-cell lymphoma (EATL). ‘4 number of rare entities, including histiocytic neoplasms and granulocytic Sarcoma (myeloid leukemia), also may occur as primary gastrointt5tinal lesiot’s.

B-CELL

LYMPHOMAS

OF MALT TYPE

ln western countries MALT lymphomas occur most commonly in the stomach. Intestinal MAI.T lymphomas occur less frequently, whereas esophageal MAI.T lymphomas are vrry rare.

LOW GRADE B-CELL OF MALT TYPE

GASTRIC

LYMPHOMA

Most low grade gastric lymphomas arise in the antrum where they appear as an ill defined. thickened, inflamed area often with one or more ulcers and superficial erosions. The histological features closely simulate those of‘ MAl,T.” Keactive non-neoplastic follicles are invariably present. ‘The lymphoma cells infiltrate around the follicles in the region corresponding to the Peyer’s patch marginal zone. spreading out into surrounding tissue (Fig 1B) and invading individual gastric glands to form characteristic lymphoepithelial lesions (Fig I<:). The tumor cells are characteristically smallto medium-sized with moderately abundant, often pale staining cytoplasm and nuclei that have an irregular outline, hearing a close resemblance to the nuclei of centrocytes (small cleaved cells). Although the term “centrocyte-like” (CCL) is most co~n~~~o~~lyused to describe the cells of low grade MALT lymphoma, their cytological characteristics are more variable and they may more closely resemble small lymphocytes or show the features of so-called monocytoid B cells with ahundant pale-staining cytoplasm (Fig 2). A small to rnoder-atr number of larger blast cells are us~~ally present. A feature of low grade MALT lymphomas is the presence of lymphoepithelial lesions formed hy invasion of epitheliurn lining glands or crypts by aggregates of. CCI, cells usually associated with epithelial destruction’!’ (Fig ICI). I.ymphoepithelial lesions out of‘ context should not he overinterpreted because intraepithelial B cells are a normal component of MAI,T and may he quite prominent in florid H ,t$ori gastritis (follicular gastritis). Plasma cell differentiation is frequent in MAl.T lymphoma hut is often masked hy reactive plasmacytic infiltration li-om which it can only be distinguished by immunohistochemical demonstration of imnlunoglohulin (Ig) light-chain restriction. In some instances the plasma cells contain flocculent 01. crystalline inclusions of Ig. l,ow grade B-cell gastric lymphoma is lrequently multifocal.‘” Small foci of tumor may he present remote from the main site tumor, the smallest consisting of a single follicle surrounded hy an rxpanded marginal zone of tunror cells.

B-CELL FOLLICLES LYMPHOMA

As rr’entioned previously, the normal stomach COW tains no organized lymphoid tissue.” After infection with Hdirolmctr~r @x-i lymphoid follicles accumulate in gastric mucosa” and B cells surrounding these follicles can he observed selectively infiltrating gastric epithrlinm to 1i~n1 a lymphoepitheliurr1 comparable with that 1021

IN GASTRIC

MALT

Even the smallest focus of lvmpho’na is accompanied by a reactive follicle sugges&g that the formation of follicles is a precondition to the development of the lymphoma. In established MAl,T Iymphomas, numerous follicles may be present and in those cases where

HUMAN

PATHOLOGY

FIGURE 1. (A) Chronic gastritis caused by H. py/ori. There (arrows). (6) Low grade B-cell gastric lymphoma of MALT infiltrate, which forms lymphoepithelial lesions (arrows). (C) gastric MALT lymphoma. (A and B, hematoxylin eosin (HE);

Volume 25, No. 10 (October

is an intramucosal B-cell follicle with clusters of intraepithelial B cells type showing a reactive follicle surrounded by the lymphomatous Prominent lymphoepithelial lesions formed by CCL cells in low grade original magnification x 100; C ~200.)

they are not observed immunostaining shows numerous aggregates of follicular dendritic cells representative of follicles that have been overrun by tumor. The neoplastic CCI, cells interact with the reactive follicles in a way that may lead to an appearance closely resembling follicular (centroblastic/centrocytic [ch/cc]) lymphoma. This is known as follicular colonization”’ (Fig 3) and can he divided into three types. In the first type (Fig 3A) reactive follicles are replaced by CCL cells resulting in a nodular appearance. In the second type (Fig 3B) follicle centers are selectively replaced by CCL cells, although thr mantle zone may remain intact. The intrafollicular CCI. cells arc larger and more “active” than the surrounding diffuse infiltrate and may even undergo blast transformation; this can lead IO appeal-antes alrnost indistinguishable from cb/cc follicular lymphoma. Finally. in the third type the intrafollicular CCI, cells mldergo plasma cell differentiation.

