Download Lymphoproliferative Disorders of the Gastrointestinal Tract

Lymphoproliferative Disorders of the
Gastrointestinal Tract
A Review and Pragmatic Guide to Diagnosis
Jerome S. Burke, MD
gastrointestinal tract is the most common
NsiteContext.—The
of extranodal lymphomas. Although all histologic categories of malignant lymphoma develop in the gastrointestinal
tract, large B-cell lymphomas predominate, followed by
extranodal marginal zone lymphomas of mucosa-associated
lymphoid tissue (MALT) type; the latter is especially prevalent
in stomach. The acceptance of extranodal marginal zone
lymphoma of MALT type as a clinicopathologic entity has
reduced the number of cases that formerly were interpreted as
florid lymphoid hyperplasia (‘‘pseudolymphoma’’). Nonetheless, the distinction of lymphoid hyperplasia from a lymphoma
of MALT type in small biopsy specimens remains problematic.
Objective.—To assess the relevant morphologic, immunologic, molecular, and genetic properties of gastrointestinal lymphomas and to present a feasible tactic for
diagnosis, expressly for small biopsy specimens.
Data Sources.—Case-derived material and literature
review using PubMed (National Library of Medicine).
he gastrointestinal tract is the most common location of
T
extranodal lymphomas, with the stomach as the most
frequent site of involvement and with the small intestine
second in frequency.1 Large intestinal and rectal lymphomas are far less common but are discovered in patients
with AIDS and sporadically in patients with ulcerative
colitis and Crohn disease.2–4 In a study of 371 patients with
primary gastrointestinal lymphomas registered in a German multicenter study, stomach accounted for 277 of
cases (74.8%), whereas small intestine and ileocecal region
represented 61 cases (16.4%).5 Only 9 cases (2.4%) in that
series were restricted to the colorectal area, with the
remaining cases involving multiple gastrointestinal sites.
The incidence of primary gastric lymphomas, specifically
extranodal marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT) type, has vacillated, with
Accepted for publication June 9, 2011.
From the Department of Pathology, Alta Bates Summit Medical
Center, Berkeley, California.
The author has no relevant financial interest in the products or
companies described in this article.
Presented in part at the Tutorial on Pathology of the GI Tract,
Pancreas, and Liver, Westin Diplomat Resort & Spa, Hollywood,
Florida, November 15–19, 2010.
Reprints: Jerome S. Burke, MD, Department of Pathology, Alta
Bates Summit Medical Center, 2450 Ashby Ave, Berkeley, CA 94705
(e-mail: [email protected]).
Arch Pathol Lab Med—Vol 135, October 2011
Conclusions.—Most gastrointestinal lymphomas are readily amenable to an unqualified diagnosis, primarily those
cases consisting of monomorphic large cells whether of B- or
T-cell lineage, including cases associated with enteropathy.
Diagnosis for infiltrates dominated by small lymphocytes
remains taxing, as the differential diagnosis embraces not
only MALT lymphoma and lymphoid hyperplasia but also
mantle cell lymphoma, follicular lymphoma, and chronic
lymphocytic leukemia/small lymphocytic lymphoma. Adherence to strict morphologic criteria is the standard for
diagnosis, but these criteria should be augmented by
immunologic studies together with judicious use of molecular techniques to determine clonality. In establishing a
diagnosis of gastric marginal zone lymphoma of MALT type,
determination of t(11;18)(q21;q21) status may be required
since this translocation has clinical ramifications.
(Arch Pathol Lab Med. 2011;135:1283–1297; doi: 10.
5858/arpa.2011-0145-RA)
a peak reached in the 1990s subsequent to the increasing recognition of MALT lymphoma as a specific
diagnostic entity, followed by a persistent decline in the
past decade; this decline may be related to the improved
clinical management and reduction in Helicobacter pylori
infection.6
The concept of extranodal marginal zone lymphoma
of MALT type has revolutionized the criteria for the
morphologic diagnosis of an extranodal lymphoma,
specifically those lymphomas dominated by small lymphocytes. Since the initial descriptions of lymphomas of
MALT in 1983 and 1984, the morphologic criteria have
evolved and expanded to encompass the following: a
more precise definition of various cell types in MALT
lymphoma, proposals for ‘‘lymphoepithelial lesions’’ and
‘‘follicular colonization,’’ the relationship between MALT
lymphomas and marginal zone B cells, and a scoring
system for diagnosis of gastric MALT lymphoma.7–12
Moreover, the morphologic criteria have expanded to
embrace immunophenotypic, biologic, molecular genetic,
and clinical discoveries.9,13–18 Developments, such as the
association of gastric MALT lymphoma with H pylori
infection, the notion of acquired MALT, the biology of
autoantigen activation and continuous somatic mutations,
the documentation of genetic aberrations, for example, the
discovery of the t(11;18)(q21;q21) chromosomal translocation in lymphomas of MALT, and the clinical implications
GI Lymphoproliferative Disorders—Burke
1283
of specific cytogenetic alterations, have been the subject of
excellent reviews and will not be recapitulated to any
degree.19–21 The goal of this review is to critique the salient
morphologic, immunologic, molecular, and genetic attributes of gastrointestinal lymphomas and to provide a
strategy for a solid foundation for diagnosis, especially
with respect to small gastrointestinal biopsy specimens.
FLORID LYMPHOID HYPERPLASIA
(‘‘PSEUDOLYMPHOMA’’) VERSUS
MALIGNANT LYMPHOMA
In establishing a histologic diagnosis of an extranodal
lymphoma, pathologists are aware that various forms of
reactive lymphoid hyperplasia clinically and pathologically mimic gastrointestinal lymphomas, such as gastric
lymphoid hyperplasia and chronic lymphocytic gastritis.
To confuse the issue, malignant lymphoma of extranodal
marginal zone (MALT) type may develop in association
with these reactive lymphoid infiltrates, including those in
stomach.22
In the 1960s and 1970s, the morphologic criteria to
distinguish extranodal lymphoma from extranodal lymphoid hyperplasia were derived from those used traditionally to distinguish malignant lymphoma from lymphoid hyperplasia in lymph nodes.23 The major criteria
for this distinction included monomorphic lymphocytic
infiltrates, cellular atypia, germinal centers, and architectural disruption.24
Since most gastrointestinal lymphomas are large B-cell
lymphomas with associated monomorphism, cellular atypia, and architectural destruction (eg, eradication of glands),
these conventional criteria generally have proved germane.
At the converse end of the continuum, obvious reactive
lymphoid conditions similarly do not usually present
diagnostic difficulties. Lymphocytic infiltrates that display
polymorphism, that contain a range of mature lymphocytes
encompassing plasma cells and immunoblasts, that exhibit
well-defined germinal centers, and that do not raze the
architectural landmarks of the gastrointestinal site usually
can be diagnosed assertively as benign and reactive.
