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Coeliac disease and malignancy
MINISYMPOSIUM
Coeliac
disease
DISEST LIVER DIS 2002;34:229-37
and malignancy
G.K.T.Holmes
The development of malignancy particularly lymphoma, is the most serious complication to affect patients with coeliac disease. Although the association has been known for about 40 years, there are still gaps in our understanding. The prevalence of lymphoma and why only some coeliac patients develop this are not clear but environmental and genetic factors must be at work. Based on data from a large coeliac clinic in Derby about 55 lymphomas per year would arise in the coeliac population of the United Kingdom, of which half would affect the small bowel. Whether patients with coeliac disease who have atypical or no symptoms at diagnosis, are at the same risk as those who are diagnosed as a result of classical symptoms as was more the case in the past, is not known. Some patients, howevel: do have coeliac disease and lymphoma diagnosed at the same presentation. This consideration has implications for initiating screening programmes to detect coeliac disease and thus offer patients a gluten-free diet early that would help to reduce the risk of lymphoma from developing. In this context, casefinding rather than blanket population screening is to be recommended on present evidence. Research into the role of intraepithelial lymphocytes in the genesis of lymphoma has indicated that non-responsive coeliac disease [refractory sprue] and ulcerative jejunoileitis (ulcerative jejunitis] are part of the lymphoma spectrum. The diagnosis of lymphoma can be difficult and the prognosis, in general, is poor: although with modern chemotherapeutic regimes and surgery in selected cases, long-term survival is possible. The best option is to try and prevent lymphoma from arising by advising all patients to adhere to a strict gluten-free diet. Malignant complications of coeliac disease are uncommon but will continue to challenge clinicians and clinical scientists. Unravelling the mechanisms that contribute to the development of lymphoma and other tumours in coeliac disease may well contribute to a wider understanding of oncogenesis.
Digest
Liver
Key words:
Dis 2002;34:229-37 coeliac
disease;
lymphoma;
malignancy
Introduction
Fmm Departmentof Medicine,DerbyshireRoyal Infirmaq Darby,UK.
Alwmsahw Dr. G.K.T.Holmes,DepaiZmentof Medicine,DerbyshireRoyalinfirmary, DerbyDE12Q’oy, UK Fax:+44-1332-2%764, E-mail:gea#reyho~mes&~mpuserve.c~m I
Patients with lymphoma and steatorrhoea were documented in the early literature when malabsorption was attributed to the presence of tumour in every instance. In 1962 however, Gough and his colleagues ’ suggested, for the first time, that lymphoma occurs as a complication of coeliac disease and this view was strengthened over the next few years 2-4.An increase in gastrointestinal carcinoma, in general, and oesophageal cancer, in particular, was also found to occur 3. Carcinoma of the small intestine in association with coeliac disease was first reported in 1958 5 and is now known to be the second most common invasive malignancy after lymphoma 6. O’Farrelly et al. 7 coined the term enteropathy-associated T-cell lymphoma (EATL) in 1986 but this has recently been updated to enteropathy-type in. -___ _ -_. testmal ‘l:cell lymphoma. This is rare and only accounts for less than 1% of 228
Coeliac disease and malignancy
all non-Hodgkin’s lymphoma x. Much is known about the malignant complications of coeliac disease 9 but much remains obscure and some of these areas are addressed in this review.
Prevalence of malignant complications The precise prevalence of malignancy in coeliac disease is unknown. There are several reasons for this. Thus, it is now clear from screening and case-finding studies that many coeliac patients without symptoms or only mild or atypical complaints may never be diagnosed ‘O“, so that the prevalence of coeliac disease in the general population is unknown. If postmortems are not carried out, the presence of malignancy, particularly lymphoma, will be underestimated. Furthermore, patients with established lymphoma may have coeliac disease that remains undiagnosed ‘* and information reported from referral centres is unlikely to be representative and cannot be extrapolated to the whole coeliac population in a particular locality. Finally, the wider use of the gluten-free diet (GFD) is known to alter the risk of lymphoma developing and some coeliac populations may be at greater risk than others. When speaking of the prevalence of malignancy in coeliac disease, therefore, it is necessary to add a number of caveats. Prevalence must be considered in the light of the completeness of case collection for coeliac disease and malignancy, the population and geographical area under review, the length of follow-up and when the series were collected, how malignancies were diagnosed, the causes of death, whether patients were attending a referral centre and the use and strictness of the GFD. Several series of patients with malignancy and coeliac disease are available 34 ‘3-‘5.Although the prime intent in assembling these was not to obtain prevalence data for malignant complications, nevertheless, figures are often quoted as if this were the case (Table I). Even in those series that did attempt to determine prevalence 16-*0fig-
tible I. Prevalence of malignancy in coeliac disease. Years
N. CD
Tellleers
N.
%
1941-65
202
Malignancy Lymphoma
32 14
16 7
3
1941-75
202
Malignancy Lymphoma
43 18
21 9
4
1969-81
198
Malignancy Lymphoma
16 10
8 5
13
1969-94
166
Lymphoma
13
8
14
1972-94
400
Lymphoma
31
8
15
230
lleference
l&bla II. Prevalence of malignancy in coeliac disease. Yem
N. CD
linneen
N.
%
lbfmwe
196577
74
Lymphoma
5
7
16
1958-78
93
Malignancy Lymphoma
IO 4
11 4
17
1964-82
100
Malignancy Lymphoma
i
i
18
1980-90
335
Malignancy Lymphoma
IO 0
3 0
19
1980-97
216
Malignancy Lymphoma
ures varied from 3% to 11% for all cancers and 0% to 7% for lymphoma, which are quite widely differing results (Table II). In a study of cancer mortality among 653 patients with coeliac disease from Edinburgh and the Lothians after 22.5 years of follow-up, 21 deaths (3.2% of the series and 11.2% of all deaths) resulted from lymphoproliferative disorders 2’. The number of patients with oesophageal and intestinal carcinoma was small. Associated disorders were analysed in a casecontrol study of 458 patients with coeliac disease who were discharged from hospitals of the Department of Veterans Afairs between 1986 and 1995 22. The association with lymphoma was confirmed with an odds ratio of 4.5. An association with gastrointestinal cancer in general and with individual cancers could not be demonstrated but studies of this kind, as the authors recognised, are subject to selection bias. In a study from Sicily20 between 1980 and 1997 of 216 coeliac patients, 12 deaths were observed for an expected number of 4.12. Lymphoma occurred in 7 patients of whom 4 had died. As acknowledged by the authors, these data came from a referral centre and the variety of malignancies that were found over a 17-year period appeared to be limited. The frequency of other tumours in coeliac disease such as lung and colon cancer should receive more attention because of a possible link 2’ 23. Lymphoma may also complicate dermatitis herpetiformis with a frequency up to 2.8% 24. In contrast to coeliac disease without dermatitis herpetiformis, there is no evidence for an increased risk of gastrointestinal cancer 15.
Prevalence of coeliac disease in the Derby area Coeliac disease was first diagnosed in the Derby area in 1958 and by the end of 1999,673 cases were on the coeliac register of whom 599 are alive. I have run the Derby coeliac clinic personally since 1978. The population from which these patients come is approximate-
-
G.K.T. Holmes
ly 360,000 so that the prevalence for all cases is 1 in 535 and for those alive 1 in 601. Of the 74 deaths, 33 were due to malignancy and 4 1 to non-malignant causes but in this latter group 4 had malignant disease. Altogether, there were 70 malignancies in 65 patients (4 patients each had more than 1 tumour). Twenty-eight patients with malignancy were alive at the end of 1999 and 37 had died but 4 patients with malignancy died of non-malignant causes. Ten lymphomas occurred and 5 of these involved the small bowel. Of the 24 tumours involving the gastrointestinal tract, 2 were in the oesophagus and 2 in the jejunum (Table III). These data give an indication of how commonly lymphoma will be encountered as a complication of coeliac disease and indicate that 1 lymphoma would occur among 673 coeliac patients accrued over 4.2 years. A lymphoma involving the small bowel would be seen every 8.4 years. The frequency of carcinoma of the oesophagus and jejunum is much less and only 1 such tumour would be seen in 673 coeliac patients accrued over 21 years.
Table III. Lymphomas and carcinomas involving gastrointestinal tract arising in 673 patients with coeliac disease diagnosed in Derby area 1956-l 999. Lymphomas Gastrointestinal carcinomas Tongue Oasophagus Jejunum Pancreas Rectum Parotid Stomach Hepatoma Colon
24 2 2
3
It is also possible to make an estimate of the total number of lymphomas that would be encountered in the whole coeliac population of the United Kingdom based on the Derby figures. For a prevalence of coeliac disease in the population of 1 in 535 the number of coeliacs in the United Kingdom would be 102,804. In this group, 55 lymphomas would be expected per year and of these 28 would involve the small bowel. A full analysis of these data is currently being undertaken. It is of interest that preliminary data coming from a national survey of primary small intestinal tumours presenting in the United Kingdom over a recent 12-month period gave figures for lymphomas associated with coeliac disease to be 20 but account must be taken of the return rate for questionnaires which was about half of those sent out 26.
