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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 94 No. 1 (July 1), 1999:
pp. 260-264
Mucosal Intra-epithelial Lymphocytes in Enteropathy-Associated
T-Cell Lymphoma, Ulcerative Jejunitis, and Refractory Celiac
Disease Constitute a Neoplastic Population
By
Eniko Bagdi,
Timothy C. Diss,
Philippa Munson, and
Peter G. Isaacson
From the Department of Histopathology, Royal Free and University
College Medical School, University College London, London, UK.
 |
ABSTRACT |
Loss of response to a gluten-free diet (refractory sprue) and
ulcerative jejunitis are complications of celiac disease that may
progress to enteropathy-associated T-cell lymphoma (EATL). Both
conditions are characterized by the presence of a nonlymphomatous monoclonal T-cell population in the enteropathic mucosa. In EATL, a
similar monoclonal population that shows clonal identity with the
lymphoma itself is also present in the enteropathic mucosa. In this
study we show that in all three circumstances the monoclonal T-cell
population is constituted by cytologically normal, noninvasive intraepithelial T lymphocytes that share an identical aberrant immunophenotype with EATL. Patients with refractory sprue and/or ulcerative jejunitis are, therefore, suffering from a neoplastic T-cell
disorder for which hematological treatment strategies need to be devised.
© 1999 by The American Society of Hematology.
| |
INTRODUCTION |
ENTEROPATHY-ASSOCIATED T-cell lymphoma
(EATL) of the small intestine is a well-documented complication of
celiac disease.1 It may occur in patients with a life-long
history of celiac disease (gluten sensitive enteropathy) but more often
follows a short history of adult celiac disease, the assumption being
that these patients have had lifelong, albeit cryptic, gluten
sensitivity. In either case EATL is often heralded by a loss of
response to a gluten-free diet, a condition sometimes called refractory
sprue.2,3 However, not all cases of refractory sprue
necessarily progress to EATL. In a related complication of celiac
disease known as ulcerative jejunitis,4,5 nonspecific
inflammatory mucosal ulcers are present and these patients, too, become
resistant to a gluten-free diet. Some patients with ulcerative
jejunitis progress to develop EATL and, interestingly, multiple
inflammatory mucosal ulcers frequently accompany EATL itself.
The neoplastic cells of EATL are most commonly CD3+,
CD4 , CD8 and contain cytotoxic
granules recognized by the TIA-1 antibody.6 In a minority
of cases the cells may express CD8 and a subtype of the lymphoma has
recently been described in which the cells are both CD8+
and CD56+.7 These immunophenotypic features
approximate those of intra-epithelial T lymphocytes (IEL), which are
thought to be the normal cell counterpart of EATL.8
Intraepithelial lymphocytes are, however, phenotypically heterogeneous.9,10 Most are cytotoxic T cells that express CD3 and CD8 and have rearranged TCR chain genes. There is a minority population of CD4 CD8 IEL with
rearranged   but not chain genes. These T cells comprise 10% to 15% of IEL in normal mucosa but may increase in concentration in patients with celiac disease up to a level of 30%.11 Finally, there is a third population of
CD56+ cells that accounts for a very small fraction of
IEL10 that is virtually undetectable in immunostained
paraffin sections of normal or celiac mucosa (unpublished observations, 1998).
Isaacson et al,1 using Southern blotting and DNA extracted
from fresh frozen tissue, were the first to report monoclonal rearrangement of TCR genes in EATL. Subsequently, several groups have shown monoclonal rearrangement of TCR genes in EATL using polymerase chain reaction (PCR).12,13 This method has the
advantage that it is applicable to formalin-fixed paraffin-embedded
specimens, thus dramatically increasing the number of cases that can be
studied. Using PCR followed by sequence analysis, Murray et
al13 showed that there was a T-cell population in the
"uninvolved" enteropathic small intestinal mucosa adjacent to
EATL that shared the same monoclonal TCR rearrangement as the
lymphoma. Ashton-Key et al5 confirmed this finding and
further showed TCR monoclonality in the nonspecific
"inflammatory" ulcers and intervening enteropathic mucosa in
ulcerative jejunitis in the absence of any overt lymphoma. In cases of
ulcerative jejunitis where lymphoma subsequently developed, the same
clone could be detected in the malignant cells by PCR and sequence
analysis. This finding has recently been confirmed by Carbonnel et
al,14 who also confirmed the findings of Cellier et
al,15 who had shown that in refractory sprue monoclonal
populations of T cells were present in the small intestinal mucosa.