The main difficulty in the separation of gastrointestinal
lymphomas from lymphoid hyperplasia concerns marginal zone lymphomas of MALT type that are dominated
by small lymphocytes and that commonly are associated
with germinal-center formation.25 For such cases, the
conventional histologic criteria are not valid (Figure 1, A
and B). Many histologically ambivalent gastrointestinal
small lymphocytic proliferations prove to be monoclonal
and are probably malignant lymphomas, especially of
MALT type.26 The application of immunologic and
molecular genetic analyses to gastrointestinal sites, especially gastric small lymphocytic proliferations, has served
to vividly alter the traditional histologic criteria and has
exposed innumerable inconsistencies in these criteria.24 At
the Armed Forces Institute of Pathology, for example, of
97 cases reviewed from 1970 to 1985, which formerly were
diagnosed as gastric pseudolymphoma, 79% were reclassified as malignant lymphoma, and two-thirds of the
newly classified lymphoma cases subsequently were
designated as lymphomas of MALT type.27 Lymphoid
hyperplasia or atypical lymphocytic infiltrates comprised
the remaining cases. As a result, the term pseudolymphoma
is currently considered nebulous and obsolescent and is
no longer suitable as a diagnostic term.10
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The current perception of small gastrointestinal lymphocytic proliferations that appear mature has changed
significantly, not only by refinement of the morphologic
criteria, but also by the utilization of immunologic
techniques, including immunohistochemistry, in situ
hybridization, flow cytometry, and gene rearrangement
to analyze the clonality of these lesions. For example, in
patients with documented suspicious lymphocytic infiltrates in gastroscopic biopsy specimens, multiple repeated
biopsy fragments of the lesion submitted fresh for flow
cytometry analysis frequently result in the demonstration
of monoclonality and verification of lymphoma.28 Caution,
however, is required in the evaluation of immunoglobulin
studies using polymerase chain reaction (PCR) techniques
in fixed, paraffin-embedded tissues; small monoclonal
bands may occur in extranodal reactive lymphoid
hyperplasia, as for example in chronic active gastritis
associated with H pylori and associated with lymphoid
follicles.29,30 Therefore, if PCR for immunoglobulin gene
rearrangement is to be performed, the test should be
limited to those gastric cases with strong morphologic
suspicion for actual lymphoma.21,30
Lymphoid follicles or reactive germinal centers create
another conundrum in diagnosis. Germinal centers are a
commonly accepted histologic trait of gastric lymphoid
hyperplasia, and isolated follicles are a common finding in
gastric biopsy specimens.31 Germinal centers, however,
are regular components of many lymphomas of MALT.
The critical morphologic characteristic of MALT lymphomas is their simulation of normal MALT as typified by
Peyer patches found in the terminal ileum.9 The neoplastic
B lymphocytes of MALT lymphomas are found in
marginal-type zones adjoining reactive follicles and often
diminished rims of mantle zone lymphocytes. The
germinal centers frequently are atrophic owing to encroachment by the encircling small lymphocytes. In
MALT lymphomas of stomach, affiliated with peptic
ulcer, germinal centers occur at the base of the ulcer and in
the adjacent mucosa, where they appear entrapped by the
monotonous marginal zone lymphocytes. Frequently, the
neoplastic marginal zone lymphocytes invade the germinal centers in a process referred to as ‘‘follicular
colonization.’’ 11 When follicles are numerous, follicular
colonization may imitate follicular lymphoma. In some
cases, the lymphomatous infiltrate may result in architectural destruction with concealment of remaining germinal
centers; however, the presence of cryptic germinal centers
can be accentuated by the immunohistochemical demonstration of follicular dendritic cells with an antibody
against CD21 or CD23.25,32
Despite honing of the criteria to separate gastrointestinal lymphoid hyperplasia from lymphoma, gastrointestinal lymphoid hyperplasia remains a relatively common
histologic alteration. Gastrointestinal lymphoid hyperplasia involves not only stomach, but may occur anywhere
in the intestine, as for example the ileum, where Peyer
patches may be particularly pronounced.33 Lymphoid
hyperplasia of the gastrointestinal tract may be focal or,
rarely, nodular, encompassing long segments of the small
and large intestine, where it needs to be distinguished
from mantle cell lymphoma and follicular lymphoma.34
Lymphoid hyperplasia also may affect the rectum and,
on occasion, cause a diagnostic challenge. Localized
lymphoid hyperplasia of the rectum recently has been
referred to as rectal ‘‘tonsil.’’ 35 Patients may present with
GI Lymphoproliferative Disorders—Burke
Figure 1. Massive gastric infiltrate (A) from an archival case in a study from the late 1960s, labeled as ‘‘pseudolymphoma.’’ The diagnosis of
pseudolymphoma most likely was based on the fact that the infiltrate is dominated by small, round lymphocytes with scattered germinal centers (B).
With current criteria, this case likely would be labeled gastric marginal zone lymphoma of MALT type (hematoxylin-eosin, original magnifications
3150 [A] and 3300 [B]).
Figure 2. Florid lymphoid hyperplasia in the rectum. At both lower (A) and higher magnifications (B), tingible body macrophages are apparent and
indicate that the follicles are reactive and not lymphoma. In the rectum, florid lymphoid hyperplasia has been referred to as rectal ‘‘tonsil’’ and some
cases can be mistaken for lymphoma (hematoxylin-eosin, original magnifications 330 [A] and 3150 [B]).
Figure 3. Large B-cell lymphoma is the most common type of lymphoma in stomach (A). The diagnosis is supported by an immunoperoxidase stain
for CD20 (B) (hematoxylin-eosin, original magnification 3300 [A]; original magnification 3300 [B]).
Arch Pathol Lab Med—Vol 135, October 2011
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Table 1. Classification of
Gastrointestinal Lymphomasa
B Cell
Extranodal marginal zone, MALT type
IPSID (heavy chain disease)
Others (lymph node equivalents)
Mantle cell (lymphomatous polyposis)
Follicular
Large B cell, NOS (,40% extranodal)
Burkitt
T Cell
Enteropathy associated (EATL)
Classic and type II
Others (non–enteropathy associated)
NK/T, nasal type
gd
ALCL
Abbreviations: ALCL, anaplastic large cell lymphoma; EATL, enteropathyassociated T-cell lymphoma; IPSID, immunoproliferative small intestinal
disease; MALT, mucosa-associated lymphoid tissue; NK, natural killer;
NOS, not otherwise specified.