Cellular origins of lymphoma T and B lymphocytes The lymphoma that complicates coeliac disease is now widely referred to as EATL’ but B-cell tumours also occur. Morgan et al. 27 regarded 7 out of 11 cases to be of B-cell origin but this work was criticised on the grounds that coeliac disease was not clearly defined in these patients 28 and the authors themselves considered that their study required re-evaluation 2y. Two B-cell tumours were discovered in a series of 13 lymphomas but only one occurred in the intestine 14.One patient regarded as having immunoproliferative disease of the small intestine complicated by B-cell lymphoma ‘O may have had coeliac disease 3’. In a series of coeliac associated lymphomas, one of 24 tumours available for assessment was of B-cell type 15.B-cell lymphomas as well as Hodgkin’s disease may affect dermatitis herpetiformis 25. Of 13 lymphomas found in 976 patients with dermatitis herpetiformis, most were of B-cell type and occurred outside the gastrointestinal tract and only one could be classified as EATL 24. Lymphomas that occurred in 487 cases of dermatitis herpetiformis were of T- and B-cell lineage 32. A Birkitt-type intestinal lymphoma in a child with coeliac disease originated from B cells 33. A T-cell rich B-cell lymphoma 34and a lymphoma of B-cell origin 35 have also been described in children. Anecdotal evidence suggests that lymphoma may affect children with coeliac disease more commonly than reports in the literature indicate and a group of paediatricians is currently exploring this. In a review of 119 primary small bowel lymphoma, 41 were of T- and 78 of B-cell phenotype 36. In 20 patients, the T-cell tumour was associated with enteropathy and these tumours predominated in the jejunum. No B-cell lymphomas were associated with enteropathy. No morphological differences were found in T-cell lymphomas with or without enteropathy. Thus, EATL appears to be a clinical rather than a distinct pathological entity. Intraepithelial lymphocytes The earliest morphological abnormality of the small intestinal mucosa in coeliac disease is infiltration by lymphocytes. Most intraepithelial lymphocytes (IEL) express CD3 and CD8 and have rearranged T-cell receptor (TCR) I3 chain genes. A minority are CD4- and CD8- with rearranged y/S chain genes and normally these form lo- 15% of the IEL population but, in coeliac disease, comprise up to 30%. A very small proportion are CD56 positive. IELs are cytotoxic cells and, as judged by granzyme B- and T-cell restricted intracellular antigen, are in a resting state in normal mucosa but are activated in coeliac mucosa 37. There has been growing interest in IELs and their role
231
Coeliec disease and malignancy
in the development of EATL. A monoclonal antibody, HML- 1, developed against IEL also reacts with T-cells of T-cell lymphoma that complicates coeliac disease 3x. De Bruin et al. 39 found that 10 out of 13 (77%) EATLs contained granzyme B positive cells and subsequently provided further evidence that EATL are derived from cytotoxic IEL in that, of 8 cases studied, all exhibited a cytotoxic phenotype 4o. Others have supported this view 4’. A patient with coeliac disease was reported with a low grade, small cell intestinal lymphoma of IEL and concomitant EATL 42. The neoplastic IEL showed cytoplasmic granules and expressed the alp TCR. The phenotype of the small cell tumour was HLM-l+, CD3+, CD7+, CD4-, CD8- which resembles that of EATL, although CD8+ tumours do occurJ3. Unfortunately, the large cell lymphoma in this report was not typed. A T-cell population was found in mucosa adjacent to EATL that shared the same monoclonal TCRy rearrangement as the lymphoma444s. These observations support the concept that a low grade T-cell lymphoma can be present in the epithelium and lie dormant for a long time before giving rise to overt lymphoma. In the T-cell lymphomas described by Domizio et al. 36, the phenotype of the IELs fell into two main groups. Some showed a phenotype similar to the associated lymphomas suggesting that these were intraepithelial neoplastic cells, while others appeared to be infiltrating native T-cells.
Non-responsive coeliac disease [refractory spruel and lymphoma The large majority of patients with coeliac disease improve clinically and in terms of small intestinal mucosal architecture when they adhere to a strict GFD. Some of the few patients who do not improve, may have a lymphoma, jejunoileitis (ulcerative jejunitis) or mesenteric lymph node cavitation syndrome, or be non-responders for no apparent cause. The prognosis is poor. Non-response may be present from the outset of the coeliac diagnosis or occur after a period of response to GFD. In a study of 6 cases, all had the DQAl*0501/DQB 1*0201 phenotype and endomysial and/or antigliadin antibodies were present before starting a GFD or during a time of poor dietary compliance 4h. These markers provide strong evidence for the presence of underlying coeliac disease. Over 20 years ago, Isaacson and Wright 47argued that ulcerative jejunitis is a manifestation of lymphoma because these two conditions are so closely related. Wright et al. 48, in 1991, posed the provocative question, is adult coeliac disease due to a low grade lymphoma of intraepithelial T-lymphocytes? They studied a resected specimen of jejunum apparently complicated by chronic ulceration
from a patient with coeliac disease. The authors suggested that the abnormal typing of the lymphoid cells and the clonality of the infiltrate favoured a diagnosis of lymphoma. Polymerase chain reaction amplification of the T-cell receptor y chain gene was carried out on DNA extracted from lymphoma, associated benign inflammatory ulcers and intervening mucosa in 6 patients with EATL and from ulcers and intervening mucosa in 7 cases with ulcerative jejunitis 44. The same cell clone could be demonstrated in EATL, associated ulcers and uninvolved mucosa and in ulcerative jejunitis, and uninvolved mucosa. Furthermore, when lymphoma developed in ulcerative jejunitis the same clone was shown to be present in both. A study of 6 cases of non-responsive coeliac disease, showed that the normal IEL population was replaced by morphologically normal but phenotypically abnormal cells that express intracytoplasmic CD3 but not surface CD3 and lacked TCR, CD8 and CD4 and showed restricted TCRy gene rearrangements 16 4y. None of these patients had overt lymphoma but the prognosis was poor in that 3 patients died. Further evidence has been provided that patients who do not respond to GFD with or without ulcerative jejunitis have low grade T-cell 1ymphoma”O. Bagdi et al. s1 bring together the evidence that IEL in ulcerative jejunitis, non-responsive coeliac disease and EATL constitute a neoplastic population of cells. Furthermore, Cellier et al. szprovide evidence that coeliac disease and refractory sprue are related and that refractory sprue links coeliac disease and EATL. These authors demonstrated the presence of endomysial and antigliadin antibodies, the HLA-DQw2 phenotype and an earlier clinical and histological response to the GFD in many of their patients with refractory sprue. In addition, those patients with an aberrant phenotype namely, intracytoplasmic CD3 but not surface CD8 and TCRy gene rearrangement had a poor prognosis. Conversely, 3 patients without these abnormalities experienced prolonged clinical and histological remission when given steroids and a GFD. A simple immunostaining method using anti-CD3 and anti-CD8 on paraffin sections can differentiate untreated coeliac disease from refractory sprue 53. A normal CD3, CD8 IEL population indicates poor compliance with a GFD or slow response. Those patients with an abnormal CD3+, CD& phenotype should be tested further for TCRy rearrangement to confirm the diagnosis of refractory sprue which carries a poor prognosis and requires more intensive follow-up. It is not known why the small intestinal mucosa of these patients does not respond to GFD but remains flat. It is possible that the IELs damage the enterocytes and, thereby, the mucosa, directly or via pro-inflammatory cytokines. I have encountered a patient who first presented in
G.K.T. Holmes
1983 with diarrhoea, weight loss and anaemia. A small intestinal biopsy was unsuccessful and because of radiological appearances of ulcerative jejunoileitis and clinical deterioration, a laparotomy was performed. The jejunum was oedematous and a 40 cm length was resected on the suspicion of lymphoma. Histological examination of the specimen revealed villous atrophy and an experienced histopathologist confidently diagnosed lymphoma on the strength of intraepithelial lesions with clusters of lymphocytes invading and destroying the crypts. The patient however, responded well to a GFD and no further treatment was undertaken. Between 1988 and 1992 he failed to attend the clinic for review but in 1992 presented with a mass in the left iliac fossa which proved to be a large cell, anaplastic lymphoma. It is not known whether this man had involvement of the small bowel with lymphoma but he responded to chemotherapy and survived until November 1999. It is likely that a small cell lymphoma of the IEL gave rise, after a long latent period, to a large cell tumour and he enjoyed a long survival. Another patient of mine presented in 1987 when coeliac disease was diagnosed by small bowel biopsy and she responded well to a GFD. About 1 year later however, she presented with weight loss and diarrhoea and jejunoileitis was diagnosed from radiological appearances of the small bowel. She was gravely ill and required prolonged parenteral nutrition and corticosteroids. She slowly improved and is presently in complete remission and maintained on a GFD and azathiaprine. This patient has survived for 12 years without any evidence of overt lymphoma, indicating the long latency that may be encountered and how difficult it is to know whether and when chemotherapeutic regimes should be offered. Mesenteric lymph node cavitation syndrome is a rare cause of non-responsive coeliac disease ” and may be associated with ulceration affecting the ileum ss. Abdominal scanning will show large cystic areas and so differentiate this benign condition from lymphoma affecting the lymph nodes. In one case, cavitating lymph nodes were found in association with multifocal lymphoma affecting the small bowel s6.