LYMPH

1994)

NODE INVOLVEMENT

The characteristic pattern of lymph node involvement consists of an interfollicular infiltrate of CCL cells that surrounds follicles occupying the area corresponding to the marginal zone (Fig 4A). This infiltrate may extend IO form broad confluent sheets with eventual

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replacement of the node. If the CCI, cells are monocytoid in appearance the lymph node histolo
THE PHENOTYPE AND GENOTYPE OF LOW GRADE GASTRIC MALT LYMPHOMA The CCL B cells of MALT lymphoma express surface and, to a lesser extent, cytoplasmic lg (usually IgM), which shows light-chain restriction.‘)” The cells are CD.5 and CDIO-negative and express hcl-2 protein. They usually express both CD21 and CD%. There is a low proliferation fraction as detected with Ki-67. This immunophenotype is maintained in those cases showing type I follicular colonization,” but in type II the intrafollicular cells display a very high proliferation fraction and are /N-L-2 protein-negative. The phenotype is B cells, which homologous with that of marginal zone also share cytological and functional roperties (eg, fol<>a licular colonization) with CCL cells.- This suggests that CCL cells may be the neoplastic equivalent of marginal zone B cells. Genotypic investigations” show monoclonal lg gene rearrangement. Unlike follicular (cb/cc) lymph-

GASTROINTESTINAL

FIGURE 2. The morphological spectrum of low grade gastric MALT lymphoma. In (A) irregular “ccleaved” nuclei. In (B) the cells resemblance to small lymphocytes, whereas of the cytoplasm results in a “monocytoid” (HE; original magnification ~,800.)

otm, hr.

LYMPHOMA

CCL cells from the cells have bear a closer in (C) clearing appearance.

MAli ,‘I‘ Iwnphonns. ;ippt’w;lIl&.

ceding low grade disease.“’ Because this rnixt11rc. of grades is so com1non it can sometimes he difficult to decide whethu a gastric lymphoma is low grade with high grade (rlls or high gradr. It is g(btlrr;dly agreed of‘ that the presence or confluent clusters ()I- sheets transformed cells outside of colo11iLed tbllicles serves to define 21gastric MAI,?’ lymphoma as high grade. There arc no histological OI cytological katures (‘an he reliably whereby high grade MAI.T lymphoma differentiated from other high grade B-cell tumors. Thcb characteristic features of low grade MN.? lymphoma, including the presence of reactive follicles and lvmphoepithelial lesions, are no longu present. Cytologicallv, the 1111nor cells may rrsrrnhlr centrohlasts (large

inclr1ding those with a follicushow rearrangement of the /NY( I( 14: 181 tralslocation) or thr /&l gent do

riot

” gent.“’ I[ 1; 141 tl.ilIlSlO~~~tiOIl)

HIGH GRADE

GASTRIC

MALT LYMPHOMA

The presetice of’ larger transformed blast cells in and blast transfor1nation low grade MA1.T lymphoma in colonia~d fbtlicles has been described already. More c&Gous fi)ci of high grade transformatio1i may he oh~rved in low grade MA1.T lymphomas and 1na11y high gradt. B-~11 gast1-ic I~~rnphornas show evide11cc of pre-

FIGURE 3. Low grade mognificotion 20.)

B-cell gastric

(Peter G. Isaacson)

MALT lymphoma

showing

(A) fype I and (B) fype II follicular

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colonrzation

(HE; original

HUMAN

PATHOLOGY

Volume 25, No. 10 (October

1994)

FIGURE 4. Involved lymph nodes from low grade gastric B-cell MALT lymphoma showing (A) CCL cells surrounding follicles, and (6) focal type II follicular colonization. (HE; A, original magnification x 100: B, original magnification ‘* 10.)

non-cleaved cells) or plasmablasts and sometimes they are bizarre with numerous multinucleated forms. Immunohistochemistry frequently shows prominent cytoplasmic Ig and hcl-2 protein that, although usually expressed in high grade lymphomas of follicle center cell (FCC) origin, is usually not present in high grade MALT lymphomas.‘” Molecular studies have suggested that c-my rearrangement also may he a distinguishing feature of high grade MALT lymphoma.”