a
Reprinted and modified with permission from Isaacson.39
either rectal bleeding or abdominal pain and at endoscopy
exhibit a raised polypoid lesion or mucosal nodularity and
even a mass. The lymphoid hyperplasia or tonsil involves
the lamina propria or submucosa (Figure 2, A and B). In
most examples, the lymphoid follicles are readily recognized, but a minority of cases require immunohistochemistry to verify that the lesions are reactive rather than
lymphoma.35 Chlamydial proctitis may be a cause of some
cases of florid lymphoid hyperplasia of the rectum.36
CLASSIFICATION OF GASTROINTESTINAL LYMPHOMAS
No separate classification for gastrointestinal lymphomas is offered by the World Health Organization (WHO),
although extranodal marginal zone lymphoma of MALT
(including immunoproliferative small-intestinal disorder)
and enteropathy-associated T-cell lymphoma form 2 distinct categories among the mature B-, T- and natural killer
(NK)–cell neoplasms.37,38 Isaacson39 previously proposed
a classification of primary gastrointestinal non-Hodgkin
lymphoma that comprised cases of both low-grade and
high-grade MALT; however, the current WHO lymphoma
classification no longer uses such terminology, and cases of
high-grade MALT have been subsumed into the large B-cell
lymphoma category (Table 1).37,40
GASTROINTESTINAL B-CELL LYMPHOMAS,
PREDOMINATELY NON-MALT
Most primary gastrointestinal lymphomas, both in
stomach and intestine and irrespective of their association
with MALT, are large B-cell lymphomas, especially those
composed of centroblasts, but may also include cases
dominated by immunoblasts and, on occasion, plasmablasts. The relationship between the more common large
B-cell gastrointestinal lymphomas and the low-grade
lymphomas of MALT is unclear. In a recent German
multicenter study of 398 cases of gastric lymphoma, 59.5%
were large B-cell lymphomas of which 18.1% had a
simultaneous small cell component compatible with
derivation from MALT.40 This incidence is consonant with
2 studies from the 1990s in which 17% to 21% of primary
malignant lymphomas of the stomach showed coexistence
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of a low-grade and a high-grade lymphoma;41,42 it was
suggested that increased numbers of histologic sections
might demonstrate a still higher percentage of cases with a
low-grade component. The terms low-grade MALToma and
high-grade MALToma formerly were used to describe such
lesions, but, as discussed above, the diagnosis of MALT
lymphoma currently is restricted to a lymphoma composed principally of small lymphocytes and should not be
used to classify large B-cell lymphomas, including those
associated with a MALT component or arising in a MALT
site.37
The diagnosis of large B-cell lymphoma usually is not
a problem because of the tendency of the lymphoma to
be diffuse, to lack cohesive cell aggregates, and to be
composed of cells that are approximately double the size of
normal small lymphocytes with open vesicular chromatin
and nucleoli, which are either adjacent to the nuclear
membrane or, in the case of immunoblasts, central and
frequently eosinophilic. In small endoscopic biopsy specimens, the diagnosis may be more tenuous, but immunohistochemical verification of the diagnosis is advised and is
particularly valuable in delineating cases of large B-cell
lymphoma from undifferentiated gastrointestinal carcinoma. The infiltration by lymphoma around, or into, partially
intact gastric and intestinal glands, negative mucin and
keratin staining, positive reactivity for B-cell antigens such
as CD20, and the lack of syncytial cell aggregates or
malignant acinar formation aid in the distinction of large
B-cell lymphoma from poorly differentiated or undifferentiated carcinoma, even in small biopsy specimens
(Figure 3, A and B). Occasionally, gastrointestinal large Bcell lymphoma requires distinction from other large cell
malignant neoplasms that simulate lymphoma, as for
example malignant melanoma and myeloid sarcoma.22
Small gastrointestinal biopsy specimens, however, are
prone to sampling errors and artifactual distortion, and it
may be necessary to request a second biopsy in order to
deliver a more complete diagnosis.
Mantle cell lymphoma is another type of non-MALT
lymphoma found in the gastrointestinal tract that can
present as a nonspecific lymphocytic infiltrate, but is
best known for presentation as multiple lymphomatous
polyposis.43,44 This is an unusual, but distinct, gastrointestinal lymphoma characterized by the polypoid accumulation of lymphoma involving long segments of the small
and large intestine.3 Lymphomatous polyposis has a
reported frequency of 4% to 9% among all gastrointestinal
B-cell non-Hodgkin lymphomas.45 Patients generally are
middle-aged males who present with weight loss, fatigue,
diarrhea, abdominal pain, and often iron deficiency.44–46
The lymphoma forms a series of coalescing polypoid nodules composed of atypical centrocyte-type cells involving
mucosa and/or submucosa (Figure 4, A). Occasionally,
reactive germinal centers are trapped in the nodular
lymphomatous infiltrate and this observation aids in
morphologically distinguishing lymphomatous polyposis
from follicular lymphoma of the gastrointestinal tract
(Figure 4, B). The mantle cells in lymphomatous polyposis
exhibit a characteristic CD20+, CD5+, CD232 phenotype
and cyclin D1 overexpression, as well as bcl-1 rearrangements with t(11;14)(q13;q32).46–48 Cases of intestinal mantle
cell lymphoma also frequently contain the a4b7 mucosal
homing receptor.49 However, a subset of lymphomatous
polyposis cases are, in fact, follicular lymphomas and
such cases appear limited to the small intestine, whereas
GI Lymphoproliferative Disorders—Burke
Figure 4. Mantle cell lymphoma of the small intestine, composed of a series of polypoid nodules, presents as multiple lymphomatous polyposis
(A). In this case, occasional residual germinal centers (B, left) aid in the distinction of mantle cell lymphoma from follicular lymphoma. Unlike
marginal zone lymphoma of MALT type, the atypical lymphocytes extrinsic to the germinal center express CD5 and nuclear reactivity for cyclin D1
(not shown). Follicular lymphoma of the small intestine also may present as lymphomatous polyposis (C). Unlike mantle cell lymphoma, follicular
lymphoma of the intestine generally is of grade 1 type, composed of centrocytes, and without residual germinal centers (D) (hematoxylin-eosin,
original magnifications 360 [A and C], 3300 [B], and 3600 [D]).
the primary mantle cell cases involve both small and
large intestine.46,47 As well, patients with clinical presentation of lymphomatous polyposis occasionally have been
reported as having marginal zone lymphomas of MALT
type.48,50 The immunophenotype of the follicular and
MALT lymphoma variants of lymphomatous polyposis
clearly differs from that of the more common mantle cell
cases.
Secondary intestinal dissemination by mantle cell
lymphoma also is exceedingly common in patients with
generalized, primary lymph node–based mantle cell
lymphoma and encompasses cases that exhibit a lymphomatous polyposis pattern with involvement of colon.46
Approximately 25% of patients with documented nodal
mantle cell lymphoma have gastrointestinal symptoms,
yet the lymphoma is present histologically in the lower
gastrointestinal tract in 77% to 88% of patients and in the
upper gastrointestinal tract in 43% to 77%.51,52 Moreover,
microscopic documentation of mantle cell lymphoma is
reported in 84% of patients with normal visual findings by
lower endoscopy and in 45% of patients with macroscopically normal findings by upper endoscopy.51 Such
Arch Pathol Lab Med—Vol 135, October 2011
examples can be histologically indistinguishable from
focal lymphoid hyperplasia, but immunohistochemical
stains, including nuclear cyclin D1 reactivity, confirm
gastrointestinal involvement by mantle cell lymphoma.52
Despite the often subtle microscopic involvement of the
gastrointestinal tract in patients with node-based mantle
cell lymphoma, aggressive staging evaluation of the
gastrointestinal tract has little impact on patient management decisions.51 Primary mantle cell lymphoma of the
gastrointestinal tract, in the form of lymphomatous
polyposis, generally has an aggressive clinical course
and patients have a median survival of approximately 3 to
4 years.45
Primary follicular lymphoma of the gastrointestinal
tract is uncommon, but when it occurs it tends to involve
the small intestine, especially the duodenum.53,54 As
considered previously, such cases may present with
multiple small polyps, including the appearance of
lymphomatous polyposis (Figure 4, C).46,47,55,56 Histologically, follicular lymphoma of the gastrointestinal tract is
similar to node-based follicular lymphoma (Figure 4, D).
Most examples are grade 1, but cases of grade 2 and 3 also
GI Lymphoproliferative Disorders—Burke
1287
occur in the gastrointestinal tract;54,56 however, precise
grading may prove difficult in small biopsy specimens.