Genetic markers in coeliac disease and EAT1 Exploration of human leukocyte antigen (HLA) class II markers has shown that EATL arises on the same genetic background as that predisposing to coeliac disease I3 s7s8. In a recent study s8 on both disorders, significant increases were found in DRB1*03, DQA 1*050 1 and DQB 1*020 1. DRB 1*03,04 heterozygosity was significantly increased in EATL compared with coeliac patients and controls and reflects an
increase in DRBl*O4 in EATL patients. Thus DRB 1*04, or a sub-type, may be a potential marker for those coeliac patients who are at increased risk of developing lymphoma. No DQB I*020 1 homozygotes were found in the EATL series. How might DQB 1*0201 homozygosity confer protection against the development of EATL? A non-significant trend was observed towards a decreased DQB 1*0201 homozygosity and an increased incidence of DRB 1*04 in late, compared with early, age of onset of coeliac disease. So that those who are homozygous may have more severe symptoms that brings them to earlier diagnosis of coeliac disease and earlier treatment with a GFD. Since a GFD reduces the lymphoma risk, these patients would be at reduced risk of developing this malignancy s9. Conversely, those who are non DQB 1*020 1 homozygous may have subclinical disease that remains undetected and untreated with a GFD so that the risk of lymphoma developing is increased. A study of patients with coeliac disease and healthy controls indicated that in those individuals carrying the DQAl*0501 and DQB 1*0201 alleles, the presence of a second copy of the DQB 1*020 1 allele conferred an increased susceptibility to develop coeliac disease 60. Furthermore, a double dose of DQAl”O501, DQB 1*0201 genes may predispose patients to develop more severe manifestations of coeliac disease that, in turn, leads to earlier diagnosis “. These observations, while in their infancy, help to explain the heterogeneity of coeliac disease and the susceptibility of some patients to lymphoma.
Presentation and diagnosis The diagnosis of lymphoma complicating coeliac disease can be difficult because the presenting features are often non-specific and similar to those of uncomplicated coeliac disease at presentation or in relapse for other reasons such as lack of adherence to GFD. Unexplained deterioration, abdominal pain, weight loss, severe muscle weakness, lymphadenopathy, abdominal mass and pyrexia should arouse suspicion of lymphoma 436263. Presentation may be acute with intestinal obstruction or perforation or bleeding from lymphoma but, in many cases, the course is insidious I5 3643 62. There are those patients with long established coeliac disease who have responded to a GFD but with the onset of malignancy they deteriorate. It is accepted that, in these cases, lymphoma complicates coeliac disease. In others, the diagnosis of lymphoma and the demonstration of a flat upper small intestinal biopsy occur at about the same time and whether or not these have coeliac disease has been disputed on the grounds, for example, that such patients do not mount an antigliadin antibody response 7. Among the 16 patients reviewed 233
Coeliac disease and malignancy
by O’Farrelly et al. 7 however, were three with symptoms originating from childhood, whilst another had a 30-year history of diarrhoea suggesting that some of these cases did have coeliac disease complicated by malignancy, simply because it is unrealistic to attribute such long histories to lymphoma. The evidence indicates that most if not all of these have coeliac disease complicated by lymphoma. Thus, they have a similar HLA antigen profile l3 s758 as outlined above, a similar frequency of splenic atrophy or hyposplenism 6465 and similar changes in intraepithelial T-cell subsets 66 to patients with uncomplicated coeliac disease. This view is also supported by clonality studies 4s. The number of patients falling into this group is quite large. Of 13 lymphomas, 6 were diagnosed at the presentation of coeliac disease4. In the study of Swinson et al. 6 coeliac disease and malignancy were diagnosed, in the same episode, in 44 out of 215 patients, while in the series of Egan et al. I5, 23 out of 30 cases of lymphoma were in this category. Of 31 cases of EATL, only 12 were said to have a history of coeliac disease prior to the diagnosis of lymphoma 43. Although it is the development of lymphoma that precipitates the diagnosis of coeliac disease, in these patients, they often have long histories, sometimes from childhood, that are compatible with coeliac disease that has eluded previous diagnosis 4. One patient developed coeliac disease 42 months after the diagnosis of lymphoma and may well have been an example of latent coeliac disease that was precipitated by the emergence of a lymphoma36 as previously described 67. A small intestinal adenocarcinoma may present with intestinal obstruction, an abdominal mass or haemorrhage 6x. No pattern of routine blood tests allows the diagnosis of lymphoma to be made early. Subtle changes in small intestinal biopsies have been described in those with uncomplicated coeliac disease who go on to develop lymphoma compared with those who do not, such as lower plasma cell counts and higher lymphocyte counts in the lamina propria and lower lymphocyte counts in the epithelium (j9, the presence of hypoplastic crypts 70 and histiocytic aggregates 7’ but these are unlikely to be helpful in individual cases. Bowel radiology is mandatory but the typical multiple, narrowed segments characteristic of small intestinal involvement are not always seen and only a malabsorption radiological pattern may be evident even in the presence of lymphoma. Other investigations might include liver biopsy, examination of the bone marrow and small bowel enteroscopy but this is not without danger of perforation, Staging of lymphoma should be undertaken by computed tomography (CT) scanning so that appropriate treatment can be planned. CT scanning may also be of value in making a primary diagnosis of lymphoma 72. Definitive diagnosis may only be made at laparotomy or autopsy I5 43‘j2. 234
Screening for coeliac disease and case-finding An important question is whether those who are asymptomatic or have atypical or mild symptoms at the diagnosis of coeliac disease are at the same risk of developing lymphoma as those with more classical symptoms. It is likely that some are because, as mentioned above, in the various series there are patients in whom coeliac disease and lymphoma were diagnosed together and the development of malignancy precipitated the diagnosis of coeliac disease. These patients often had symptoms over many years that could be attributed to coeliac disease but because they were so mild did not lead patients to seek medical attention. Occasionally, patients regarded themselves as asymptomatic prior to developing malignancy 4. It could be argued that an earlier diagnosis of coeliac disease and treatment with a GFD might have prevented lymphoma from arising. This consideration raises the issue of screening for coeliac disease. Mass population screening would be an enormous undertaking with considerable costs. Overall health benetits of such programmes are not understood and there are ethical issues that require careful consideration. Case-finding rather than population screening is to be advocated on present evidence 73.
Treatment and prognosis Surgery, radiotherapy and chemotherapy may be used in suitable cases depending on the overall condition of the patient and the pathological staging. Unfortunately, in most patients, lymphoma is widespread at diagnosis and the prognosis is very poor with few patients surviving for more that one year I54362. Occasionally, a lymphoma may involve only a short segment of the small intestine and resection will result in a cure. I have a patient with established coeliac disease who presented with a single focus of lymphoma obstructing the jejunum. This was successfully resected and she remains well 16 years after the operation. Swinson et al. 6, found that of 84 coeliac patients with lymphoma diagnosed during life, 8 survived for more that 5 years after diagnosis and all of these presented with small intestinal lesions. Seven of the 8 underwent resection and some received chemotherapy and radiotherapy. Adenocarcinoma of the jejunum may similarly present with obstruction and be curable. I have encountered such a patient who has now survived for 14 years after surgery. Two recent papers have addressed the treatment and prognosis of EATL and are important because single centre experience is reviewed and the value of combination chemotherapy assessed. Thirty patients from Galway, Ireland, in records referring to the period be.--
G.K.T. Holmes
tween 1972 and 1994 were divided into 2 groups “. Group 1 was formed of 7 previously diagnosed coeliac patients who had responded to GFD but had subsequently developed lymphoma. Group 2 comprised 23 patients in whom coeliac disease and lymphoma were diagnosed simultaneously. In these, the symptoms of lymphoma led to the diagnosis of coeliac disease and they had never received or had been unresponsive to a GFD given for less than 1 year. Of the 23, 8 were not given treatment for lymphoma or were diagnosed at autopsy. The prognosis of these 8 (3 diagnosed during life) and those in group 1 (4 diagnosed during life) was very poor with average mean survival times from the diagnosis of lymphoma of 3.3 and 2.25 months, respectively. From group 2, 15 patients diagnosed during life had the lymphoma treated usually by surgery and chemotherapy. All but one of these presented as emergencies with intestinal obstruction or perforation or had an abdominal mass. The exception was a patient with diffuse gastric ulceration and B-cell nonHodgkin’s lymphoma on peripheral lymph node biopsy. Of the 15 cases, the assessment of 1 was still incomplete. Five died of lymphoma within 1 year, while 9 survived for a mean of 74 months (range lo- 196 months). Five were disease free and 3 died of other causes. Overall l-year survival was 3 1% and 5-year survival 11%. A number of chemotherapeutic regimes were used together with surgery. Gale et al. 43reported their experience of 31 patients gathered in Southamptom, United Kingdom, between 1979 and 1996. A total of 24 patients were given combination chemotherapy after diagnosis. A variety of regimes were used. Less than half of the patients completed their courses because of poor nutritional state or complications associated with the treatment such as gastrointestinal bleeding and small bowel perforation. At the time of report, 26 (84%) of the 31 patients had died and their median survival was only 7.5 months (range O-83). Five patients who were still alive and disease free had survived for 49 to 219 months after diagnosis. The actuarial I- and 5-year survival rates were 38.7% and 19.7%, respectively and 1- and 5-year failure free survival rates of 19.4% and 3.2%, respectively. The prognosis of coeliac-associated lymphoma has been considered worse than for primary gastrointestinal lymphoma 15.This has been attributed to the added debility from malabsorption or the adverse effects of immunological abnormalities that occur in coeliac disease. In the review of Domizio et al. 36however, the presence of enteropathy had no significant effect on survival of those with EATL. Bowel perforation, multiple tumours and high grade histology were noted to have an adverse effect on outlook. For low grade B-cell lymphomas, the 5-year survival was 75% but for T-cell tumours, of which 83 were high grade, the figure was 25%.