THE CLINICAL LYMPHOMA

BEHAVIOR

OF GASTRIC

MALT

called western type,“’ should he distinguished from IPSID (see below), which is a special subtype of MAI.T lyrnphoma characterized by its restricted epidemiology and the synthesis of alpha heavy-chain paraprotein (alpha chain disease). Most intestinal lymphomas occur in the elderly and present with obstruction or melena. III colorectal cases there may he a history of inflammatory bowel disease.““,” The majority comprise single lesions and any part of the intestine can he involved. Mesenteric lymph node involvement is common, but extra-abdominal spread is unusual at presentation.

Pathology

In comparison with nodal low grade B-cell lymphoma that, at the time of diagnosis, characteristically involves multiple lymph node sites and the bone marrow (stage IV), low grade MALT lymphoma is usually confined to the site of origin (stage Ib: or IIK) when diagnosed and is slow to disseminate, especially to the Hence, low grade MALT lymphoma bone marrow.” responds favorably to local measures and there is an excellent rate of survival unlike that of low grade nodal lymphoma, which is essentially incurable. The prognosis of high grade MALT lymphoma also is rnore favorable than equivalent nodal disease and the presence OI absence of synchronous low grade foci appears to make no difference.“’ The reasons for such favorable clinical behavior of gastric MALT lymphoma are unclear hut may reflect partial dependence of these tumors on antigenic drive. In a recent study of low grade gastric MALT lymphoma the neoplastic lymphocytes were shown to he specifically responsive to H py1or-iantigens.‘)x This response is mediated via intratumoral T cells. In five of six patients eradication of H j#m’ resulted in striking regression of. the lymphoma.“”

INTESTINAL LYMPHOMA (“WESTERN” TYPE)

residual

OF MALT TYPE

The histology is identical to that of gastric MAl.T lymphoma. In low grade tumors reactive B-cell follicles are prominent and there is a surrounding infiltrate of CCI, cells that often shows plasma cell differentiation. I,ymphoepithelial lesions are characteristic hut are more difficult to find in comparison to gastric lymphoma. Follicular colonization may lead to confusion with follicular lymphoma. High grade lymphomas are much more common, and in a proportion of these a low grade MALT component is present. These high grade lymphomas again resemble their gastric counterparts. Both the high and low grade intestinal MALT lymphomas exhibit the same immunophenotypic and molecular genetic features as gastric MALT lyrnphomas.

Clinical Behavior The clinical behavior of intestinal MALT lymphoma is not as favorable as that of gastric lymphoma.“‘.” Five-year survival rates of 44% to 75% and 25% to 37% are reported for low and high grade lymphomas, respectively. Histological grade, stage, and resectahility are all significant factors.

IMMUNOPROLIFERATIVE DISEASE

Most types”‘.”

intestinal B-cell lymphomas are of MA1.T The majority arise in the small intestine, with colorectal lymphomas being uncommon. Intestinal Bcell lymphomas that occur throughout the world, so-

1024

SMALL

INTESTINAL

This condition is a subtype of MA1.T lymphoma that occurs almost exclusively in the Middle East, although small numbers of cases have been reported else-

GASTROINTESTINAL

LYMPHOMA

(Peter G. Isaacson)

FIGURE 5. lmmunoproliferative small intestinal disease. (A) A lymphoplasmacytic infiltrate extends below the muscularis mucosae and forms lymphoepithelial lesions (arrows). (B) Mucosal infiltrate immunostained for alpha heavy chain. Plasma cell cytoplasm is densely (alpha heavy chain-positive and there is perinuclear space staining of CCL cells that form lymphoepithelial lesions original magnification x 120.) (arrow). (A, HE; original magnification <20: B, immunoperoxidase;