The immunophenotype is identical to that of nodal
follicular lymphoma (CD20+, CD10+, bcl-6+, bcl-2+) and
the cases also exhibit t(14;18).53–56 In contrast to nodal
follicular lymphoma, the primary gastrointestinal cases
frequently express immunoglobulin A (IgA) as well as the
a4b7 mucosal homing receptor, to suggest origin from
local antigen-experienced B-cells.57 Unlike nodal follicular
lymphoma, duodenal follicular lymphoma also exhibits
VH4 gene deviation and lacks activation-induced cytidine
deaminase expression; moreover, its dendritic cell meshworks tend to be disrupted.58,59 Follicular lymphoma of the
duodenum additionally reveals ongoing hypermutation
but the mechanisms differ from those in nodal cases and
are more in parallel with the antigen-dependent origin of
MALT lymphoma.59 Clinically, patients with primary
follicular lymphomas of the gastrointestinal tract tend to
have low-stage IE and IIE disease. As compared to mantle
cell lymphoma, gastrointestinal follicular lymphoma
exhibits an indolent clinical course, with patient survival
of 62% or more at 5 years.54,56 Moreover, primary stage IE
follicular lymphoma of the duodenum is exceedingly
indolent and patients who are not treated usually do not
develop extraintestinal spread, nor does the disease
transform to large cell lymphoma, leading to the recommendation of a ‘‘watch and wait’’ approach.60
Immunoproliferative small intestinal disease (IPSID),
formerly known as Mediterranean lymphoma or a heavy
chain disease, is an uncommon and unusual type of
gastrointestinal lymphoma that is included under the
umbrella of MALT lymphoma in the current WHO
classification scheme.37 Immunoproliferative small intestinal disease mainly occurs in the Middle East and arises
in association with a morphologically benign-appearing
infiltrate, often characterized by a dense, plasma cell
proliferation in the intestinal mucosa.39,61 As opposed to
the Western type of lymphoma commonly encountered in
Europe and North America, IPSID tends to manifest as
malabsorption instead of obstruction, presents in the
duodenum or proximal jejunum rather than distal ileum,
and exhibits villous atrophy as well as plasma cell
infiltration of the adjacent intestine.61–63 Immunoproliferative small intestinal disease is either a lymphoma of
MALT with a lymphoplasmacytic appearance or large
cell, frequently immunoblastic plasmacytoid lymphoma
with IgA heavy-chain restriction, which is related to a
heavy chain disease with lack of the V region and light
chains.63–65 The discovery of benign-appearing follicles,
together with lymphomatous cells that conform to the
centrocyte-like cells of MALT, add credence to the
classification of IPSID as a form of extranodal marginal
cell lymphoma of MALT type developing in mucosaassociated lymphoid tissue of the small intestine.37,64–66 The
exact antigenic stimulus to form reactive follicles in IPSID
is unknown, but recent molecular and immunohistochemical studies demonstrate a proposed association with
Campylobacter jejuni, although this relationship remains
tenuous.65,67,68 Patients at an early stage of mucosal
involvement frequently respond to antibiotics, whereas
patients whose disease evolves to large cell lymphoma,
specifically the immunoblastic variant, classically have a
better median survival than Western patients with de
novo large B-cell lymphoma of the intestine.61,62,65
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GASTROINTESTINAL T-CELL LYMPHOMAS,
PREDOMINATELY ENTEROPATHY ASSOCIATED
Most malignant lymphomas that complicate the diagnosis of celiac sprue are not IPSIDs but rather T-cell
lymphomas. These cases have been designated as ‘‘enteropathy-associated T-cell lymphoma’’ (EATL) and they are
characterized by prominent intramucosal lymphomatous
spread and villous atrophy of uninvolved mucosa (Figure 5,
A).38,69 T-cell lymphomas unassociated with malabsorption
also develop in the intestine and cases may simulate the
histologic pattern of EATL.69,70 T-cell lymphomas can
involve any part of the gastrointestinal tract especially in
patients in the Far East, and whereas some cases may be
examples of EATL, the Far East is nonendemic for celiac
disease and most cases in this geographic region are
peripheral T-cell lymphomas, not otherwise specified
(NOS), NK/T-cell lymphomas of nasal type, and cases
linked with the human T-cell lymphotropic virus type 1.71–76
In the current WHO classification, EATL is divided into
2 forms. Patients with the first variant have features of
celiac disease and may present with abdominal pain and
even small intestinal perforation.38 The lymphomatous
nature of the intestinal infiltrate usually is obvious, but the
cases are cytologically mutable, ranging from cases
containing neoplastic large cells with conspicuous nucleoli; cases with pleomorphic, multinucleated cells; and
cases dominated by small to medium-sized lymphocytes
(Figure 5, B).69,70,77 Most examples of this type of EATL
exhibit necrosis and infiltration by inflammatory cells,
specifically histiocytes and eosinophils, which can obscure
the lymphoma.20 Although occasionally subtle, the intestinal mucosa adjacent to the main tumor mass frequently
exhibits enteropathy with villous atrophy, crypt hyperplasia, increased inflammatory cells in the lamina propria,
as well as intraepithelial lymphocytosis.38,77–79
Unlike the primary form of EATL, the type II variety
exhibits villous atrophy, blunting, and intraepithelial lymphocytosis that is usually confined to the area of lymphoma
and perhaps adjacent mucosa (Figure 5, C), whereas the
more distant nonlymphomatous mucosa is effectively
unremarkable and without villous atrophy.78 Despite
inclusion as a form of EATL, paradoxically, most patients
with type II disease do not have a history of celiac disease.
The morphologic features of the lymphoma also differ, as
the lymphomas in the type II cases tend to be more homogeneous and are composed of small to medium-sized
lymphocytes with slightly irregular nuclei and small
nucleoli surrounded by a rim of pale or clear cytoplasm
(Figure 5, D).38,78 The type II form of EATL usually
expresses CD8 and CD56 in contrast to expression of CD8
in only 20% and CD56 in fewer than 10% of cases of the
more classic form of EATL.38 Both forms exhibit common
genetic abnormalities with complex segmental gains of the
9q31.3 chromosomal region or with deletions in 16q12.1.80,81
Alternatively, the classic form of EATL associated with
celiac disease frequently has chromosomal gains in 1q and
5q, whereas the type II variant is often characterized by
8q24 (MYC) amplifications.81,82 The HLA haplotypes also
differ. Like patients with celiac disease, more than 90% of
patients with the first type of EATL share the HLA-DQ2/DQ8 genotype, while the genotype found in type II EATL is
more akin to that of normal white populations.38,82
In Northern Europe, EATL generally is regarded as a
complication of celiac disease, but in some patients no
GI Lymphoproliferative Disorders—Burke
Figure 5. Enteropathy-associated T-cell lymphoma (EATL) in a patient with celiac disease results in infiltration of the adjacent small intestinal
mucosa with associated villous atrophy (A). The neoplastic T cells in EATL are frequently pleomorphic (B). In type II EATL, the neoplastic T cells also
invade the adjacent mucosa, leading to villous blunting (C). The neoplastic T cells in the type II variant tend to be of medium size and are relatively
homogenous (D). In the latter case, the neoplastic T cells expressed CD8 and CD56 versus the usual lack of reactivity for these antigens in classic
EATL (not shown). EATL must be distinguished from NK-cell enteropathy, a newly described entity in which atypical cells infiltrate the lamina
propria and encircle residual colonic glands (E). Despite the significant atypia, patients with NK-cell enteropathy experience a benign clinical course
(hematoxylin-eosin, original magnifications 360 [A], 3600 [B and D], 3150 [C], and 320/0.75NA [E]). E, Reproduced with permission from
Mansoor et al94 and courtesy of Elaine S. Jaffe, MD, Chief, Hematopathology Section, Laboratory of Pathology, Center for Cancer Research, National
Canter Institute, Bethesda, Maryland.