Prevention of lymphoma The treatment of lymphoma occurring in coeliac disease is unsatisfactory which makes the prognosis poor. The question arises, therefore, does adherence to a GFD reduce the risk? There are reasons to suppose that this might be the case. Hence, the cellular infiltrate in the small intestinal mucosa is reduced by a GFD so that the number of potentially malignant cells is also reduced. The integrity of the mucosa and its enzymes are restored toward normal by a GFD so that carcinogens are less likely to gain access to the body and so the malignant risk is again potentially reduced. A study of 210 patients with coeliac disease showed that, in those who had adhered to a strict GFD for 5 or more consecutive years, the overall cancer risk was not significantly increased, while there was significantly increased risk for those on a reduced gluten diet or a normal diet 5y. Excess morbidity, calculated as observed minus expected numbers of tumours divided by the person years at risk, showed a clear relationship between the amount of gluten ingested and this index. A significantly decreasing trend in excess morbidity over increasing elimination of gluten from the diet was observed. For those on a normal diet, the excess morbidity was 10.7 compared with 1.2 for those on strict GFD. Other reports support this contention. Eight lymphomas occurred in 487 patients with dermatitis herpetiformis and all were found in those who had taken a normal diet or a GFD for less than 5 years 32. Egan et al. I5 interpreted their data as reflecting the protective effect of a GFD in a population where coeliac disease is common. The rule continues to hold true in my Derby coeliac clinic. list
of abbreviations
r CT: computed tomography; limphoma; GFD: gluten-free 1 intraepithelial lymphocytes;
EATL: enteropathy-associated T-cell ’ diet; HLA: human leucocyte antigen; IEL: TCR: T-cell receptor,
References ’ Gough KR, Read AE, plication of idiopathic
Naish JM. steatorrhoea.
Intestinal reticulosis Gut 1962;3:232-9.
’ Austad WI, Cornes JS, Gough KR, Steatorrhoea and malignant lymphoma. malignant tumours of lymphoid tissue Dig Dis 1967; 12:475-90.
as a com-
McCarthy CF, Read AE. The relationship between and coeliac disease. Am J
? Harris OD, Cooke WT, Thompson H, Waterhouse JAH. nancy in adult coeliac disease and idiopathic steatorrhea. Med 1967;42:899-912.
MaligAm J
’ Holmes GKT, Stokes PL, Sorahan TM, Prior P, Waterhouse Cooke WT. Coeliac disease, gluten free diet and malignancy. 1976;17:612-9.
JAH, Gut
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5 Case records of the Massachussetts General Hospital. New Engl J Med 1958;259:491-5. ’ Swinson CM, Slavin G, Coles EC, Booth CC. Coeliac disease and malignancy. Lancet 1983;i: 11 I-5. ’ O’Farrelly C, Feighery C, O’Briain DS, Stevens F, Connolly CE, McCarthy C, et al. Humoral response to wheat protein in patients with coeliac disease and enteropathy associated T cell lymphoma. Br Med J 1986;293;908-10. * The non-Hodgkin’s Lymphoma Classification Project. A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin’s lymphoma. Blood 1997;89:3909-18. ’ Holmes GKT, Thompson H. Malignancy as a complication of coeliac disease. In: Marsh MN. editor. Coeliac disease. London: Blackwell; 1992. ‘” Hin H Bird G, Fisher P, Mahy N, Jewel1 D. Coeliac disease in primary care: case finding study. Br Med J 1999;3 18: 164-7. ‘I Johnson SD, Watson RGP, McMillan SA, Sloan J, Love AHG. Coeliac disease detected by screening is not silent - simply unrecognized. Q J Med 1998;91:853-60. I2 Freeman HJ, Weinstein WM, Shnitka TK, Piercy JRA, Wensel RH. Primary abdominal lymphoma. Presenting manifestations of coeliac sprue, or complicating dermatitis herpetiformis. Am J Med 1977;63:585-94. Ii O’Driscoll BRC, Stevens FM, O’Gorman TA, Finnegan P, McWeeney JJ, Little MPG, et al. HLA type of patients with coeliac disease and malignancy in the west of Ireland. Gut 1982;23:662-5. I4 Ilyas M, Niedobitek G, Agathanggelou A, Barry RE, Tiemey R, Young LS, et al. Non-Hodgkin’s lymphoma, coeliac disease, and Epstein-Barr virus: a study of 13 cases of enteropathy-associated T- and B-cell lymphoma. J Path01 1995;177:115-22. is Egan LJ, Walsh SV, Stevens FM, Connolly CE, Egan EL, McCarthy CF. Coeliac-associated lymphoma. J Clin Gastroenterol 1995;21:123-9. Ih Brandt L, Hagander B, Norden A, Stenstam M. Lymphoma of the small intestine in adult coeliac disease. Acta Med Stand 1978;204;467-70. ” Selby WS, Gallagher ND. Malignancy in a 19 year experience of adult coeliac disease. Dig Dis Sci 1979;24:684-8. Ix Nielsen OH, Jacobsen 0, Pedersen ER, Rasmussen SN, Petri M, Laulund S, et al. Non-tropical sprue. Malignant disease and mortality rate. Stand J Gastroenterol 1995;20: 13-8. ry Collin P, Reunala T, Pukkala E, Laippala P, Keyrilainen 0, Pasternack A. Coeliac disease - associated disorders and survival. Gut 1994;35:1215-8. 2o Cottone M, Termini A, Oliva L, Magliocco A, Marrone C, Orlando A, et al. Mortality and causes of death in celiac disease in a Mediterranean area. Dig Dis Sci 1999;44:2538-47. 21Ferguson A, Kingstone K. Coeliac disease and malignancies. Acta Paediatr 1996;412(Suppl):78-81. 22Delco F, El-Serag H, Sonnenberg A. Celiac sprue among US Military Veterans. Associated disorders and clinical manifestations. Dig Dis Sci 1999;44:966-72. *3 Casserly I, Stevens F, McCarthy CF. Carcinoma of the right side of the colon and celiac disease. Dig Dis Sci 1997;42:862-4. 24 Sigurgeirsson B, Agnarsson BA, Lindelof B. Risk of lymphoma in patients with dermatitis herpetiformis. Br Med J 1994;308:13-5. 25 Reunala TL, Leonard JN. Malignant disease in dermatitis herpetiformis. Clin Dermatol 1992;9:369-73. lh Jalal PK, Holmes GKT, Houlston RS, Howdle PD. The efficacy of a questionnaire study in a prospective survey to determine the incidence of primary small bowel malignancy in the United Kingdom. Gut 2000;46(Suppl 1 l):A24.