Cellier et al15 had also shown that this monoclonal
population was constituted by phenotypically abnormal
CD3 (CD3 +) CD4,
CD8 IEL.
The studies summarized above raise several questions regarding the
significance of the detection of a monoclonal T-cell population in the
small intestine. First, where exactly do these cells reside and what is
their phenotype? Second, what is the link, if any, between these
different complications of celiac disease that are characterized by
monoclonal populations of T cells in enteropathic mucosa? Third, is
clonality synonymous with neoplasia or even malignancy; and,
finally, what are the implications of detecting such a
population for patient management?
| |
MATERIALS AND METHODS |
Paraffin blocks of duodenal or jejunal biopsy specimens from cases of
uncomplicated celiac disease with biopsy evidence of gluten sensitivity
(n = 17) and from cases of celiac disease where there had been no
response to a gluten-free diet (n = 6) were retrieved from the surgical
pathology and consultation files of University College London Hospital.
In addition, representative blocks of ulcers or lymphomas and of
uninvolved enteropathic mucosa from small intestinal resection
specimens from patients with ulcerative jejunitis (n = 5) and EATL (n = 9) were retrieved from the same files. Nine of the biopsy specimens
from uncomplicated celiac patients, and tissue from all 5 cases of
ulcerative jejunitis and from 5 of the EATL cases had been partially
studied and reported previously.5 The clinical features
were briefly reviewed and the routine histopathological appearances
were also reviewed in each case.
Immunohistochemistry.
Paraffin sections were taken to water and heat-mediated antigen
retrieval was performed. Sections for CD3 and CD8 single or double
staining and CD56 staining were pressure cooked in citrate buffer (pH
6.0) for 2 minutes at full pressure. Slides for CD4 staining were
pressure cooked in EDTA buffer (pH 8.0) for 2 minutes at full pressure.
Sections were hand stained with CD4 (Vector Labs, Peterborough,
Lincs, UK) and CD56 (Bradsure Biologicals Ltd, Loughborough, Leicester, UK) using an immunoperoxidase ABC method and
counterstained with hematoxylin. Slides were stained with
polyclonal CD3 (polyclonal anti-CD3; Dako, Ely, Cambridge, UK) and
CD8 (Dako) on a Dako TechMate 500 using the Dako ChemMate
Labelled Streptavidin Peroxidase/DAB kit (K5001). Sequential double
staining for CD8 followed by CD3 was also carried out on a Dako
TechMate 500. CD8 was detected using the Peroxidase/DAB kit (brown
reaction product) and CD3 was subsequently detected using the Dako
ChemMate Alkaline Phosphatase kit (K5005) and visualized using Fast
Blue/Naphthol AS-BI (blue reaction product). Because the number of
CD4+ IEL is vanishingly small, the percentage of
CD4 CD8 IEL can be obtained by
counting the number of CD3+ cells (blue) in a total of 100 IEL (brown and blue) in preparations double-stained sequentially for
CD8 and CD3.
Molecular genetics.
DNA was extracted from paraffin sections using proteinase K digestion
without subsequent organic extraction as previously described.16 Duplicate aliquots of each sample were
analyzed for rearrangement of the TCR- chain gene using two sets of
primers.12 Set 1 consisted of primers directed to the
VI, VIII-IV, and J1/2 segments and set 2 of primers targeting
VI, VIII-IV, and JP1/2. Forty cycles of PCR of 1 minute at
93°C, 1 minute at 55°C, and 1 minute at 73°C were performed
after hotstart by addition of Taq polymerase at 55°C after 5 minutes at 95°C. The final extension time was extended to 6 minutes. DNA extracted from a paraffin block of a T-cell
lymphoma was used as a positive control and a reaction without template
DNA was run as a negative control in all experiments. Products were run
on 10% polyacrylamide gels, stained with ethidium bromide, and viewed
under UV light.
| |
RESULTS |
Results are summarized in Table 1.
Uncomplicated celiac disease.
There were 15 women and 2 men ranging in age from 19 to 73 years. All
patients had presented with malabsorption as adults and had responded
both clinically and histologically to a gluten-free diet. The initial
biopsy specimen was available for review in each case.