Arch Pathol Lab Med—Vol 135, October 2011
GI Lymphoproliferative Disorders—Burke
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history of malabsorption exists and villous atrophy and
crypt hyperplasia are discovered only at the time of
lymphoma resection. Isaacson and Du20 and Ashton-Key
and associates83 have demonstrated that EATL may be
preceded by refractory celiac disease frequently associated
with ulcers and referred to as ‘‘ulcerative jejunitis.’’
Polymerase chain reaction and sequence analysis showed
that ulcerative lesions and unremarkable, normal-appearing intraepithelial lymphocytes share the identical monoclonal T-cell receptor rearrangement as the adjacent
lymphoma. In refractory celiac disease, the intraepithelial
lymphocytes may exhibit a normal CD3+, CD8+ immunophenotype, but they often are phenotypically anomalous
with loss of surface CD3, and usually CD8, and also
cytogenetically anomalous with partial trisomy of the 1q
region in parallel to cases of EATL.79,84–86 Moreover, clonal
T-cell gene rearrangements have been recorded in patients
with refractory celiac disease who do not present with
lymphoma, and in cases in which EATL later develops, the
identical clone can be detected in the lymphoma.79,83,84,85,87
Such cases are regarded as ‘‘cryptic EATL’’ (EATL in situ)
and patients with refractory celiac disease require continual monitoring of both intraepithelial lymphocyte immunophenotype and clonality because of the significant risk
of the disease evolving to EATL.38,83,84,87,88
The differential diagnosis of EATL includes not only
large B-cell lymphoma of intestine, but also other forms of
T-cell lymphoma including peripheral T-cell lymphoma
NOS, anaplastic large cell lymphoma, and extranodal NK/
T-cell lymphoma, nasal type.69,72,74,77 For example, the
extranodal NK/T-cell lymphomas of nasal type that
present in intestine exhibit the usual broad cytologic
spectrum of that form of lymphoma, ranging from small
to intermediate-size to large cells with marked nuclear
pleomorphism.74,89–91 The adjacent mucosa does not exhibit
villous atrophy. The lymphoma frequently demonstrates
ulceration, angiocentricity, and angioinvasion with fibrinoid and coagulative necrosis.74,89–91 Phenotypically, the
extranodal NK/T-cell lymphomas of nasal type express
cytoplasmic, but not surface, CD3 and similar to type II
EATL, they show TIA-1 and CD56 positivity.74,89,90 Unlike
the type II form of EATL, the extranodal NK/T-cell
lymphomas generally are CD82 and also are negative for
bF1. Most importantly, the NK/T-cell lymphomas of nasal
type are Epstein-Barr virus positive as opposed to
EATL.74,89–91 NK/T-cell lymphomas are clinically aggressive and the extranasal cases, encompassing those in the
gastrointestinal tract, convey a statistically significant even
worse prognosis.74,92 In general, patients with intestinal
T-cell lymphoma fare worse that those with intestinal
B-cell lymphoma.72,93
One caveat is that EATL and extranodal NK/T-cell
lymphoma must be distinguished from 2 similar, if not
identical, newly described entities, ‘‘NK-cell enteropathy’’
or ‘‘lymphomatoid gastropathy,’’ especially in small
endoscopic biopsy specimens.94,95 Patients present with
either no or varying gastrointestinal symptoms, but have
no features of celiac or inflammatory bowel disease. The
atypical NK-cell infiltrates involve either single or multiple
sites, including stomach, duodenum, small intestine, and
colon.96 At endoscopy, multiple superficial, discrete, flat or
hemorrhagic lesions may be observed or small (less than
1 cm), patchy, superficial ulcers are discovered.94–96 Biopsy
specimens demonstrate a diffuse, well-circumscribed, mucosal infiltrate of atypical intermediate to large lymphoid
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Arch Pathol Lab Med—Vol 135, October 2011
cells with clear to eosinophilic cytoplasm and with invasion or destruction of mucosal glands (Figure 5, E).94–96
Acute inflammation may accompany the infiltrate. The
atypical lymphocytes express cytoplasmic, but not surface,
CD3, as well as CD56 and TIA-1. Similar to true NK-cell
lymphomas of extranodal nasal type, the T-cell receptor in
the enteropathy cases is germline; but, in contrast to NK
nasal-type lymphomas, studies for Epstein-Barr virus
using Epstein-Barr virus–encoded RNA yield negative
results.94–96 Of most significance, and as opposed to both
extranodal NK/T-cell lymphomas and EATL, patients
with NK-cell enteropathy pursue an uneventful clinical
course.94,95 The etiology of this syndrome is unknown.
GASTRIC LYMPHOMAS, ESPECIALLY MARGINAL ZONE
LYMPHOMAS OF MALT TYPE
The morphologic features of extranodal marginal zone
lymphoma of MALT type have witnessed gradual changes
since the initial descriptions by Isaacson and Wright.7,8
Although originally interpreted to be of follicular center cell
origin, the lymphoma cells of MALT were later designated
as ‘‘centrocyte-like’’ and currently are termed marginal zone
cells.7,9,37 Gastric lymphomas of MALT type typically are
characterized by an expansion of the marginal-like zones
surrounding benign germinal centers (Figure 6, A and B).
Marginal zone cells comprise a variety of cell types ranging
from small to intermediate-sized lymphocytes to large cells.
The marginal zone or centrocyte-like cells are small to
medium-sized lymphocytes with variable nuclear membrane irregularities, resembling a centrocyte.20 Commonly,
the marginal zone cells appear monocytoid with abundant
pale-staining cytoplasm and well-delineated borders (Figure 6, C).9 Other forms of gastric MALT resemble small
lymphocytes or are dominated by plasma cells to the extent
of simulating a plasmacytoma. Signet ring–type cells also
are described in gastric MALT lymphomas and appear to
represent a curious type of lymphoepithelial lesion in
which the foveolar cells, disaggregated by the lymphomatous infiltrate, attain a globoid, signet ring–type appearance.97 Regardless of cytologic composition, the marginal
zone cells of MALT cells share immunophenotypic
characteristics. Gastric MALT lymphomas are B cell
derived with CD20 expression and frequently contain
numerous admixed CD3+ reactive T cells. Despite the B-cell
phenotype, determination of monoclonality by immunoperoxidase in fixed, paraffin-embedded tissue usually is
not possible with the exception of cases containing a
conspicuous plasma cell component; however, up to 50% of
cases exhibit aberrant coexpression of CD43 that can prove
helpful in diagnosis (Figure 6, D).20 Unlike chronic lymphocytic leukemia/small lymphocytic lymphoma and
mantle cell lymphoma, the lymphomas of MALT origin
usually lack CD5 and are without bcl-1 gene rearrangements.10,20 Mucosa-associated lymphoid tissue lymphomas
differ from follicular lymphomas in that they are CD102
and do not exhibit bcl-2 rearrangements.98 The absence of
CD10 in gastric lymphoma with an apparent follicular
architecture has been rationalized by the concept of
‘‘follicular colonization.’’ 11 As noted earlier, follicular
colonization refers to the replication of follicular lymphoma
as a result of invasion by the marginal zone cells of MALT
into preexisting reactive follicles (Figure 6, E and F).