?’ Morgan DR, Holgate, CS, Dixon MF, Bird CC. Primary small intestinal lymphoma: a study of 39 cases. J Path01 1985; 147:2 I l-2 1. *’ Isaacson PG. Malignant histiocytosis of the intestine. J Path01 1985;147:227-8. 2y Morgan DR. Malignant histiocytosis of the intestine. J Path01 1985;147:229-30. 3” Blumstein M, Bank S, Greenberg RE, Abrol RP, Kahn L, Siegal F. Immunoproliferative small intestinal disease in an American patient with lymphoma and macroamylasaemia. Gastroenterology 1992;103:1071-4. ” Igbal TH, Gearty JC, Cooper BT. Immunoproliferative small intestinal disease or coeliac disease. Gastroenterology 1993;104:1887-8. 1* Lewis HM, Renaula TL, Garioch JN, Leonard JN, Fry JS, Collin P, et al. Protective effect of gluten-free diet against development of lymphoma in dermatitis herpetiformis. Br J Dermatol 1996;135:363-7. 33 Horvath K, Gimesi A, Hill ID, Nemes-Nagy A, Nemeth L, Meouch H. Burl&-type intestinal lymphoma in a child with coeliac disease. J Pediatr Gastroenterol Nutr 1995;21:308-12. 34 Stenhammar L, Masreliez V. T-cell-rich B-cell lymphoma in a child with coeliac disease. J Pediatr Gastroenterol Nutr 1993;17:337-8. 35 Amaud-Battandier F, Schmitz J, Ricour C, Rey J. Intestinal malignant lymphoma in a child with familial coeliac disease. J Pediatr Gastroenterol Nutr 1983;2:320-3. 3h Domizio P, Owen RA, Shepherd NA, Talbot IC, Norton AJ. Primary lymphoma of the small intestine. A clinicopathological study of I 19 cases. Am J Surg Path01 1993; 17:429-42. 37 Oberhuber G, Vogelsang H, Stolte M, Muthenhaler S, Kummer AJ, Radaszkiewicz T. Evidence that intestinal intraepithelial lymphocytes are activated cytotoxic T-cells in celiac disease but not in giardiasis. Am J Path01 1996; 148: 135 l-7. iK Cerf-Bensussan N, Jan-y A, Brousse N, Lisowska-Grospierre B, Guy-Grand D, Griscelli CA. A monoclonal antibody (HML-I) defining a novel membrane molecule present on human intestinal lymphocytes. Eur J Immunol 1987; 17: 1279-85. Xyde Bruin PC, Kummer JA, van der Valk P, van Heerde P, Kluin PM, Willemze R, et al. Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa-associated lymphoid tissue localisation. Blood 1994;84:3785-91. 4o de Bruin PC, Connolly CE, Oudejans JJ, Kummer JA, Jansen W, McCarthy CF, et al. Enteropathy-associated T-cell lymphomas have a cytotoxic T-cell phenotype. Histopathology 1997;3 I:3 13-7. 41 Daum S, Foss H, Anagnostopoulos I, Dederke B, Demel G, Araujo I, et al. Expression of cytotoxic molecules in intestinal T-cell lymphomas. J Path01 1997;182:311-7. 4? Alfsen GC, Beiske K, Bell H, Marton PF. Low-grade intestinal lymphoma of intraepithelial T-lymphocytes with concomitant enteropathy-associated T cell lymphoma: case report suggesting a possible histogenic relationship. Human Path01 1989;20:909-13. 43 Gale J, Simmonds PD, Mead GM, Sweetenham JW, Wright DH. Enteropathy-type intestinal T-cell lymphoma: clinical features and treatment in 31 patients in a single centre. J Clin Oncol 2000;18:795-803. 44 Ashton-Key M, Diss TC, Pan L, Du MQ, Isaacson PG. Molecular analysis of T-cell clonality in ulcerative jejunitis and enteropathy-associated T-cell lymphoma. Am J Path01 1997;151:493-8. 15 Murray A, Cuevas EC, Jones DB, Wright DH. Study of the immunohistochemistry and T cell clonality of enteropathy-associated T cell lymphoma. Am J Path01 1995: 146:509- 19. 4h Cellier C, Patey N, Mauvieux L, Jabri B, Delabesse E, Cervoni
G.K.T. Holmes
M, et al. Abnormal intestinal fractory sprue. Gastroenterology
intraepithelial lymphocytes 1998; 114;471-8 1.
47 lsaacson P, Wright DH. Malignant Hum Pathol 1978;9:661-77.
histiocytosis
in re-
of the intestine.
‘8 Wright DH, Jones DB, Clark H, Mead GM, Hodges WM. Is adult-onset coeliac disease due to a low-grade of intraepithelial lymphocytes? Lancet 199 1 ;i: 1373-4.
E, Howell lymphoma
Jy Brousse N, Verkarre V, Patey N, Cellier C, Cerf-Bensussan N, Delabasse E, et al. Is complicated celiac disease or refractory sprue an intestinal intra-epithelial cryptic T-cell lymphoma? Blood 1999;93:3154-5. 5” Carbonnel F, Grollet-Bioul L, Brouet JC, Teihac MF, Angonin R. Are complicated forms of celiac disease cell lymphomas? Blood 1998:92:3879-86. ” Bagdi E, Diss TC, Munson P, lsaacson ha1 lymphocytes in enteropathy-associated cerative jejunitis, and refractory celiac plastic population. Blood 1999;94:260-4.
Cosnes cryptic
J, T-
PG. Mucosal intra-epitheT-cell lymphoma, uldisease constitute a neo-
jZ Cellier C, Delabesse E, Helmer C, Patey N, Matuchansky C, Jabri B, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. Lancet 2000;356:202-8. 53 Patey-Mariaud de Serre N, Cellier C, Jabri B, Delabesse E, Verkarre V, Roche B, et al. Distinction between coeliac disease and refractory sprue; a simple immunohistochemical method. Histopathology 2000; 17:70-7 ” Holmes GKT. Mesenteric ease. Gut 1986;27:728-33.
lymph
5s Matuchansky C, Colin R, Hemet C, et al. Cavitation in mesenteric and a flat small intestinal 1984;87:606-14. 56 Freeman plicating syndrome. 57 Swinson coeliac
node
cavitation
in coeliac
dis-
rX Howell WM, Leung ST, Jones DB, Nakshabendi I, Hall MA, Lanchbury JS, et al. HLA-DRB, -DQA, and -DQB polymorphism in coeliac disease and enteropathy-associated T-cell lymphoma. Common features and additional risk factors for malignancy. Hum lmmunol 1995;43:29-37.
‘* Cooper BT Holmes GKT, Ferguson R, Cooke WT. Coeliac disease and malignancy. Medicine 1980;59:249-61. h3 Mathus-Vliegen EMH, van Halteren H, Tytgat GNJ. Malignant lymphoma in coeliac disease: various manifestations with distinct symptomatology and prognosis? J Intern Med 1994;236:43-9. 64 Robertson DAF, Swinson CF, Hall R, Losowsky MS. Coeliac ease, splenic function and malignancy. Gut 1982;23:666-9. 65 O’Grady JG, Stevens FM, McCarthy CF. Coeliac hyposplenism predispose to the development of ease? Am J Gastroenterol 1985;80:27-9.
disease: maligant
disdoes dis-
66 Spencer J, MC Donald TT, Diss TC, Walker-Smith JA, Ciclitira PJ, lsaacson PG. Changes in intraepithelial lymphocyte subpopulations in coeliac disease and enteropathy assciated T cell lymphoma (malignant histiocytosis of the intestine). Gut 1989:30:339-46. ” Freeman HJ. Chiu BK. Multifocal small bowel lymphoma and latent coeliac sprue. Gastroenterology 1986;90: 1992-7.
h9 Ferguson R, Asquith P, Cooke WT. The jejunal celluar infiltrate coeliac disease complicated by lymphoma. Gut 1974; 15:458-6
lymphoma comnode cavitation
CM, Hall PJ, Bedford PA, Booth CC. HLA antigens disease associated malignancy. Gut 1983;24:925-8.
60 Ploski R, Ek J, Thorsby E, Sollid LM. On the HLA-DQ( a I *050 1, pl*0201)-associated susceptibilty in coeliac disease: a possible effect of DQBI *0201. Tissue gene dosage Antigens 1993;41:173-7. 6’ Congia M, Cucca F, Frau F, Lampis R, Melis L, Clemente MG et al, A gene dosage effect of the DQA1*0501/DQB1*0201 allelic combination influences the clinical heterogeneity of coeliac disease. Hum lmmunol 1994;40: 138-42.
6x Holmes GKT, Dunn Gl, Cockel R, Brookes VS. Adenocarcinoma of the small bowel complicating coeliac disease. Gut 1980;21:1010-6.
J, Touchard G, Babin P, Eugene lymph nodes, splenic atrophy, mucosa. Gastroenterology
HJ, Chiu BK. Small bowel malignant celiac sprue and the mesenteric lymph Gastroenterology 1986;90:200812.
5y Holmes GKT, Prior P, Lane MR, Pope D, Allan RN. Malignancy in coeliac disease - effect of a gluten free diet. Gut 1989;30:333-8.
in
in I.
