Context Celiac disease is one of the most common lifelong disorders. Non-Hodgkin
lymphoma is a possible complication of celiac disease and may lead to a large
portion of lymphoma cases.
Objective To quantify the risk for developing non-Hodgkin lymphoma of any primary
site associated with celiac disease.
Design and Setting Multicenter, case-control study conducted between January 1996 and December
1999 throughout Italy.
Patients Cases were older than 20 years (median, 57; range, 20-92 years) with
non-Hodgkin lymphoma of any primary site and histological type and were recruited
at the time of the diagnosis. Controls were healthy adults (2739 men and 2981
women) from the general population.
Main Outcome Measure Positive test result for class A serum antiendomysial antibody.
Results Celiac disease was diagnosed in 6 (0.92%) of 653 patients with lymphoma.
Of the 6 cases, 3 were of B-cell and 3 were of T-cell origin. Four of 6 cases
had lymphoma primarily located in the gut. In the control group, 24 (0.42%)
had celiac disease. The odds ratio (adjusted for age and sex) for non-Hodgkin
lymphoma of any primary site associated with celiac disease was 3.1 (95% confidence
interval [CI], 1.3-7.6), 16.9 (95% CI, 7.4-38.7) for gut lymphoma, and 19.2
(95% CI, 7.9-46.6) for T-cell lymphoma, respectively. The risk for non-Hodgkin
lymphoma for the overall population, which was adjusted for age and sex, was
0.63% (95% CI, − 0.12% to 1.37%).
Conclusion Celiac disease is associated with an increased risk for non-Hodgkin
lymphoma, especially of T-cell type and primarily localized in the gut. However,
the association does not represent a great enough risk to justify early mass
screening for celiac disease.
The association between celiac disease (CD) and lymphoma has long been
established. In 1937, Fairly and Mackie1 reported
the association of malignant lymphoma of the small intestine with steatorrhea.
In 1962, Gough et al2 described 5 cases of
small intestinal lymphoma in patients with long-standing CD. A series of celiac-associated
lymphomas have since been reported.3-5
The most frequent malignancy associated with CD is a high-grade, T-cell non-Hodgkin
lymphoma (NHL) of the upper small intestine, currently defined as enteropathy-associated T-cell lymphoma (EATL), that peaks in the sixth
or seventh decade of life.6 Also CD may be
associated with other NHL types of both the B- and T-cell type in either the
gut or other primary sites.7,8
Holmes et al provided evidence that dietary compliance to a gluten-free diet
(GFD) reduces the risk of lymphoma and other malignancies in CD.9
Although it is widely accepted that EATL is a possible complication
of CD, this is a rare malignancy accounting for less than 0.5% of new NHL
cases.10,11 From the public health
perspective, the overall NHL risk associated with CD is more important, but
this is far from clear.12 Available studies
indicate a strongly increased relative risk (RR), in the range of 40 through
100,9,13 emphasizing the high
prevalence of this cancer's association in adults with CD. Such a "pessimistic"
view is apparently confirmed by mortality analysis in CD patients showing
(1) a 31- to 69-fold increased risk for dying from lymphoma,14,15
(2) an 18% prevalence of lymphoma as cause of death.16
It has recently become clear that CD is one of the most common lifelong disorders
both in Europe and the United States, affecting around 1 in 200 persons in
the general population. Most cases currently remain undiagnosed due to lack
of symptoms or atypical complaints (5 to 10 for each patient clinically diagnosed
with CD).17,18 All these untreated
persons are potentially exposed to the risk for long-term sequelae.19,20 This has led to renewed interest
in the NHL connection because CD could be responsible for a large portion
of the NHL burden. In the United States, NHL is the sixth most common cancer,
in terms of both new cases and mortality,21
with an incidence of 17.1 person-years per 100 000 among men and 11.5
among women.22
To accurately estimate the CD-associated risk for NHL, we conducted
this multicenter, case-control study to compare the prevalence of CD in patients
with newly diagnosed NHL and in population controls, using the class A serum
antiendomysial antibody (EMA) as the screening test. The aims were to evaluate
whether CD is a risk factor for developing NHL and to quantify the odds ratio
(OR); measure the impact of CD in causing NHL in the general population by
quantifying the population attributable risk (AR); and investigate the histopathological
and clinical spectrum of CD-associated NHL.