All biopsy specimens showed villous atrophy with crypt hyperplasia and
marked increase in IEL. Immunostaining confirmed that the IEL were
CD3+ T cells and showed scattered CD3+ T cells
in the lamina propria with occasional concentrations just above the
muscularis mucosae. The majority of IEL were CD8+ with only
rare CD4+ cells and even rarer CD56+ cells. The
lamina propria T cells were a mixed population that expressed both CD4
and CD8 in a ratio of approximately 2:1. In double-stained preparations
(see Fig 2A), the percentage of
CD4CD8 IEL ranged from 7% to
24%, with a mean of 17%. PCR analysis of TCR genes showed a
polyclonal ladder or smear in all cases
(Fig 1A).
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| Fig 1.
Polyacrylamide gels of TCR (set 1) PCR products. Lanes
M,  XHinfl molecular-weight markers (the 82-bp fragment is
indicated); lanes 1, positive control T-cell lymphoma; lanes 2, negative control without template DNA. (A) Lanes 3, 4, and 5, 6, and 7, 8: duplicate amplifications of three cases of uncomplicated celiac
disease. (B) Lanes 3, 4 and 5, 6: duplicate amplifications of two cases
of nonresponsive celiac disease. (C) Lane 3, EATL tumor mass; lanes 4 through 7, nonlymphomatous mucosa.
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| Fig 2.
Enteropathic mucosa from cases of (A) gluten-responsive
celiac disease, (B) refractory sprue, (C) ulcerative jejunitis, and (D)
EATL sequentially immunostained for CD8 (peroxidase-brown) and CD3
(alkaline phosphatase-blue). In (A) IEL are predominantly
CD8+ (brown) with only occasional CD3+,
CD4/8 (blue) cells. Note predominance of
CD3+, CD4+ (blue) cells in the lamina
propria. In (B through D), most IEL are CD3+,
CD4/8 (blue) with only occasional CD8+
(brown) cells.
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| Fig 3.
Enteropathic mucosa from a case of type B EATL . (A)
sequentially immunostained for CD8 (peroxidase-brown) and CD3 (alkaline
phosphatase-blue); (B) immunostained for CD56 (peroxidase-brown). Most
IEL are CD8+ (brown in A) and CD56+.
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Celiac disease unresponsive to a gluten-free diet.
This group comprised 5 women and 1 man whose ages ranged from 57 to 68 years. In three cases celiac disease had been diagnosed 3, 9, and
"many" years previously on the basis of malabsorption with
clinical and biopsy evidence of gluten sensitivity; none of these
patients had been tested for antibodies to endomysium, but one patient
had tested positive for antibodies to  -gliadin. In the three other
cases the patients presented with malabsorption and villous atrophy
with no prior clinical or biopsy evidence of gluten sensitivity. One of
these patients had two sisters in whom celiac disease had
been diagnosed and one had tested positive for endomysial
antibodies. Currently all six patients have persistent diarrhea and
anemia with iron and vitamin B12 deficiency; none has developed lymphoma.
The histological appearances were similar to the biopsy specimens from
uncomplicated celiac disease with an increase in cytologically normal
IEL. The lamina propria CD3+ T-cell population showed a
similar mixture of CD4 and CD8 cells, but there was a marked decrease
in the proportion of CD8+ IEL. This was confirmed in
CD8/CD3 double-stained preparations where the percentage of
CD4CD8 T cells ranged from 47%
to 90%, with a mean of 72.6% (Fig 2B).
PCR analysis of TCR genes showed a reproducible dominant band
indicative of a monoclonal population in five cases; in one case there
were two dominant bands consistent with biallelic monoclonal rearrangement (Fig 1B).
Ulcerative jejunitis.
There were 4 men and 1 woman whose ages ranged from 28 to 67 years. All
presented with severe abdominal pain due to an obstructing stricture or
perforation after a diagnosis of childhood celiac disease in three
cases and malabsorption "several" years and 2 years before
presentation, respectively, in two cases. Two patients had developed
EATL, 1 and 6 years, respectively, after the onset of ulcerative
jejunitis. Surgical resections of the intestine to include both
ulcerated and intact mucosa were performed in each case.