” Barry RE, Read AE. Coeliac disease and malignancy. Q J Med 1973:42:665-75. ” lsaacson P. Malignant histiocytosis of the intestine: the early histological lesion. Gut 1980;2 I :38 1-6. ‘* Loberant N, Cohen I, Noi I, Herskovits M, Szvalb S. Enteropathyassociated T-cell lymphoma: a case report with radiologic and computed tomography appearance. J Surg Oncol 1997;65:50-4. 73 Logan RFA. Screening for coeliac disease - has the time come for mass screening? Acta Paediatr 1996;4 I2(Suppl): 15-9.
Digestive and Liver Disease and The Italian Journal of Gastroenterology (Volumes 29-33) are available on-line at the web site:
http://www.dldjournal.it Possibility of on-line subscriptions.
237
Coeliac
disease
DISEST LIVER DIS 2002;34:229-37
and malignancy
G.K.T.Holmes
The development of malignancy particularly lymphoma, is the most serious complication to affect patients with coeliac disease. Although the association has been known for about 40 years, there are still gaps in our understanding. The prevalence of lymphoma and why only some coeliac patients develop this are not clear but environmental and genetic factors must be at work. Based on data from a large coeliac clinic in Derby about 55 lymphomas per year would arise in the coeliac population of the United Kingdom, of which half would affect the small bowel. Whether patients with coeliac disease who have atypical or no symptoms at diagnosis, are at the same risk as those who are diagnosed as a result of classical symptoms as was more the case in the past, is not known. Some patients, howevel: do have coeliac disease and lymphoma diagnosed at the same presentation. This consideration has implications for initiating screening programmes to detect coeliac disease and thus offer patients a gluten-free diet early that would help to reduce the risk of lymphoma from developing. In this context, casefinding rather than blanket population screening is to be recommended on present evidence. Research into the role of intraepithelial lymphocytes in the genesis of lymphoma has indicated that non-responsive coeliac disease [refractory sprue] and ulcerative jejunoileitis (ulcerative jejunitis] are part of the lymphoma spectrum. The diagnosis of lymphoma can be difficult and the prognosis, in general, is poor: although with modern chemotherapeutic regimes and surgery in selected cases, long-term survival is possible. The best option is to try and prevent lymphoma from arising by advising all patients to adhere to a strict gluten-free diet. Malignant complications of coeliac disease are uncommon but will continue to challenge clinicians and clinical scientists. Unravelling the mechanisms that contribute to the development of lymphoma and other tumours in coeliac disease may well contribute to a wider understanding of oncogenesis.
Digest
Liver
Key words:
Dis 2002;34:229-37 coeliac
disease;
lymphoma;
malignancy
Introduction
Fmm Departmentof Medicine,DerbyshireRoyal Infirmaq Darby,UK.
Alwmsahw Dr. G.K.T.Holmes,DepaiZmentof Medicine,DerbyshireRoyalinfirmary, DerbyDE12Q’oy, UK Fax:+44-1332-2%764, E-mail:gea#reyho~mes&~mpuserve.c~m I
Patients with lymphoma and steatorrhoea were documented in the early literature when malabsorption was attributed to the presence of tumour in every instance. In 1962 however, Gough and his colleagues ’ suggested, for the first time, that lymphoma occurs as a complication of coeliac disease and this view was strengthened over the next few years 2-4.An increase in gastrointestinal carcinoma, in general, and oesophageal cancer, in particular, was also found to occur 3. Carcinoma of the small intestine in association with coeliac disease was first reported in 1958 5 and is now known to be the second most common invasive malignancy after lymphoma 6. O’Farrelly et al. 7 coined the term enteropathy-associated T-cell lymphoma (EATL) in 1986 but this has recently been updated to enteropathy-type in. -___ _ -_. testmal ‘l:cell lymphoma. This is rare and only accounts for less than 1% of 228
Coeliac disease and malignancy
all non-Hodgkin’s lymphoma x. Much is known about the malignant complications of coeliac disease 9 but much remains obscure and some of these areas are addressed in this review.
Prevalence of malignant complications The precise prevalence of malignancy in coeliac disease is unknown. There are several reasons for this. Thus, it is now clear from screening and case-finding studies that many coeliac patients without symptoms or only mild or atypical complaints may never be diagnosed ‘O“, so that the prevalence of coeliac disease in the general population is unknown. If postmortems are not carried out, the presence of malignancy, particularly lymphoma, will be underestimated. Furthermore, patients with established lymphoma may have coeliac disease that remains undiagnosed ‘* and information reported from referral centres is unlikely to be representative and cannot be extrapolated to the whole coeliac population in a particular locality. Finally, the wider use of the gluten-free diet (GFD) is known to alter the risk of lymphoma developing and some coeliac populations may be at greater risk than others. When speaking of the prevalence of malignancy in coeliac disease, therefore, it is necessary to add a number of caveats. Prevalence must be considered in the light of the completeness of case collection for coeliac disease and malignancy, the population and geographical area under review, the length of follow-up and when the series were collected, how malignancies were diagnosed, the causes of death, whether patients were attending a referral centre and the use and strictness of the GFD. Several series of patients with malignancy and coeliac disease are available 34 ‘3-‘5.Although the prime intent in assembling these was not to obtain prevalence data for malignant complications, nevertheless, figures are often quoted as if this were the case (Table I). Even in those series that did attempt to determine prevalence 16-*0fig-
tible I. Prevalence of malignancy in coeliac disease. Years
N. CD
Tellleers
N.
%
1941-65
202
Malignancy Lymphoma
32 14
16 7
3
1941-75
202
Malignancy Lymphoma
43 18
21 9
4
1969-81
198
Malignancy Lymphoma
16 10
8 5
13
1969-94
166
Lymphoma
13
8
14
1972-94
400
Lymphoma
31
8
15
230
lleference
l&bla II. Prevalence of malignancy in coeliac disease. Yem
N. CD
linneen
N.
%
lbfmwe
196577
74
Lymphoma
5
7
16
1958-78
93
Malignancy Lymphoma
IO 4
11 4
17
1964-82
100
Malignancy Lymphoma
i
i
18
1980-90
335
Malignancy Lymphoma
IO 0
3 0
19
1980-97
216
Malignancy Lymphoma
ures varied from 3% to 11% for all cancers and 0% to 7% for lymphoma, which are quite widely differing results (Table II). In a study of cancer mortality among 653 patients with coeliac disease from Edinburgh and the Lothians after 22.5 years of follow-up, 21 deaths (3.2% of the series and 11.2% of all deaths) resulted from lymphoproliferative disorders 2’. The number of patients with oesophageal and intestinal carcinoma was small. Associated disorders were analysed in a casecontrol study of 458 patients with coeliac disease who were discharged from hospitals of the Department of Veterans Afairs between 1986 and 1995 22. The association with lymphoma was confirmed with an odds ratio of 4.5. An association with gastrointestinal cancer in general and with individual cancers could not be demonstrated but studies of this kind, as the authors recognised, are subject to selection bias. In a study from Sicily20 between 1980 and 1997 of 216 coeliac patients, 12 deaths were observed for an expected number of 4.12. Lymphoma occurred in 7 patients of whom 4 had died. As acknowledged by the authors, these data came from a referral centre and the variety of malignancies that were found over a 17-year period appeared to be limited. The frequency of other tumours in coeliac disease such as lung and colon cancer should receive more attention because of a possible link 2’ 23. Lymphoma may also complicate dermatitis herpetiformis with a frequency up to 2.8% 24. In contrast to coeliac disease without dermatitis herpetiformis, there is no evidence for an increased risk of gastrointestinal cancer 15.
Prevalence of coeliac disease in the Derby area Coeliac disease was first diagnosed in the Derby area in 1958 and by the end of 1999,673 cases were on the coeliac register of whom 599 are alive. I have run the Derby coeliac clinic personally since 1978. The population from which these patients come is approximate-
-
G.K.T. Holmes
ly 360,000 so that the prevalence for all cases is 1 in 535 and for those alive 1 in 601. Of the 74 deaths, 33 were due to malignancy and 4 1 to non-malignant causes but in this latter group 4 had malignant disease. Altogether, there were 70 malignancies in 65 patients (4 patients each had more than 1 tumour). Twenty-eight patients with malignancy were alive at the end of 1999 and 37 had died but 4 patients with malignancy died of non-malignant causes. Ten lymphomas occurred and 5 of these involved the small bowel. Of the 24 tumours involving the gastrointestinal tract, 2 were in the oesophagus and 2 in the jejunum (Table III). These data give an indication of how commonly lymphoma will be encountered as a complication of coeliac disease and indicate that 1 lymphoma would occur among 673 coeliac patients accrued over 4.2 years. A lymphoma involving the small bowel would be seen every 8.4 years. The frequency of carcinoma of the oesophagus and jejunum is much less and only 1 such tumour would be seen in 673 coeliac patients accrued over 21 years.