The study was carried out between January 1996 and December 1999. Cases
were patients who were at least 20 years old with NHL of any primary site
and histological type, at the first time of diagnosis, who had not yet started
chemotherapy and/or radiotherapy. Patients with acquired immunodeficiency
syndrome were excluded from the study. Cases were recruited on a consecutive
basis (all eligible patients seen consecutively by each center were asked
to enter this study). The control group was obtained by merging the results
of 2 population studies that have been separately described elsewhere.23,24 The overall control sample included
5720 adults who participated in 2 mass CD screening projects performed in
small towns with low immigration; thus, 99% of the population is homogeneous
(3483 in Campogalliano in Northern and 2237 in San Marino in Central Italy).
After obtaining informed consent, we first asked each participant for
detailed clinical information that focused on NHL characteristics (cases only)
and asked them whether they had ever had a previous diagnosis of and had received
treatment for CD. The type of NHL was recorded according to the Revised European-American
Lymphoma (REAL)25 and the Working Formulation26 classifications. We then measured serum levels of
IgA class EMA and total IgA. Measurement of IgG– and IgA–antigliadin
antibodies (AGA) was performed in patients with NHL and associated CD. The
small intestinal biopsy was offered to 2 participants having either positive
EMA results or a deficiency in IgA serum levels (before starting chemotherapy).
The study protocol was approved by the ethical committee of the University
of Ancona.
In each participating center, the EMA determination was performed on
serum samples diluted 1:5 by indirect immunofluorescence, using either monkey
esophagus or human umbilical cord as the antigenic substrate, as previously
described.27 The quality control on EMA determination
was performed prior to the study and then yearly (5 EMA-positive and 5 EMA-negative
sera sent by the coordinating center to each participating center) showed
full, intercenter, consistent EMA readings. Every EMA-positive sera from all
NHL cases were checked by the coordinating center. The AGA levels were measured
by an enzyme-linked immunosorbent assay, using a commercially available kit
(Alfa-gliatest, Eurospital, Trieste, Italy).
In participants who tested positive for EMA, a minimum of 4 biopsy specimens
were taken by endoscopy from different levels of the descending duodenum.
According to current criteria,28 patients
with NHL were diagnosed as having CD if they had a positive EMA test result
that was associated with a typical celiac enteropathy at the small bowel biopsy
(partial or subtotal villous atrophy with an increase in the intraepithelial
lymphocyte count) or had a clinical history of treated CD as documented by
the previous findings of subtotal or partial villous atrophy at the small
intestinal biopsy and clinical and/or histological improvement after treatment
with a GFD. All slides of the intestinal biopsies were re-evaluated by the
coordinating center that finally assigned the patient to either the CD group
or the CD-unaffected group.
Preliminary calculations showed that with a sample size of at least
640 NHL cases, a study power of 0.92 was reached, given (1) the fixed number
of controls (n = 5720), (2) an estimated prevalence of CD in the general population
of 1 in 300 subjects, (3) an expected OR of 5, and (4) a .05 2-sided type
I error.
The risk for NHL associated with CD was estimated after adjustment for
sex and age and expressed as the Mantel-Haenszel estimator of the OR and the
corresponding 95% confidence interval (CI).29
Differences in ORs were evaluated by testing their heterogeneity among both
sex and age strata.30 The risk for NHL attributable
to CD was quantified by the Mantel-Haenszel estimator of OR and the proportion
of exposed cases.29 Asymptotic variance of
AR and the corresponding 95% CI were computed according to Greenland.31 For all hypotheses tested, 2-tailed P values less than .05 were considered significant.
A total of 1390 NHL cases were contacted and 653 were included in this
study (inclusion rate, 47%). Reasons for exclusion were lack of consent (25%),
missing serological data (18%), and failing inclusion criteria (10%). A check
performed at the end of the study showed that none of the participating departments
of pathology saw any other cases of EATL during the recruitment period (apart
from those included in this series).