whet-e.‘.‘.“’ Ittttttttttopr~~lifer~ttivr small intestittal disease i\ characcerirc~cl by diffuse lyntphoplastttac~tic infiltratiott of the small intestinal mucosa attd synthesis of abIIOI-ma1 alpha heavy chaitt, without light chaitt. by the ~ktsma ct~lls. II is a disease of young adults and usually 1)resents with severe tnalabsorption. In the early stages this tnalahsorption tttay he responsive to broad spectrum antibiotics, which also tttay cause the lytttphoplastnacvtic ittfiltratc~ to resolve.‘“’ Pathology Irl IMIS~ cases there is diffuse, even thickening of Ihe proximal small intestine and enlarged tnesenteric lymph ncodcs, hut circumscribed, often multiple, lymphomatons masses may be present. The histology of 1PSID exhibits all the features of low grade B-cell lymphonta of VlALT with marked plasma cell differentiation. Three stages are recognized.‘” In stage A the lyntphoplasmacytic infiltrate is confined to the mucoya and tnesenteric lvmph nodes. In stage B nodular mucosal lvmphoid infiltrates are present and the infiltrate extends below the muscularis mucosac (Fig 5A). Stage C is characterized by the presence of lyntphomatous masses and transformation to high grade lymphoma. Already present in stage A IPSID and increasing in prominence in stage B are aggregates of (XL, B cells that clus,ter around epithelial crypts and form lymphoepithelial lesions. Reactive follicles vary in nutnber and it is colonization of these by CCL cells that results in the lymphoid nodules of- stage B IPSID” and may lead to the so-called follicular lymphoma variant.“’ Transformation to high grade lymphoma occurs in the same way as in gastric lymphoma except that the high grade cells more frequently show bizarre cytological features. Lymph Node Involvement Tht> mesettteric lytttph nodes arc involved early in the course of II’SID. Initially there is filling of the sinusoids by mature plasma cells, but later the characteristic tttarginal zone infiltrate of‘C
Phenotype

and Genotype

of IPSID

Ittttnuttottistocherrlical studies 01 It’SID cottfirttt tltc’ synthesis of alpha heavy chain, without light chain. blast by the plasttta cells, CCI, cells. arid tratisforttted cells (Fig 5B). The 1gA4is always of subclass IgAI except for occasional cases in which sytttttesis of both IgAl mod IgA2 has hectt observed.‘; In a ntinority ol‘casrs Ig light chain is synthesized and whet1 this occurs there is lightchaitt restricliott.“” Cases in which the infiltrate appear-s to consist only of’ plasma cells staining with anti-(;I)20 will ofien show clusters of B cells cottcentrated around stttall intestinal crypts and forntittg lytttplioepithelial hasions. (ietie rearrangetnent studies ‘Ii have* sttown IIIOIIOclottal heavy- and light-chain gene rearrangetnent that is present even itt stage A whet1 the Iytn~~ttoplastnacytic ittfiltratr is still responsive to antibiotics. ‘I’ Clinical Behavior Imtttutioproliferalive small intestinal disease t-LII~S a prolott~ged course, often over many years, and rarely disseminates front the abdotttt~tt WII il tttr tertttinal stages after high grade traItsforlttatiot1. MALIGNANT LYMPHOMA, MANTLE CELL TYPE (LYMPHOMATOUS POLYPOSIS) l.ytttphontatous polyposis is an ~~nco~tt~nott discasc but is well described in Westertt cc,tttttries.“,” Most cases occur in patients oldet- than 3). ‘I‘he ltresettfittg sytttptonts are those of ahdontittat pain, sometimes accompanied hy tnelena, and hariunt stutlics OI- e~tdoscopy shows multiple polyps chat ~~rovc to he lvmphotttatorts. Any part of the gastroinlestittal trac‘t ntav be involved. hut the largrst ltmtot-s lend lo 0ccu1- iti the ilroccxxl region. Pathology Macroscopicallv, tttert. a~‘(’ ttiultiple white tlrstt\ ntucosal polyps ranging itt silt Ii-01tt 0.5 to 2 cut. The mesr.rileric $rtiplt ttodes are risiiallv in\~olved.

HUMAN

PATHOLOGY

Volume 25, No. 10 (October

The smallest lesions consist of a single mucosal lymphoid nodule diffusely replaced by lymphoma, sometimes with preservation of the reactive follicle center. The larger polyps may show either a diffuse or nodular lymphoid infiltrate, in some cases so nodular as to resemble follicular lymphoma. Characteristically, reactive follicle centers are trapped in the lymphomatous infiltrate, which appears selectively to replace their mantle zones. Intestinal glands are displaced and obliterated, but lymphoepithelial lesions are not present. The cells in lymphomatous polyposis resemble centrocytes (small cleaved cells) and the lymphoma conforms to the entity recently characterized as mantle cell lymphoma.“” The immunophenotype is in keeping with a derivation from a subpopulation of CD5-positive mantle zone B cells. In addition to CD5, the cells also express mature B-cell markers. Other features include expression of CD35, absence of CDlO, and presence of a rather loose and nodular network of follicular dendritic cells. Cytogenetic and molecular studies have shown t( 11; 14) or bcF1 gene rearrangement in many cases.