The intact mucosa showed the histological features of celiac disease as
described above. The immunohistochemical findings were almost identical
to those of the cases of unresponsive celiac disease except that the
percentage of CD4CD8 IEL in
double-stained sections was much higher, ranging from 73% to 100%,
with a mean of 88.6% (Fig 2C). Sections from the ulcer bases contained
a mixed CD4+, CD8+ population of T cells
without any detectable excess of CD3+,
CD4, CD8 cells in either single-
or double-stained preparations.
PCR analysis of TCR genes showed a reproducible dominant band
indicative of a monoclonal population in blocks taken from both the
intact mucosa and the ulcers in each case.
Enteropathy-associated T-cell lymphoma.
There were 3 women and 6 men whose ages ranged from 41 to 75 years. All
presented with complications of a small intestinal lymphoma with a
long-standing diagnosis of celiac disease in two cases. Surgical
resection of the lymphoma and uninvolved mucosa was performed in each case.
In six cases (type A), the lymphoma consisted of pleomorphic
medium-sized to large cells that were CD3+,
CD4, CD8. In three cases (type B)
the tumor cells were small and monomorphic and were CD3+,
CD4, CD8+, and CD56+. In all
cases the lymphoma cells contained TIA-1+ cytotoxic granules.
In all nine cases the intact mucosa showed the histological features of
celiac disease with marked increase in IEL. In the six group A cases
the percentage of CD4 CD8 IEL
calculated in double-stained sections ranged from 48% to 86% (Fig
2D). However, in the three group B cases the percentage of
CD4 CD8 IEL ranged from 7% to
18% (Fig 3A) and the great majority of CD3+ IEL expressed
both CD8 and CD56 (Fig 3B). In one of these cases small numbers of
CD56+ IEL were easily identified in both duodenal and
gastric biopsies that had been performed before resection of the lymphoma.
PCR analysis of TCR genes showed a reproducible dominant band
indicative of a monoclonal population in blocks taken from both the
lymphoma and uninvolved mucosa in each case (Fig 2C).
| |
DISCUSSION |
The presence of a monoclonal T-cell population in nonlymphomatous
enteropathic small intestinal mucosa has been described in EATL,
ulcerative jejunitis, and nonresponsive celiac disease.
5,12,13-15 Cellier et al,15 in a study of fresh
mucosal biopsy specimens, showed that in nonresponsive celiac disease
this population resides in the intraepithelial T-cell compartment. They
also showed that this population had a markedly aberrant
immunophenotype (sCD3, cCD3+,
CD4, CD8,
TCR, and ) in
comparison with the major sCD3+, CD8+,
TCR+ and minor CD4,
CD8 + populations of T cells that
comprise the increased IEL in uncomplicated celiac disease. Such
comprehensive immunophenotyping cannot be achieved in paraffin-embedded
material, but the same monoclonal IEL population can nevertheless be
demonstrated in paraffin sections of mucosal biopsy specimens from
nonresponsive celiacs by sequential double staining for CD8 and CD3,
which allows an estimation of CD3+,
CD4, CD8 T cells. The presence of
a similar increase in cCD3+, CD4,
CD8 IEL in the "uninvolved" enteropathic
mucosa in ulcerative jejunitis and type A EATL, which in both
conditions harbors a monoclonal T-cell population,5,13,16
strongly suggests that here, too, the clonal population resides in the
IEL compartment. Thus, the presence of a monoclonal IEL population
links the mucosa in these three conditions. It proved impossible to
show these abnormal T cells in the bases of the nonlymphomatous ulcers
in ulcerative jejunitis, despite molecular evidence of a monoclonal
population of T cells because of the large number of CD4+
and CD8+ T cells present as part of the inflammatory
process (data not shown).
Most cases of EATL are of the type A variety in which the neoplastic
cells express CD3 but are CD4 and
CD8. Sequence analysis has shown that these tumor
cells are clonally identical with a T-cell population in the
enteropathic mucosa now identified as the IEL.5,13 This
points to a direct link between the monoclonal T-cell population in
nonresponsive celiac disease, ulcerative jejunitis, enteropathic
nonlymphomatous mucosa in EATL, and EATL itself. In keeping with this,
EATL is a well-recognized complication of the two former conditions.