The study group included 374 white men (57%) and 279 white women (43%)
with a median age of 57 years (range, 20-92 years). According to the clinical
staging, 364 (56%) of these were nodal, 275 (42%) extranodal, and 14 (2%)
undefined. Based on the Working Formulation classification, the malignancy
grading was low in 164 cases (25%), intermediate in 118 (18%), high in 338
(52%), and undefined in 33 (5%). Immunohistochemical analysis showed that
543 (83%) of these NHL specimens were of B-cell origin, 55 (8%) of T-cell
origin, 3 (1%) of null type, and 52 (8%) undefined. Overall there were 98
(15%) primary gut NHLs. These were localized in the mouth (2), stomach (64),
intestine nonspecified (6), small intestine (10), duodenum (2), jejunum (2),
ileum (5), colon (6), and rectum (1). Table
1 shows the NHL distribution according to the REAL classification.
No case of serum IgA deficiency was found in this NHL series.
Of 653 patients with NHL, 6 (0.92%) of them had an associated diagnosis
of CD, 3 were of B-cell and 3 of T-cell origin. Four out of 6 cases had lymphoma
primarily located in the gut. Table 2
shows the clinical features of the 6 NHL patients with associated CD. The
possibility of associated CD was considered in another patient, a 48-year-old
man with an anaplastic T-cell NHL of the tonsils. Two years before developing
the NHL, he presented with signs of intestinal malabsorption at which time
CD had been diagnosed. He also showed common variable hypogammaglobulinemia.
This case was not included in the CD-affected group since it was not possible
to ascertain whether the small intestinal damage was caused by the primary
immunodeficiency or by true CD.
Table 3 shows the distribution
of CD cases in the control group. The overall prevalence of CD in this population
sample was 24 of 5720 (1 in 238, 0.42%).
The CD-associated ORs and ARs of NHL are shown in Table 4. Significant association between CD and NHL of any primary
site was observed in both the overall and the male sample without significant
differences in OR between sexes. Stronger associations were found between
CD and either primary gastrointestinal or T-cell type NHL. The ARs were lower
than 1% for overall NHL. Attributable risk values higher than 1% were observed
for both primary gut and T-cell NHL without reaching statistical significance.
The strength of association between a suspected risk factor and the
event, in this study CD and NHL, respectively, can be assessed by a case-control
study, provided that both cases and controls are representative of the target
population.32 Because the 47% recruitment rate
in this study was low, selection bias cannot be excluded. Exclusion was more
commonly related to logistics (eg, missing serological data or chemotherapy
having just started) than to personal or disease-related factors. Lack of
selection is suggested by the distribution of histological types and primary
sites of the 653 NHL cases that were investigated for CD. From study inception,
we excluded patients who were already receiving chemotherapy because this
treatment could affect the immunological response and reliability of the serological
screening tests (antiendomysial antibody). For the same reason, we did not
test patients who escaped the initial recruitment. The proportion of T-cell
lymphomas in this study was 8%, well within the range (6%-12%) expected from
previous European33 and North American studies.34,35 Likewise, the percentage of primary
gastrointestinal NHLs (15%) overlapped with the 12% to 16% prevalence reported
in previous European, population-based studies.10,36
As far as the control group is concerned, we believe that the prevalence of
CD in this healthy adult population sample (1:238) reflects the frequency
of the disease in the general Italian population because of the large size
of the sample and the homogeneous genetic background. This prevalence result
agrees substantially with previous data from both Italy37
and other Western countries.18,38
The IgA class serum EMA test, used for the celiac screening in this study,
is a powerful diagnostic tool with a reported sensitivity of 70% to 100%.39 It has recently been shown that tissue transglutaminase
is the autoantigen responsible for serum EMA positivity.40
Although EMA-negative CD patients have occasionally been described,41 this has never been reported in association with
NHL, a disease that is characterized, at least at the onset, by a preserved
serological response against self-antigens.42
Serum EMA disappear after starting treatment with a GFD, usually after 3 to
6 months. Not surprisingly, 3 of the 6 patients with associated CD who were
on a GFD when the diagnosis of NHL was made had negative EMA test results.
Although the proportion of T-cell type and intestinal NHL was greater
than expected among the 6 patients with associated CD, a typical EATL was
diagnosed in only 1 of the 6 cases, confirming that the spectrum of CD-associated
NHL is not restricted to this specific form of intestinal T-cell lymphoma.