Clinical Behavior Lymphomatous polyposis can be regarded as the intestinal form of mantle cell lymphoma that more commonly arises in peripheral lymph nodes. There is usually wide dissemination early in the course of the disease and involvement of liver, spleen, bone marrow, and peripheral lymph nodes soon follows identification of the polyps or may be present at the time of diagnosis. This type of clinical behavior is quite different from that of MALT lymphoma and thus distinction between the two conditions is important.

BURKWS LYMPHOMA LYMPHOMAS

AND BURKITT-LIKE

but in only approximately one third of sporadic cases. Both endemic and sporadic tunlors show characteristic chromosomal translocations involving the c-mvr oncogene locus on chromosome 8 and the Ig genes bn chromosome 14,2, or 22. However, the breakpoints involved in these translocations are different in the endemic and sporadic tumors. “’

OTHER TYPES OF PRIMARY B-CELL LYMPHOMA CORRESPONDING TO PERIPHERAL LYMPH NODE EQUIVALENTS There is no reason why any type of lymphoma cannot arise from MALT, but in practice entities common in peripheral lymph nodes, such as follicular (cb/cc) lymphoma, only rarely arise in the gastrointestinal tract. The reasons for this are obscure.

ENTEROPATHY-ASSOCIATED LYMPHOMA

T-CELL

The first accounts of the association of malabsorption and gastrointestinal lymphoma attributed the malabsorption to the lymphoma.” In 1962 Cough et al.*‘” reported several cases in which the malabsorption preceded the diagnosis of lymphoma by rnany years. Isaacson and Wright’” later concluded that these celiac disease-associated lymphomas were of a single histogenetic type, probably derived from histiocytes. Subsequent immunohistochemical and molecular studies indicated that these tumors are of T-cell origin.“‘.” O’Farrelly et al- coined the now widely used term, “enteropathy-associated T-cell lymphoma” (EATL) to designate these tumors.

Clinical Features

Endemic Burkitt’s lymphomas infrequently present with gastrointestinal disease, such as obstruction or In contrast, Burkitt-like or sporadic intussusception.‘” Burkitt’s lymphoma in the Western world and areas of the Middle Easta often presents with abdominal pain and obstructive features caused by ileocecal involvement.

The median age at diagnosis of EATI, is 60 years and there is a slight male preponderance. Most patients have a history of a few months to a few years of abdominal pain and weight loss, whereas a smaller proportion have a history of celiac disease dating back to childhood. Presentation as an acute emergency with perforation, obstruction, or hemorrhage is common.

Pathology

Pathology The cells of endemic Burkitt’s lymphoma and Burkitt-like or sporadic Burkitt’s lymphoma have been categorized as small, noncleaved cells.“’ They have granular nuclear chromatin, three to four nucleoli, and a well defined rim of deeply basophilic cytoplasm within which small lipid droplets may be observed. Because of the high proliferation fraction and the high rate of apoptosis, large numbers of “tingible body” macrophages accumulate in the tumor leading to the chardcteristic starry sky appearance.

Molecular

1994)

Genetics

Epstein-barr virus genomes are found tumor cells of all cases of endemic Burkitt’s

within the lymphoma

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Enteropathy-associated T-cell lymphoma occurs commonly in the jejunum, either alone or in combination with multiple other sites in the gastrointestinal tract. Lesions usually take the form of circumferential ulcers without the formation of large tumor masses, although these can occur. Enlargement of mesenteric lymph nodes is characteristic. Microscopic tumor may be found at other sites, including the liver, spleen, and bone marrow. The histological appearances of EATI, are variable both between cases and between different sites of tumor in the same patient (Fig 6). The most frequently encountered type is composed of medium to large blast cells with moderately abundant cytoplasm and vesicular nuclei with prominent eosinophilic nucleoli. Some

GASTROINTESTINAL

LYMPHOMA

(Peter G. Isaacson)

FIGURE 6. Enteropathy associated T-cell lymphoma: (A) immunoblastic variant. (6) pleomorphic variant, and (0 small lymphocytic variant. (HE: original magnification r 320.)