The marginal zone cells of MALT invade not only
residual reactive follicles but also epithelium. Epithelial
invasion with frequent destruction by the B cells of MALT
GI Lymphoproliferative Disorders—Burke
Figure 6. In classic extranodal marginal zone lymphoma of MALT type, the lymphoid infiltrate in stomach is often massive (A). Residual germinal
centers often are evident that are surrounded and encroached upon by the proliferating neoplastic marginal zone lymphocytes (B). The marginal
zone lymphocytes exhibit irregular nuclear contours and frequently have pale-staining cytoplasm to impart a monocytoid appearance (C). The
neoplastic marginal zone B cells may aberrantly coexpress CD43 in contrast to the absence of CD43 expression in a residual germinal center seen at
the upper left (D). Gastric MALT lymphoma also may display a false follicular architecture (E) as the malignant marginal zone cells invade residual
germinal centers referred to as ‘‘follicular colonization’’ (F) (hematoxylin-eosin, original magnifications 360[A and E], 3150 [B], 3600 [C], and
3300 [F]; immunoperoxidase, original magnification 3150 [D]).
Arch Pathol Lab Med—Vol 135, October 2011
GI Lymphoproliferative Disorders—Burke
1291
Table 2.
Grade
Gastric Marginal Zone (MALT) Lymphomas: Histologic Scoringa
Description
0
Normal
1
Chronic active gastritis
2
Chronic active gastritis with florid
lymphoid follicle formation
Suspicious lymphoid infiltrate in LP,
probably reactive
Suspicious lymphoid infiltrate in LP,
probably lymphoma
Marginal zone (MALT) lymphoma
3
4
5
Histologic Features
Plasma cells in LP
No lymphoid follicles
Lymphocyte clusters in LP
No follicles, LELs
Prominent follicles with surrounding mantle zone and plasma cells
No LELs
Follicles surrounded by lymphocytes that infiltrate diffusely in LP
and +/2 epithelium
Follicles surrounded by CCL cells (MZC) that infiltrate diffusely in
LP and epithelium
Dense diffuse infiltrate of CCL cells in LP with prominent LELs
Abbreviations: CCL, centrocyte-like; LELs, lymphoepithelial lesions; LP, lamina propria; MALT, mucosa-associated lymphoid tissue; MZC, marginal
zone cells.
a
Reprinted with permission from Wotherspoon et al.12
has been referred to as a ‘‘lymphoepithelial lesion’’ and is
a vital morphologic attribute in the diagnosis of gastric
MALT-derived lymphomas.8,9,34 An immunohistochemical stain for cytokeratin usually accentuates these lesions.
Lymphoepithelial lesions are most noteworthy as a
diagnostic trait in the stomach, but are less germane in
other extranodal sites, since they may be observed in
nonlymphomatous extranodal lymphocytic infiltrates.10,33
In stomach, lymphoepithelial lesions usually are defined
as invasion of gastric epithelium by 3 or more lymphomatous B cells.20 A decade following the primary proposal
for a lymphoma of MALT, a histologic scoring system for
gastric MALT lymphoma was proposed in which invasion
of epithelial structures or lymphoepithelial lesions is
considered paramount to the diagnosis (Table 2).12
With the scoring system, a definite diagnosis of lowgrade B cell lymphoma of MALT is predicated on the
existence of a dense, diffuse infiltrate of centrocyte-like
cells/marginal zone cells in the lamina propria with
prominent lymphoepithelial lesions. Cases regarded as
suspicious lymphocytic infiltrates are those in which
reactive follicles are surrounded by marginal zone cells
that diffusely infiltrate into the lamina propria and into
epithelium in small groups.12 However, caution is required as dense infiltrates, slight cytologic atypia, and also
lymphoepithelial-like lesions may be found in cases of
lymphoid hyperplasia in the stomach. As well, the criteria
may be difficult to apply. In an interobserver study,99 17
pathologists, including hematopathologists, gastrointestinal pathologists, and general pathologists, reviewed 41
hematoxylin-eosin sections of stomach that ranged from
simple gastritis to lymphoma. Interobserver reproducibility was suboptimal and the degree of disagreement was
directly related to the experience of the pathologist in
evaluating gastric biopsy specimens for MALT lesions.
The study recommended that clinical information, extensive sampling, recognition of lymphoepithelial lesions,
immunophenotypic information, and cytogenetic results
would enhance diagnostic accuracy.99 This recommendation was supported by another report100 stating that a
combination of the morphologic scoring system and B cell
clonality analysis by an advanced PCR method accurately
discriminated chronic gastritis from covert gastric marginal zone lymphoma. Polymerase chain reaction was
particularly valuable in the interpretation of cases that
exhibited an ambiguous score of grade 3 or 4.
Currently, it is well established that most gastric
marginal zone lymphomas of MALT arise in a setting of
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Arch Pathol Lab Med—Vol 135, October 2011
‘‘acquired’’ MALT, whereby nonindigenous extranodal
lymphoid tissue is acquired secondary to H pylori
infection.20,101,102 Ample epidemiologic, clinical, and histologic evidence effectively shows a fixed association
between gastric MALT lymphomas and H pylori infection.12,19,20,103–105 For example, in a collaborative study of
more than 230 000 patients whose serum had been stored,
33 cases of gastric lymphoma developed in a median of
14 years after serum collection.103 The patients with gastric
lymphoma were significantly more likely than matched
controls to have evidence of previous H pylori infection. In
contrast, among 31 patients who developed nongastric,
non-Hodgkin lymphoma, no association was discovered
between this lymphoma and previous H pylori infection.103
In addition, molecular analysis by PCR has documented
the clonal progression from H pylori–associated chronic
gastritis to MALT lymphoma of the stomach, and H pylori
provides the antigenic stimulus for prolonging the
clonal expansion of gastric MALT lymphomas.13,19,106 Of
most significance, antibiotic treatment with obliteration of
H pylori usually leads to remission of gastric MALT
lymphoma.12,18,20,21,107
Clinically, gastric MALT lymphomas arise in adults
with a peak in the seventh decade of life and with a male
to female ratio of approximately 1.5:1.34 Patients commonly present with nonspecific gastritis and/or a peptic ulcer
and at endoscopy, reddened and slightly thickened rugae
are often present with superficial spreading of lesions
without formation of a tumor mass.18 The gastric lesions
commonly are multifocal and most patients have stage IE
disease.107,108 The link between H pylori and gastric MALT
lymphoma led to antibiotic therapy for treatment of lowgrade gastric lymphomas of MALT, and this therapy
induces sustained remissions in more than 75% of
patients.21,107 Consequently, eradication of H pylori is the
recommended primary therapy for almost all patients
with MALT lymphoma of stomach irrespective of stage or
even documentation of associated H pylori infection.109,110
With a gastric mapping procedure, an initial follow-up
endoscopy is recommended at 3 to 6 months after therapy
for H pylori infection, and additional follow-up evaluations should be done at 4- to 6-month intervals for
2 years.109,110 For patients monitored for up to 2 years
whose disease remains refractory to H pylori therapy,
other modalities, such as radiotherapy, chemotherapy,
or combined treatment are offered; however, no consensus exists for the optimal treatment of primary gastric
lymphoma unresponsive to H pylori therapy, particularly
GI Lymphoproliferative Disorders—Burke
with evidence of progressive lymphoma, although recent
analysis of pooled data proposed that radiotherapy may
be most appropriate in this setting.110–112 Overall, gastric
MALT lymphoma is indolent and in one study of this
lymphoma treated by various modalities, the 5-year
projected overall survival was 82%.18
One significant issue for pathologists is the interpretation of stomach biopsy specimens after antibiotic therapy
for gastric MALT lymphoma. Clearly, no diagnostic
problem exists if the biopsy specimen reveals regression
of the lymphoma with loss of lymphocytic aggregates
in the lamina propria (Figure 7, A) or if the specimen
exhibits a total absence of histologic regression with
persistence of lymphoma. Parallel to the histologic scoring
system used for the initial diagnosis of gastric marginal
zone lymphoma, a histologic grading system has been
proposed for treated patients which evaluates not only
the cellular infiltrate and lymphoepithelial lesions but also
stromal changes (Table 3).12,113 The probable minimal
disease category does not signify a requirement for further
therapy and patients are managed with follow-up as
though they were in remission.21,110 For patients with
responding residual disease (Figure 7, B) or no change, clinical management consists of as discussed above, careful
follow-up and a watch-and-wait approach for up to 2 years
in the absence of disease progression.110
Of interest, approximately 50% of patients with histologically negative gastric biopsy findings after antibiotic
therapy exhibit persistent monoclonality by PCR, although in some patients the clonality disappears with
prolonged follow-up.114–116 For other patients, continued
monoclonality may result in a delay in realizing remission.