The immunophenotypic features of nonlymphomatous mucosa in type B EATL
in which the neoplastic cells are CD3+,
CD8+, and CD56+7 illustrates this
point more graphically. In the three cases studied, the IEL in the
enteropathic, nonlymphomatous mucosa expressed the same
CD3+, CD8+, CD56+ phenotype as
the lymphoma. In one of these cases these CD56+ IEL were
present distant from the ileal lymphoma mass in both duodenal and
gastric mucosa. This finding is similar to that reported by Cellier et
al,15 who detected immunophenotypically aberrant IEL in
rectal biopsy specimens from their cases of nonresponsive celiac disease.
The interpretation of the results reported in this study should take
into account other studies which have shown that IEL isolated from
intestinal mucosa are oligoclonal and that the same dominant clones may
be found at different sites along the small intestine.17,18
Had this been a factor one would expect a dominant clone to be present
in many, if not all, biopsy specimens from uncomplicated celiac
disease, which was not the case (Fig 1A). The PCR finding of a dominant
T-cell clone within DNA extracted from full-thickness intestinal
mucosa, which includes the T-cell rich lamina propria, is, thus, strong
evidence of a neoplastic population. This interpretation is reinforced
by the finding of the same neoplastic clone in EATL and nonlymphomatous
mucosa and in the mucosa from cases of ulcerative jejunitis and
subsequent lymphoma.
On the basis of previous molecular analyses5,13 and the
immunophenotypic findings in this study, it would seem safe to conclude
that the monoclonal IEL in patients with complications of coeliac
disease are neoplastic, although they are not cytologically abnormal
and they do not form tumor masses. The accumulation of phenotypically
aberrant, monoclonal IEL appears to be the first step in the genesis of
EATL. With the recognition that patients with nonresponsive celiac
disease and/or ulcerative jejunitis are in fact suffering from a
neoplastic T-cell disorder, possibly involving most of the
gastrointestinal tract, gastroenterologists will increasingly turn to
hematological oncologists for help in treating these difficult
patients. It remains to be seen whether current chemotherapeutic
regimes have anything to offer in this respect or whether new
strategies will need to be devised. Further cell and molecular
biological investigations are indicated particularly to establish the
precise relationship between the neoplastic IEL and the cells of fully
developed EATL.
| |
ACKNOWLEDGMENT |
The authors thank Dr A.D. Rogers, Dr L. Krenacs, and Prof P. Ciclitera
for permission to use their cases.
| |
FOOTNOTES |
Submitted December 4, 1998; accepted February 25, 1999.
Supported by the Leukaemia Research Fund.
The publication costs of this
article were defrayed in part by
page charge payment. This article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. section
1734 solely to indicate this fact.
Address reprint requests to Peter G. Isaacson, MD,
Department of Histopathology, Royal Free and University College Medical
School, University St, London WC1E 6JJ, UK.
| |
REFERENCES |
1.
Isaacson PG, O'Connor NTG, Spencer J, Bevan DH, Connolly CE, Kirkham N, Pollock DJ, Wainscoat JS, Mason DY:
Malignant histiocytosis of the intestine: A T-cell lymphoma.
Lancet
2:688, 1985[Medline]
[Order article via Infotrieve]
2.
Trier JS:
Celiac sprue.
N Engl J Med
325:1709, 1991[Medline]
[Order article via Infotrieve]
3.
Weinstein WM:
Intractable celiac sprue, in
Barkin J,
Rodgers A
(eds):
Difficult Decisions in Digestive Disease. St Louis, MO, Mosby, 1994, p 257.
4.
Jewell DP:
Ulcerative enteritis.
Br Med J
287:1740, 1983
5.
Ashton-Key M, Diss TC, Pan LX, Du MQ, Isaacson PG:
Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy associated T-cell lymphoma.
Am J Pathol
151:493, 1997[Abstract]
6.
De Bruin PC, Connolly CE, Oudejans JJ, Kummer JA, Jansen W, McCarthy CF, Meijer CJLM:
Enteropathy associated T-cell lymphomas have a cytotoxic T-cell phenotype.
Histopathology
31:313, 1997[Medline]
[Order article via Infotrieve]
7.
Chott A, Haedicke W, Mosberger I, Fodinger M, Winkler K, Mannhalter C, Muller-Hermelink H-K:
Most CD56+ intestinal lymphomas are CD8+ CD5 T-cell lymphomas of monomorphic small to medium size histology.
Am J Pathol
153:1483, 1998[Abstract/Free Full Text]
8.