(ases are muc11 more plromorphic with multinucleated Kerd-Strl-llhet-g-like cells. In a minority of’ cases the tu111oIcc~lls reselnbk srn:lll lymphocytes. Tumor cells infiltrate the epithrlirml of the surviving mucosa, either as singk cells or in srrlall clusters. In ulcerated tumors the iritelisr intlammatory cell infiltrate, often including large nmnhcrs 01‘ eosinophils and histiocytes. may ohXIII-~ the isolated malignant cells present. In such cases multiple sections may he necessary to identi? the tmnol hy appropriate inculls, which also 1r1ay hr highlighted lymph tnur~ohistoche~t~ical stains (Fig 7). Involvrd nodrs rh;lr;lc,trristic~~lly show infiltration of‘ the sinllroids and the parac‘ortcx. If thic tllmor has heen resected from the .je,junum

the uninvolved mucosa char.actet-istic;tll~, shows villous atrophy and intraepithelial lymphoqttosis, which is sometimes strikingly intense. ‘T’his 111~ IIot he the case if the patient has heen on a gluten-free dirt or if’ tht resected from the ileum where only tllmor has hem minimal changrs may he evident. Phenotype

and Genotype

In IIlost cases of EATI> 1llV c-ells al-c’ (:1):3-t ( u177. CD-, and CDX-. In a nrmlhrr of easer (38 positivity has hr*rn repel-ted. Positive, staining with the nlotloantihod) l111111a11 cl011al Ivmphocytc- I Inucc~s;Il (IIMIJ)” is characteristic 01‘ this subset of I’-cell

FIGURE 7. (A) Enteropathy associated T-cell lymphoma showing scattered large tumor cells in a mixed inflammatory infiltrate. ’ 160; B, immunoperoxidase; (B) lmmunostaining with CD30 highlights the large neoplastic cells. (A, HE; original magnification original magnification ~250.)

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HUMAN

PATHOLOGY

Volume 25, No. 10 (October

lymphomas. In cases in which large immunoblast-like or Reed-Sternberg-like cells predominate, CD30 expression is characteristic. This can he a useful markrl to distinguish the tumor cells in an inflammatory background. Genotypic studies have confirmed monoclonal T-cell receptor-p (TCRP) gene rearrangement.“’

IS EAT1 A TUMOR LYMPHOCYTES?

OF INTRAEPITHELIAL

The majority of cases present in the small intestine where, like B-cell lymphomas of MALT, they may remain without evidence of extraintestinal spread for a prolonged period. The expression of HMLI antigen on the cells of EATL is further evidence of their origin from intraepithelial lymphocytes,g”~55 although it should be noted that HMLl antigen also is expressed on a variety of extraintestinal non-Hodgkin’s lymphomas.4i”’ The CD3+, CD7+, CD4-, CDB-/+ phenotype is again consistent with derivation from intraepithelial T cells.

CELIAC

DISEASE

AND EATL

The exact relationship between celiac disease and EATL remains controversial. Some cases have a clear history of celiac disease with biopsy evidence of gluten sensitivity. Splenic atrophy and dermatitis hepatiformis, both strongly associated with celiar disease, also may occur. The HLA type in patients with uncomplicated celiac disease and EATL has been shown to be similar in two studies”“.“’ but different in a third.“’ 111 many cases of EATL there is no history of celiac disease or biopsy evidence of gluten sensitivity and, moreover, the resected jejunal mucosa may appear normal. However, there are recent reports of so-called latent celiac disease in which the jejunal mucosa characteristically is histologically normal.“’ The present consensus is that most if not all cases of EXTL occur in the setting of celiac disease.

ULCERATIVE

JEJUNITIS

Ulcerative .jejunitis occurring in a patient with celiac disease is in most cases a manifestation of EATL. The relationship of ulcerative jejunitis to celiac disease is ve’y similar to that of EATL and the clinical presentation is identical. Many cases diagnosed as ulcerative jejunitis have been complicated by the subsequent development of EATI,. In the majority of cases a careful search, sometimes of multiple blocks, will show clusters or isolated neoplastic cells whose identification is made easier by staining for CD3 and CD30 (Fig 7).

APPENDIX Abbrmiafions: MALT, mucosa-associated lymphoid tissue; IPSD, immunoprolifcrative small intestinal disease: EATL, entrropathy-associated T-cell lymphoma; (XL, centrocytr-like; Ig, immunoglobulin; cb/cc. ccntroblastic/centrocytic; F(X:, follicle center cell; HMLl, human mucosal lymphocyte-l ; T(X/?. T-cell receptor-@; HLA, human leukocyte antigen.