However, after antibiotic therapy for gastric MALT
lymphoma, the association between ongoing monoclonality and risk of relapse is tenuous.117 One bone of
contention is that serial gastric biopsy specimens frequently exhibit an oscillating clonal status, due perhaps to
sampling or recurrent H pylori infection.21 Therefore,
except for clinical investigations, the determination of
clonality with PCR currently is not considered pragmatic
or recommended in the evaluation of posttherapy gastric
MALT lymphoma biopsy specimens.21,110
The establishment of extranodal gastric marginal zone
lymphoma of MALT type as a recognized clinicopathologic
entity has progressed to incorporate molecular genetics and
specific chromosomal translocations. For MALT lymphomas
in general, the genetic abnormalities encompass trisomies
3, 12, and 18, as well as balanced translocations, specifically t(11;18)(q21;q21), t(14;18)(q32;q21), t(1;14)(p22;q32), and
t(3;14)(p14;q32).14–17,19–21,110,118,119 The most common translocation in gastric MALT lymphoma arising in approximately
20% to 30% of cases (although at a lower rate in North
America) is t(11;18)(q21;q21), which fuses the amino
terminal of the API2 gene (that encodes the inhibitor of
apoptosis) at 11q21 to the carboxyl terminal of MALT1 at
18q21, leading to a chimeric fusion product.15,17,110 The API2MALT1 fusion product is detectable by interphase fluorescence in situ hybridization or reverse transcription-PCR (RTPCR).21,110 MALT1 is involved in antigen receptor–mediated
nuclear factor (NF)–kB activation and MALT lymphomas
that express the translocation exhibit enhanced expression of
NF-kB target genes, whereas MALT lymphomas without
t(11;18)(q21;q21) support active inflammatory and immune
responses.120 The t(11;18)(q21;q21) translocation is restricted
to extranodal MALT lymphomas and has not been reported
Arch Pathol Lab Med—Vol 135, October 2011
in other forms of marginal zone lymphoma, such as splenic
or nodal, or in chronic gastritis associated with H pylori.121,122
Gastric MALT lymphomas without t(11;18)(q21;q21) often
exhibit aneuploidy, for example, trisomy 3, 12, or 18.118,119,123
The discovery of t(11;18)(q21;q21) in some patients with
gastric MALT lymphoma has led to exciting clinical
prognostic correlations. Specifically, gastric MALT lymphoma in patients who prove positive for t(11;18)(q21;q21) often
fails to respond to H pylori therapy, and this translocation
frequently arises in patients who are H pylori negative.21,107,110,116,124–126 With endosonographic staging, such
t(11;18)(q21;q21)-positive patients whose condition does
not respond to H pylori eradication with antibiotics may
have lymphoma that has proliferated beyond the gastric
submucosa into muscularis and/or serosa in contrast to
patients with lymphoma limited to the mucosa and submucosa who generally are t(11;18)(q21;q21) negative.16,21,25
Moreover, t(11;18)(q21;q21) is uncommon in extranodal
diffuse large B-cell lymphoma, and for patients harboring
this translocation, the disease rarely metamorphoses to
diffuse large B-cell lymphoma.110,118,119 In contrast, patients
with aneuploidy, who are t(11;18)(q21;q21) negative with
lymphoma unresponsive to H pylori treatment, are at risk of
having the disease evolve to diffuse large B-cell lymphoma.
For example, microsatellite screening of gastric MALT and
large B-cell lymphomas displays allelic imbalances limited
to t(11;18)(q21;q21)-negative patients, which are shared by
both MALT and diffuse large B-cell lymphomas;119 this
observation advocates that the absence of t(11;18)(q21;q21)
is the genesis of most MALT lymphomas that convert to
one of large B-cell type.121 One recent report,127 however,
deviated from this prevailing view by documenting
t(11;18)(q21;q21) in 19% (6 of 31) of cases of gastric large
B-cell lymphoma. Further investigations obviously are
required, but for patients whose condition does not respond
to anti-H pylori therapy, it remains of interest to ascertain
whether or not the gastric marginal zone lymphoma of
MALT type is t(11;18)(q21;q21) positive, since this information carries prognostic and therapeutic repercussions.21
Nonetheless, routine determination of the t(11;18)(q21;q21)
status is controversial since, from a clinical perspective,
t(11;18)(q21;q21)-positive patients also are treated initially
for H pylori infection, and no definite data exist to indicate
that determining the status of t(11;18)(q21;q21) in the course
of follow-up has a direct bearing on therapeutic decisions.110
By current criteria, marginal zone lymphoma of MALT
type is strictly an indolent or low-grade extranodal
lymphoma. Despite the considerable recent emphasis on
MALT-type lymphomas, in fact almost 60% of gastric
lymphomas are diffuse large B-cell lymphomas.40 As
noted previously, with the exception of small gastroscopic
biopsy specimens, differentiation of large cell lymphoma
from other large cell malignancies usually is not a
morphologic issue, but, immunohistochemical verification is recommended.22 One consequential diagnostic
issue is the observation of large cells in a background of
a marginal zone lymphoma of MALT type in a gastric
biopsy specimen. No current consensus prevails as to how
many large cells are required to establish the evolution
from MALT lymphoma to one of diffuse large B-cell type.
Undoubtedly, the presence of large cells in discrete
nodular aggregates or sheets is likely an indication of
transformation;20,21,41 however, diagnostic difficulties ensue for cases in which large cells are numerous and
diffusely admixed with small marginal zone lymphocytes.