Spencer J, Cerf-Bensussan N, Jarry A, Brousse N, Guy-Grand D, Krajewski AS:
Enteropathy associated T-cell lymphoma (malignant histiocytosis of the intestine) is recognized by a monoclonal antibody (HML1) that defines a membrane molecular on human mucosal lymphocytes.
Am J Pathol
132:1, 1988[Abstract]
9.
Russell GJ, Winter HS, Fox VL, Bhan AK:
Lymphocytes bearing the T-cell receptor in normal human intestine and celiac disease.
Hum Pathol
22:690, 1991[Medline]
[Order article via Infotrieve]
10.
Lundqvist C, Vladimir B, Hammarstrom S, Athlin L, Hammarstrom M-L:
Intraepithelial lymphocytes. Evidence for regional specialization and extrathymic T-cell maturation in the human gut epithelium.
Intern Immunol
7:1473, 1995[Abstract/Free Full Text]
11.
Spencer J, Isaacson PG, Diss TC, MacDonald TT:
Expression of disulfide-linked and non-disulfide-linked forms of the T-cell receptor / heterodimer in human intestinal intraepithelial lymphocytes.
Eur J Immunol
19:1335, 1989[Medline]
[Order article via Infotrieve]
12.
Diss TC, Watts M, Pan LX, Burke M, Linch D, Isaacson PG:
The polymerase chain reaction in the demonstration of monoclonality in T-cell lymphomas.
J Clin Pathol
48:1045, 1995[Abstract/Free Full Text]
13.
Murray A, Cuevas D, Jones B, Wright DH:
Study of the immunohistochemistry and T-cell clonality of enteropathy associated T-cell lymphoma.
Am J Pathol
146:509, 1995[Abstract]
14.
Carbonnel F, Grollet-Bioul L, Brouet JC, Teilhac MF, Cosnes J, Angonin R, Deschaseaux M, Chatelet FP, Gendre JP, Sigaux F:
Are complicated forms of celiac disease cryptic T-cell lymphomas?
Blood
92:3879, 1998[Abstract/Free Full Text]
15.
Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni J-P, Burtin M-L, Guy-Grand D, Bouhnik Y, Modigliani R, Barbier J-P, Macintyre E, Brousse N, Cerf-Bensussan N:
Abnormal intestinal intraepithelial lymphocytes in refractory sprue.
Gastroenterology
114:471, 1998[Medline]
[Order article via Infotrieve]
16.
Diss TC, Pan L, Peng H, Wotherspoon AC, Isaacson PG:
Sources of DNA for detecting B-cell monoclonality using PCR.
J Clin Pathol
47:493, 1994[Abstract/Free Full Text]
17.
Blumberg RS, Yockey CE, Gross GG, Ebert EC, Balk SP:
Human intestinal intraepithelial lymphocytes are derived from a limited number of T cell clones that utilize multiple V beta T cell receptor genes.
J Immunol
150:5144, 1993[Abstract]
18.
Gross GG, Schwartz VL, Stevens C, Ebert EC, Blumberg RS, Balk SP:
Distribution of dominant T cell receptor beta chains in human intestinal mucosa.
J Exp Med
180:1337, 1994[Abstract/Free Full Text]
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|
|
M. D. Aljurf, T. W. Owaidah, A. Ezzat, E. Ibrahim, and A. Tbakhi
Antigen- and/or immune-driven lymphoproliferative disorders
Ann. Onc.,
November 1, 2003;
14(11):
1595 - 1606.
[Full Text]
[PDF]
|
|
|
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|
|
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S. Daum, R. Ullrich, W. Heise, B. Dederke, H.-D. Foss, H. Stein, E. Thiel, M. Zeitz, and E.-O. Riecken
Intestinal Non-Hodgkin's Lymphoma: A Multicenter Prospective Clinical Study From the German Study Group on Intestinal Non-Hodgkin's Lymphoma
J. Clin. Oncol.,
July 15, 2003;
21(14):
2740 - 2746.
[Abstract]
[Full Text]
[PDF]
|
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P.D. Howdle, P.K. Jalal, G.K.T. Holmes, and R.S. Houlston
Primary small-bowel malignancy in the UK and its association with coeliac disease
QJM,
May 1, 2003;
96(5):
345 - 353.
[Abstract]
[Full Text]
[PDF]
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ABSTRACT
INTRODUCTION