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REFERENCES 1. FI-ceman C. Berg JW, Cutler 41: Orcurl-ence and prognosis of extmnodal lymphomas. Cancer 29:25?-260. 1972 2. Salem P, El-Hashimi I., Anaissie E, et al: Primary small intestinal lymphoma in adults: A comparative study of IPSID vcrsm nonIPSID in thr Middl? East. Cancer X+1670-1676. 1987 3. Doglioni C. Wothespoon AC, Moschini A, et al: High inridcnce ot primary gastric- lymphoma in northeastern Italy. Lancet :159:x%-85.5, 1992 4. Fischhach W, Ketcl M’. Kirchner T, et al: Malignant lymphtr mas of the upper gastrointestinal tract. Cancer 70:107.5-10X0, 1992 5. Dawsctn IMP, (Ior-nrs JS, Morson BC: Primary malignant lymphoid tumors of the mtestinal tract. Report of 37 cases with a study of factors influencing prognosis. Br J Surg 49X0-89. 1961 6. Isaacson PG. Wright DH: Malignant lymphoma of mucosaassociated lvmphoid tis&. A distinctive tvpr of B-ccl1 lymphoma. Cancer 52:141~1-1416. 1983 7. Isaacson PG, Wright DH: Extranodal maliguant Iymphoma arising from mucosa-associated lvmphoid tissue. Cancer- 53:251Fi2.524, 1984 8. (:enta KM, Hamner HU’, (k&m) DY Gastric Iymphoid follicles in Helicoharte~- pylori infbction: Frequency, distributiou. and rrsponsc to triple thrl-apy. flllM PATHOL. 44:577-W% IWJ 9. Hyjek E. Smith WJ, Isaacson PG: Primaly B-ccl1 lymphoma of the salivary gland and its relationship t(> mvoepithrlial sialadenitis. Ht’bt PAI‘HOI. 19:76&7X, 198X 10. Hyjek E. Isaacscm PC;: Primary Cell lymphoma of the thyroid and its relationship to Hashimoto’s thyroiditis. HI~M PXI'HOI. 19:131.5-13%- . 198X 1 I. Wotherspoon A(:, Ortl&Iidalgo (:. FalLon MR. et al: Helicohatter pylori-associated gastritis and primaly B-cell gastric lymphoma. I.ancet 338:11751176, 1991 12. Negrini R. I.isato I,. Zanella 1. ct al: Helicohactcr pylor~ infcrtion induces antibodies cross-reacting with human gastric mucosa. (Gastroenterology 101:437-445, 1991 13. Villuendas R, Piris MA, Orrddre Jr,, et al: Differ-cnt hrl-2 protein expression in high-grade &cell lymphomas derived from lymph node or mucosa-associated lymphoid tissue. Am J Pathol 139989-993, 199 1 14. Raghoehier S, Kramer MHH, van Krieken JHJM, et al: Essential differences in oncogene involvement between primaT nodal and cxtranodal large cell lymphoma. Blood 78:2680-2685. 1991 15. Isaacson PG. Dogan A. Price SK, et al: Imm~~nrrprolif~1-ative small intestinal disease: An irnml~nohistochernical study. Am J Surg Pathol IJ:lO%-1033. 1989 16. Ladjadi Y, Philip 7‘. Lcnior GM, et al: Abdominal Burkittlike lymphoma~ in Algeria. Br-J Cancel- 49~503-5 12, 1984 17. Isaacaon P(:, Maclxnnan KA. Suhhuswamy SC.: Multiple hmphomatous polvposis of the gastrointestinal tl-act. Histopatholog\ X:641-6.56. 1983 1X. Isaacson PC:, Spencer J: Malignant lymphoma of mucosa associated lymphoid tissue. Histopathology 11:445462. 1987 19. Pdpadaki I., Wotherspoon AC. Isaacson IX: Thr lymphocpithelial lesion of gastric low-grade Cell lymphoma of mucosa-associated lymphoid tissue (MA1.T): An ultrastructural study. Histopathol“LT 21:415-421. 1992 PO. Wotherspoon Aft. Doglioni C. Isaacson PC: (&tric B cell lymphoma of mucosa-associated lymphoid tissue is a multifocal discast. Histopathology 20:29-34, 1992 21. Isaacson PG. Wotherspoon AC. Diss TC, ct al: Follicular cob nization in B cell lymphoma of mucosa associated Ivmphoid tissue. Am J Surg Pathol 1.5:819-828, 1991 22. Traweek ST, Sheihani K, Winhcrg CD, et al: Monocytoid Bcell lymphoma: Its evolution and relationship to other low-grade B cell neoplasms. Blood 73573-578. 1989 2.7. MacLennan ICM. Lui YJ. Oldfield J, et al: The evolution of B-ccl1 clones. Curr- Top Microhiol Immunol 15937-63, 1990 24. Spencer _J, Diss TC, Isaacson PG: Primary B cell rastrir lymphoma and “pseudolymphoma”: A gcnotypic analysis. &J Pathol 135:557-564, 1989 25. Pan I., Diss TC. Cunningham D, et al: Thr hcl-2 genr in pr-imarv B cell lymphomas of. mucosa as.sociatcd lymphoid t&x (MALT). Am J Pathol 1%:7-l I. 1989 26. (:han JKC, Ng CS. Isaacson PC: Relationship hetwrcn highgrade lymphoma and low-grade B cell mucosa associated lymphoid