Table III. Lymphomas and carcinomas involving gastrointestinal tract arising in 673 patients with coeliac disease diagnosed in Derby area 1956-l 999. Lymphomas Gastrointestinal carcinomas Tongue Oasophagus Jejunum Pancreas Rectum Parotid Stomach Hepatoma Colon
24 2 2
3
It is also possible to make an estimate of the total number of lymphomas that would be encountered in the whole coeliac population of the United Kingdom based on the Derby figures. For a prevalence of coeliac disease in the population of 1 in 535 the number of coeliacs in the United Kingdom would be 102,804. In this group, 55 lymphomas would be expected per year and of these 28 would involve the small bowel. A full analysis of these data is currently being undertaken. It is of interest that preliminary data coming from a national survey of primary small intestinal tumours presenting in the United Kingdom over a recent 12-month period gave figures for lymphomas associated with coeliac disease to be 20 but account must be taken of the return rate for questionnaires which was about half of those sent out 26.
Cellular origins of lymphoma T and B lymphocytes The lymphoma that complicates coeliac disease is now widely referred to as EATL’ but B-cell tumours also occur. Morgan et al. 27 regarded 7 out of 11 cases to be of B-cell origin but this work was criticised on the grounds that coeliac disease was not clearly defined in these patients 28 and the authors themselves considered that their study required re-evaluation 2y. Two B-cell tumours were discovered in a series of 13 lymphomas but only one occurred in the intestine 14.One patient regarded as having immunoproliferative disease of the small intestine complicated by B-cell lymphoma ‘O may have had coeliac disease 3’. In a series of coeliac associated lymphomas, one of 24 tumours available for assessment was of B-cell type 15.B-cell lymphomas as well as Hodgkin’s disease may affect dermatitis herpetiformis 25. Of 13 lymphomas found in 976 patients with dermatitis herpetiformis, most were of B-cell type and occurred outside the gastrointestinal tract and only one could be classified as EATL 24. Lymphomas that occurred in 487 cases of dermatitis herpetiformis were of T- and B-cell lineage 32. A Birkitt-type intestinal lymphoma in a child with coeliac disease originated from B cells 33. A T-cell rich B-cell lymphoma 34and a lymphoma of B-cell origin 35 have also been described in children. Anecdotal evidence suggests that lymphoma may affect children with coeliac disease more commonly than reports in the literature indicate and a group of paediatricians is currently exploring this. In a review of 119 primary small bowel lymphoma, 41 were of T- and 78 of B-cell phenotype 36. In 20 patients, the T-cell tumour was associated with enteropathy and these tumours predominated in the jejunum. No B-cell lymphomas were associated with enteropathy. No morphological differences were found in T-cell lymphomas with or without enteropathy. Thus, EATL appears to be a clinical rather than a distinct pathological entity. Intraepithelial lymphocytes The earliest morphological abnormality of the small intestinal mucosa in coeliac disease is infiltration by lymphocytes. Most intraepithelial lymphocytes (IEL) express CD3 and CD8 and have rearranged T-cell receptor (TCR) I3 chain genes. A minority are CD4- and CD8- with rearranged y/S chain genes and normally these form lo- 15% of the IEL population but, in coeliac disease, comprise up to 30%. A very small proportion are CD56 positive. IELs are cytotoxic cells and, as judged by granzyme B- and T-cell restricted intracellular antigen, are in a resting state in normal mucosa but are activated in coeliac mucosa 37. There has been growing interest in IELs and their role
231
Coeliec disease and malignancy
in the development of EATL. A monoclonal antibody, HML- 1, developed against IEL also reacts with T-cells of T-cell lymphoma that complicates coeliac disease 3x. De Bruin et al. 39 found that 10 out of 13 (77%) EATLs contained granzyme B positive cells and subsequently provided further evidence that EATL are derived from cytotoxic IEL in that, of 8 cases studied, all exhibited a cytotoxic phenotype 4o. Others have supported this view 4’. A patient with coeliac disease was reported with a low grade, small cell intestinal lymphoma of IEL and concomitant EATL 42. The neoplastic IEL showed cytoplasmic granules and expressed the alp TCR. The phenotype of the small cell tumour was HLM-l+, CD3+, CD7+, CD4-, CD8- which resembles that of EATL, although CD8+ tumours do occurJ3. Unfortunately, the large cell lymphoma in this report was not typed. A T-cell population was found in mucosa adjacent to EATL that shared the same monoclonal TCRy rearrangement as the lymphoma444s. These observations support the concept that a low grade T-cell lymphoma can be present in the epithelium and lie dormant for a long time before giving rise to overt lymphoma. In the T-cell lymphomas described by Domizio et al. 36, the phenotype of the IELs fell into two main groups. Some showed a phenotype similar to the associated lymphomas suggesting that these were intraepithelial neoplastic cells, while others appeared to be infiltrating native T-cells.
Non-responsive coeliac disease [refractory spruel and lymphoma The large majority of patients with coeliac disease improve clinically and in terms of small intestinal mucosal architecture when they adhere to a strict GFD. Some of the few patients who do not improve, may have a lymphoma, jejunoileitis (ulcerative jejunitis) or mesenteric lymph node cavitation syndrome, or be non-responders for no apparent cause. The prognosis is poor. Non-response may be present from the outset of the coeliac diagnosis or occur after a period of response to GFD. In a study of 6 cases, all had the DQAl*0501/DQB 1*0201 phenotype and endomysial and/or antigliadin antibodies were present before starting a GFD or during a time of poor dietary compliance 4h. These markers provide strong evidence for the presence of underlying coeliac disease. Over 20 years ago, Isaacson and Wright 47argued that ulcerative jejunitis is a manifestation of lymphoma because these two conditions are so closely related. Wright et al. 48, in 1991, posed the provocative question, is adult coeliac disease due to a low grade lymphoma of intraepithelial T-lymphocytes? They studied a resected specimen of jejunum apparently complicated by chronic ulceration
from a patient with coeliac disease. The authors suggested that the abnormal typing of the lymphoid cells and the clonality of the infiltrate favoured a diagnosis of lymphoma. Polymerase chain reaction amplification of the T-cell receptor y chain gene was carried out on DNA extracted from lymphoma, associated benign inflammatory ulcers and intervening mucosa in 6 patients with EATL and from ulcers and intervening mucosa in 7 cases with ulcerative jejunitis 44. The same cell clone could be demonstrated in EATL, associated ulcers and uninvolved mucosa and in ulcerative jejunitis, and uninvolved mucosa. Furthermore, when lymphoma developed in ulcerative jejunitis the same clone was shown to be present in both. A study of 6 cases of non-responsive coeliac disease, showed that the normal IEL population was replaced by morphologically normal but phenotypically abnormal cells that express intracytoplasmic CD3 but not surface CD3 and lacked TCR, CD8 and CD4 and showed restricted TCRy gene rearrangements 16 4y. None of these patients had overt lymphoma but the prognosis was poor in that 3 patients died. Further evidence has been provided that patients who do not respond to GFD with or without ulcerative jejunitis have low grade T-cell 1ymphoma”O. Bagdi et al. s1 bring together the evidence that IEL in ulcerative jejunitis, non-responsive coeliac disease and EATL constitute a neoplastic population of cells. Furthermore, Cellier et al. szprovide evidence that coeliac disease and refractory sprue are related and that refractory sprue links coeliac disease and EATL. These authors demonstrated the presence of endomysial and antigliadin antibodies, the HLA-DQw2 phenotype and an earlier clinical and histological response to the GFD in many of their patients with refractory sprue. In addition, those patients with an aberrant phenotype namely, intracytoplasmic CD3 but not surface CD8 and TCRy gene rearrangement had a poor prognosis. Conversely, 3 patients without these abnormalities experienced prolonged clinical and histological remission when given steroids and a GFD. A simple immunostaining method using anti-CD3 and anti-CD8 on paraffin sections can differentiate untreated coeliac disease from refractory sprue 53. A normal CD3, CD8 IEL population indicates poor compliance with a GFD or slow response. Those patients with an abnormal CD3+, CD& phenotype should be tested further for TCRy rearrangement to confirm the diagnosis of refractory sprue which carries a poor prognosis and requires more intensive follow-up. It is not known why the small intestinal mucosa of these patients does not respond to GFD but remains flat. It is possible that the IELs damage the enterocytes and, thereby, the mucosa, directly or via pro-inflammatory cytokines. I have encountered a patient who first presented in
G.K.T. Holmes
1983 with diarrhoea, weight loss and anaemia. A small intestinal biopsy was unsuccessful and because of radiological appearances of ulcerative jejunoileitis and clinical deterioration, a laparotomy was performed. The jejunum was oedematous and a 40 cm length was resected on the suspicion of lymphoma. Histological examination of the specimen revealed villous atrophy and an experienced histopathologist confidently diagnosed lymphoma on the strength of intraepithelial lesions with clusters of lymphocytes invading and destroying the crypts. The patient however, responded well to a GFD and no further treatment was undertaken. Between 1988 and 1992 he failed to attend the clinic for review but in 1992 presented with a mass in the left iliac fossa which proved to be a large cell, anaplastic lymphoma. It is not known whether this man had involvement of the small bowel with lymphoma but he responded to chemotherapy and survived until November 1999. It is likely that a small cell lymphoma of the IEL gave rise, after a long latent period, to a large cell tumour and he enjoyed a long survival. Another patient of mine presented in 1987 when coeliac disease was diagnosed by small bowel biopsy and she responded well to a GFD. About 1 year later however, she presented with weight loss and diarrhoea and jejunoileitis was diagnosed from radiological appearances of the small bowel. She was gravely ill and required prolonged parenteral nutrition and corticosteroids. She slowly improved and is presently in complete remission and maintained on a GFD and azathiaprine. This patient has survived for 12 years without any evidence of overt lymphoma, indicating the long latency that may be encountered and how difficult it is to know whether and when chemotherapeutic regimes should be offered. Mesenteric lymph node cavitation syndrome is a rare cause of non-responsive coeliac disease ” and may be associated with ulceration affecting the ileum ss. Abdominal scanning will show large cystic areas and so differentiate this benign condition from lymphoma affecting the lymph nodes. In one case, cavitating lymph nodes were found in association with multifocal lymphoma affecting the small bowel s6.