GI Lymphoproliferative Disorders—Burke
1293
In one study of 106 patients with gastric MALT lymphomas, the prognostic influence of a large cell component
was assessed by semiquantitative analysis of clusters and
diffusely intermingled malignant large cells;128 in MALT
lymphomas, the observation of a diffuse large cell
component in the range of 1% to 10%, with and without
nonconfluent clusters of large cells, portended a significantly worse prognosis. Yet, in a report from Italy,129 the
presence of scattered large cells that comprised 5% to 10%
of the MALT lymphoma cell population was regarded
as prognostically irrelevant, whereas compact clustered
large cells that represented more than 10% of the MALT
lymphoma proved significant, as they were associated
with a worse survival. Cases of putative large B-cell
lymphoma in a background of gastric MALT lymphoma
typically express bcl-6, but not CD10 and bcl-2.130
Figure 7. Biopsy specimens of gastric MALT lymphoma after therapy
for Helicobacter pylori infection. In one example, no residual
lymphoma is present and the lamina propria contains only scattered
inflammatory cells affiliated with mild stromal fibrosis (A). In another
case, the lymphocytic infiltrate is less than that seen originally, but
atypical lymphocytes linger, corresponding to responding residual
disease (rRD) with lymphoepithelial lesions present on the right and
bottom (B) (hematoxylin-eosin, original magnifications 3300 [A and B]).
SUMMARY: A PRAGMATIC GUIDE TO DIAGNOSIS
How then does a surgical pathologist arrive at an
accurate diagnosis of suspected gastric marginal zone
lymphoma, principally in light of the vagary of the
histologic scoring scheme?12,99 An appropriate integrated
algorithm and diagnostic recommendations have been
proposed, but the all-too-common issue of a gastric biopsy
specimen containing a solitary enlarged lymphocytic
nodule composed of small lymphocytes without evident
germinal centers remains ambiguous and a diagnostic
conundrum (Figure 8).21,110 Such biopsy specimens evoke
a broad differential diagnosis ranging from gastritis
to malignant lymphoma, which encompasses not only
extranodal marginal zone lymphoma of MALT type but
also other lymphomas composed of small lymphocytes,
including chronic lymphocytic leukemia/small lymphocytic lymphoma, mantle cell lymphoma, and even
follicular lymphoma. In this scenario, the foremost role
of the pathologist is vigilant assessment of the histologic
features by the conscious determination of whether any
cytologic atypia exists, whether the cells appear monocytoid, whether plasma cells are increased, and whether
lymphoepithelial lesions are evident. Although morphology remains the standard for diagnosis, the morphologic
characteristics require supplementation by an immunoperoxidase panel, primarily CD20 and CD3, as well as
CD43 and/or CD5, CD21, and possibly cytokeratin and, if
plasma cells are numerous, staining for k and l light
chains.131 Such staining will determine whether an
aberrant immunophenotype is present, as for example,
a predominance of CD20+ B cells, and whether the B
lymphocytes exhibit coexpression with CD43 or CD5,
whether the cytokeratin stain highlights lymphoepithelial
lesions, whether occult germinal centers exist by positive
reactivity for CD21 to imply follicular colonization, and
whether a monoclonal plasma cell population is evident
with k or l light-chain restriction.11,20,25,32 For example, CD5
coexpression should trigger staining for cyclin D1 to
exclude mantle cell lymphoma. If the morphologic and
immunophenotypic study results in this setting are
strongly suggestive of, but not absolutely diagnostic of,
r
Figure 8. A gastric biopsy specimen contains an enlarged lymphocytic nodule composed of small lymphocytes without apparent
germinal centers. The differential diagnosis encompasses lymphoid
hyperplasia and malignant lymphomas, specifically gastric MALT
lymphoma as well as chronic lymphocytic leukemia/small lymphocytic
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Arch Pathol Lab Med—Vol 135, October 2011
lymphoma, mantle cell lymphoma, and follicular lymphoma. Diagnosis
requires integration of histopathology, immunophenotype analysis, and
even molecular and cytogenetic features (hematoxylin-eosin, original
magnification 360).
GI Lymphoproliferative Disorders—Burke
Table 3. Gastric Marginal Zone (MALT) Lymphoma: Posttherapy Gradinga
Score
CR
pMRD
rRD
NC
Lymphoid Infiltrate
Absent or scattered plasma cells and small
lymphoid cells in the LP
Aggregates of lymphoid cells or lymphoid
nodules in the LP/muscularis mucosa and/
or submucosa
Dense, diffuse, or nodular extending around
glands in the LP
Dense, diffuse, or nodular
LELs
Stromal Changes
2
Normal or empty LP and/or fibrosis
2
Empty LP and/or fibrosis
+/2
Focal empty LP and/or fibrosis
+/2
No changes
Abbreviations: CR, complete histologic remission; LELs, lymphoepithelial lesions; LP, lamina propria; MALT, mucosa-associated lymphoid tissue;
NC, no change; pMRD, probable minimal residual disease; rRD, responding residual disease; 2, absent; +/2, present or absent.
a
Reprinted with permission from Copie-Bergman et al.113
gastric MALT lymphoma, molecular studies using PCR
also can be requested.12,100,110 In this scenario, interpretation of the histologic, immunophenotypic, and molecular
studies must be placed in context of the clinical milieu,
particularly with the awareness that chronic active
gastritis may exhibit immunoglobulin gene rearrangements without features of clinical malignant lymphoma in
follow-up studies.29,30,131 Because of this fact and because
ambiguous cases can be treated and usually respond to
therapy for H pylori, some are of the opinion that routine
PCR analysis is unnecessary.132 However, our practice
prefers to be as resolute as possible in establishing a diagnosis; thus, discovery of a positive B-cell gene rearrangement by PCR is beneficial in the instance of an equivocal
lymphocytic infiltrate.100 If the PCR study results prove
negative, the possibility of lymphoma in the ambivalent
lymphocytic infiltrate persists so that a descriptive diagnosis is required and, depending on the clinical features,
so is a call for repeated biopsy with reservation of fresh
tissue to determine clonality, whether by flow cytometry
or snap freezing, with suitable immunoperoxidase studies. Although flow cytometry may not be a routine procedure for investigating gastric biopsy specimens, it is a
valuable technique for rapidly demonstrating clonality
and securing an absolute diagnosis.28 At the time of a
repeated biopsy, at least 10 samples are submitted without
fixative from abnormal-appearing gastric mucosa.110 After
obtaining and interpreting touch imprints from several
biopsy fragments, the multiple biopsy specimens are
triaged, with submission of pooled samples to flow
cytometry and the remainder for routine microscopy with
fixation in B5 and/or formalin. Molecular studies also can
be requested at this stage if the new biopsy findings
remain suspicious and the flow cytometry and/or snap
frozen–tissue studies prove ineffective. Should the new
biopsy specimen be successful in providing a definitive
diagnosis of gastric MALT lymphoma, but without
evidence of H pylori, then detection of t(11;18)(q21;q21)
by fluorescence in situ hybridization or reverse transcription-PCR remains an option and can also aid in diagnosis.21,110,133 Despite these additional ancillary studies, the
diagnosis may still remain unresolved. Since significant
therapeutic consequences exist in rendering a verdict of
extranodal marginal zone lymphoma of MALT type, in a
setting of uncertainty, a more fitting, noncommittal diagnosis might be an ‘‘atypical lymphocytic infiltrate of uncertain malignant potential.’’ 22,134,135 Regardless of the
terminology, it remains incontrovertible that the diagnosis
of gastric marginal zone MALT lymphoma depends on
Arch Pathol Lab Med—Vol 135, October 2011
adherence to exacting pathologic criteria augmented
by immunophenotypic and judicious molecular and/or
cytogenetic studies.
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