GASTROINTESTINAL

LYMPHOMA

S?I. Shrphct d NA. Hall PA. (bates I’J. et al: Printat3 malignant I~trrphotrta 01 the cdon ad wrtttttt. .2 histopatholofiic;II and itntnutlohi~tochcrrtt~~~l .ittalvsis of ,L5 casts with rlinir~)pattrolo,~:ical tort-clntton<. I Iistc,patholo~~, 12:235-L’s?. 198X 51. (;t~~~nstcttl 41, Muttin (:E. Strauchen Jh, r( al: I.\tnphotna !tt inflammatot-v how<‘1 disease. (beer 691 119-1 t 23, 1WL’ 35. I’rlc<~SK: lmnittnopt-olif~t-ative small intestitd discasc: A \tttrl\ of 13 c.tst’\i bctth alpha h~;t~~-chain disrasc. Histopnthc~lo~~ 17.7. 17. IWO Yti. Br,tr-Avcd F, iialphcn M. Najjar T. et al: Tt-ratttt<~nt of alpha rlihrah(~--Re5ttlts of .t prosp?rtive study in 21 Tttniaian patients hv the ‘Tntli~ian-French Itttc%inal I.vtnphotna Stttdv (;t~ottp. Cnttcct63: I’25 I- I2iri. IWJ

( htn

3X. Nevtttca %. ‘l‘hcmta/.v V, Steifcrt (;: Follicrtlat centr? cell Ivnrph~mu with alpha IteaT rhain disrase: A Itistopath~,l~,gic~l .md ttnttrtttt(~hist~~c.tlrlnic;rl stttdv. Virchows Arch ,1 Pathol Atrat Histopathol WI:1 l!r-1:1”, 1W-31 39. Isnacsc1tt I’(;. Pt-ice SK Light ch,dttl\,’ in Mtditcrt-aneatl Ivtnphottt,t. J (Yin Pathol 3X:601-607. 19X5 10. Str;ith M’, Pt-icr SK. Isaacson PC;: Immttno~lohttlin gcnr r~‘nrt~atr~cniet~t in irttmttilclproliferativc small intestinal dihcasc* (IPSID). 1(:lin Pathcbl 40:1?9)1-1297, 19X7 -41 O‘l%ri;nn DS, Krnnedv MJ, Daly P,4. ct al: Multiple lymphotttatotts polvposis of the gastrointestinal tract. A clinic-opnthott,girdll~ distinrtivc iornl of non-Hodgkin’s lytnphotna 11t K-ctll ccntroc-\tt( t\‘pC. Am ]r SWg

Pathol

13:691-699,

l98Cl

12. I&tnks PM, (hart 1, Clearv MI.. ct at: Mantlc ccII lvtnphotn;~. .A pt-oposaI fat- ttttification of morphologic. itnmutrolr>git , md tnolcctlt~1t- data. .\I11 J SWg Pathol l6:637-640, 199” 43. Vr’r-i&t DH: But-kitt‘s trnnottr in Eng$md: A cotnpat-ison c-htldh~~oti. Ivttr~~h~~sarcf~nla. ltrt 1 (:atccr I:505-514. 1Wi

wtth

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(Peter G. Isaacson)