This finding agrees with previous studies, 2 of which discussed patients with
dermatitis herpetiformis (DH), a disorder that is currently regarded as a
form of the gluten-sensitive enteropathy ("skin CD"). In a retrospective study
on 109 patients with DH, Leonard et al13 found
3 cases of NHL, 1 of which was malignant histiocytosis of the intestine, which
we interpreted as being EATL. The site of the other 2 cases was not reported
by Leonard et al. A series of 976 Swedish patients with DH who were followed
up for a mean period of 8.9 years had 13 NHL cases. Most of these tumors were
of the B-cell phenotype and were found outside the gastrointestinal tract.8 In a Dutch7 study of
14 patients with CD-associated T-cell NHL, a significant number had non-EATL
tumors, 4 having extranodal extraintestinal disease and 2 having nodal intestinal
lymphoma.7 Given the high prevalence of CD
in the general population, the association with non-EATL NHL may be due to
chance. However, the involvement of the small intestine in NHL can occasionally
be missed if it is not specifically looked for by performing a gastroduodenoscopy
and/or a small bowel x-ray examination43; then
again, it may become evident later in the course of the disease.44
The diagnosis of CD preceded the NHL onset in most cases (4 out of 6),
which somewhat limited the usefulness of the CD serological screening at the
NHL onset. The finding that NHL manifestations appear shortly after a period
of transitory response to the GFD (2 cases in this study) had previously been
reported.4 As Marsh45
theorized, it is probable that the onset of malignancy is the factor which
precipitates the shift from a silent to a clinically manifest form of CD,
with the latter diagnosed first and the NHL soon afterwards. This eventually
leads to a detection bias that could be responsible for the overestimation
of the CD-associated lymphoma risk in previous studies (see below).
This study confirmed that the risk for NHL of any primary site is significantly
greater in patients with CD than in the unaffected population. Since the estimate
of the OR was based on a small number of CD cases, this result must be interpreted
with caution. It is however interesting to note that the 3.1-fold increase
in NHL risk was notably lower than most previously available estimates. In
1983 Leonard et al13 reported an RR of 100
for lymphoma in patients with DH. In a series of 210 patients with CD from
Derby, England, followed up for at least 13 years, Holmes et al9
observed a highly significant excess of NHL of any primary site, with an RR
of 42.7 (95% CI, 19.6-81.4). In a large series of patients with DH (n = 976)
followed up for a mean period of 8.9 years, Sigurgeirsson et al8
found an RR of 5.4 (95% CI, 2.2-11.1) for developing NHL. Although the diverse
genetic and environmental backgrounds undoubtedly account for part of the
wide variation in these results, there are other conflicting factors that
have tended to produce misleading findings:
1. Due to the above mentioned detection bias, even cases of CD that
have long been clinically silent or latent46
may be found in association with EATL. Conversely, uncomplicated CD cases
often remain undiagnosed and then do not contribute (with a dilution effect)
to the calculation of the lymphoma risk. In other words, previous studies
counted CD-associated lymphomas from both the visible and the submerged part
of the celiac iceberg, but these studies compared this figure only with the
small number of clinically diagnosed cases (the tip of the celiac iceberg),
therefore overestimating the magnitude of the cancer risk.
2. On the other hand, published series often included large proportions
of treated CD patients who have been found to be at a lower risk for complications,
especially if they were treated with GFD for more than 5 years.9
It is therefore not surprising that, occasionally, no increase in the lymphoma
risk is reported, this finding being attributed to the strict adherence to
the GFD.47
In our study, the CD-associated population AR of NHL was not significantly
higher than 0. From the public health perspective, this finding suggests that
the early diagnosis of all CD cases (eg, through serological mass screening)
cannot be expected to reduce significantly the impact of NHL on the general
population. Similarly, this study does not support the routine serological
CD testing of all patients with NHL at the onset, because of both the rarity
and the natural history of this association (CD being frequently diagnosed
first). Rather, we suggest that CD should be actively searched for in at-risk
NHL patients, such as those with a T-cell type lymphoma and/or a gut primary
localization. In a series of 119 patients with primary small bowel NHL, at
least 13 (10.9%) were associated with CD.11
Treatment with a GFD may ameliorate the prognosis of these cases, eg, by improving
the nutritional status and the absorption of drugs given orally.
In conclusion, our study confirms that CD is associated with a significantly
increased risk for NHL, especially of the T-cell type and primarily localized
in the gut. The CD-lymphoma association seems, however, to be much less common
than previously thought, thereby placing CD in the range of being a moderate
risk factor (RR, 2-4) for NHL of any primary site.
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