Genetic markers in coeliac disease and EAT1 Exploration of human leukocyte antigen (HLA) class II markers has shown that EATL arises on the same genetic background as that predisposing to coeliac disease I3 s7s8. In a recent study s8 on both disorders, significant increases were found in DRB1*03, DQA 1*050 1 and DQB 1*020 1. DRB 1*03,04 heterozygosity was significantly increased in EATL compared with coeliac patients and controls and reflects an
increase in DRBl*O4 in EATL patients. Thus DRB 1*04, or a sub-type, may be a potential marker for those coeliac patients who are at increased risk of developing lymphoma. No DQB I*020 1 homozygotes were found in the EATL series. How might DQB 1*0201 homozygosity confer protection against the development of EATL? A non-significant trend was observed towards a decreased DQB 1*0201 homozygosity and an increased incidence of DRB 1*04 in late, compared with early, age of onset of coeliac disease. So that those who are homozygous may have more severe symptoms that brings them to earlier diagnosis of coeliac disease and earlier treatment with a GFD. Since a GFD reduces the lymphoma risk, these patients would be at reduced risk of developing this malignancy s9. Conversely, those who are non DQB 1*020 1 homozygous may have subclinical disease that remains undetected and untreated with a GFD so that the risk of lymphoma developing is increased. A study of patients with coeliac disease and healthy controls indicated that in those individuals carrying the DQAl*0501 and DQB 1*0201 alleles, the presence of a second copy of the DQB 1*020 1 allele conferred an increased susceptibility to develop coeliac disease 60. Furthermore, a double dose of DQAl”O501, DQB 1*0201 genes may predispose patients to develop more severe manifestations of coeliac disease that, in turn, leads to earlier diagnosis “. These observations, while in their infancy, help to explain the heterogeneity of coeliac disease and the susceptibility of some patients to lymphoma.
Presentation and diagnosis The diagnosis of lymphoma complicating coeliac disease can be difficult because the presenting features are often non-specific and similar to those of uncomplicated coeliac disease at presentation or in relapse for other reasons such as lack of adherence to GFD. Unexplained deterioration, abdominal pain, weight loss, severe muscle weakness, lymphadenopathy, abdominal mass and pyrexia should arouse suspicion of lymphoma 436263. Presentation may be acute with intestinal obstruction or perforation or bleeding from lymphoma but, in many cases, the course is insidious I5 3643 62. There are those patients with long established coeliac disease who have responded to a GFD but with the onset of malignancy they deteriorate. It is accepted that, in these cases, lymphoma complicates coeliac disease. In others, the diagnosis of lymphoma and the demonstration of a flat upper small intestinal biopsy occur at about the same time and whether or not these have coeliac disease has been disputed on the grounds, for example, that such patients do not mount an antigliadin antibody response 7. Among the 16 patients reviewed 233
Coeliac disease and malignancy
by O’Farrelly et al. 7 however, were three with symptoms originating from childhood, whilst another had a 30-year history of diarrhoea suggesting that some of these cases did have coeliac disease complicated by malignancy, simply because it is unrealistic to attribute such long histories to lymphoma. The evidence indicates that most if not all of these have coeliac disease complicated by lymphoma. Thus, they have a similar HLA antigen profile l3 s758 as outlined above, a similar frequency of splenic atrophy or hyposplenism 6465 and similar changes in intraepithelial T-cell subsets 66 to patients with uncomplicated coeliac disease. This view is also supported by clonality studies 4s. The number of patients falling into this group is quite large. Of 13 lymphomas, 6 were diagnosed at the presentation of coeliac disease4. In the study of Swinson et al. 6 coeliac disease and malignancy were diagnosed, in the same episode, in 44 out of 215 patients, while in the series of Egan et al. I5, 23 out of 30 cases of lymphoma were in this category. Of 31 cases of EATL, only 12 were said to have a history of coeliac disease prior to the diagnosis of lymphoma 43. Although it is the development of lymphoma that precipitates the diagnosis of coeliac disease, in these patients, they often have long histories, sometimes from childhood, that are compatible with coeliac disease that has eluded previous diagnosis 4. One patient developed coeliac disease 42 months after the diagnosis of lymphoma and may well have been an example of latent coeliac disease that was precipitated by the emergence of a lymphoma36 as previously described 67. A small intestinal adenocarcinoma may present with intestinal obstruction, an abdominal mass or haemorrhage 6x. No pattern of routine blood tests allows the diagnosis of lymphoma to be made early. Subtle changes in small intestinal biopsies have been described in those with uncomplicated coeliac disease who go on to develop lymphoma compared with those who do not, such as lower plasma cell counts and higher lymphocyte counts in the lamina propria and lower lymphocyte counts in the epithelium (j9, the presence of hypoplastic crypts 70 and histiocytic aggregates 7’ but these are unlikely to be helpful in individual cases. Bowel radiology is mandatory but the typical multiple, narrowed segments characteristic of small intestinal involvement are not always seen and only a malabsorption radiological pattern may be evident even in the presence of lymphoma. Other investigations might include liver biopsy, examination of the bone marrow and small bowel enteroscopy but this is not without danger of perforation, Staging of lymphoma should be undertaken by computed tomography (CT) scanning so that appropriate treatment can be planned. CT scanning may also be of value in making a primary diagnosis of lymphoma 72. Definitive diagnosis may only be made at laparotomy or autopsy I5 43‘j2. 234
Screening for coeliac disease and case-finding An important question is whether those who are asymptomatic or have atypical or mild symptoms at the diagnosis of coeliac disease are at the same risk of developing lymphoma as those with more classical symptoms. It is likely that some are because, as mentioned above, in the various series there are patients in whom coeliac disease and lymphoma were diagnosed together and the development of malignancy precipitated the diagnosis of coeliac disease. These patients often had symptoms over many years that could be attributed to coeliac disease but because they were so mild did not lead patients to seek medical attention. Occasionally, patients regarded themselves as asymptomatic prior to developing malignancy 4. It could be argued that an earlier diagnosis of coeliac disease and treatment with a GFD might have prevented lymphoma from arising. This consideration raises the issue of screening for coeliac disease. Mass population screening would be an enormous undertaking with considerable costs. Overall health benetits of such programmes are not understood and there are ethical issues that require careful consideration. Case-finding rather than population screening is to be advocated on present evidence 73.
Treatment and prognosis Surgery, radiotherapy and chemotherapy may be used in suitable cases depending on the overall condition of the patient and the pathological staging. Unfortunately, in most patients, lymphoma is widespread at diagnosis and the prognosis is very poor with few patients surviving for more that one year I54362. Occasionally, a lymphoma may involve only a short segment of the small intestine and resection will result in a cure. I have a patient with established coeliac disease who presented with a single focus of lymphoma obstructing the jejunum. This was successfully resected and she remains well 16 years after the operation. Swinson et al. 6, found that of 84 coeliac patients with lymphoma diagnosed during life, 8 survived for more that 5 years after diagnosis and all of these presented with small intestinal lesions. Seven of the 8 underwent resection and some received chemotherapy and radiotherapy. Adenocarcinoma of the jejunum may similarly present with obstruction and be curable. I have encountered such a patient who has now survived for 14 years after surgery. Two recent papers have addressed the treatment and prognosis of EATL and are important because single centre experience is reviewed and the value of combination chemotherapy assessed. Thirty patients from Galway, Ireland, in records referring to the period be.--
G.K.T. Holmes
tween 1972 and 1994 were divided into 2 groups “. Group 1 was formed of 7 previously diagnosed coeliac patients who had responded to GFD but had subsequently developed lymphoma. Group 2 comprised 23 patients in whom coeliac disease and lymphoma were diagnosed simultaneously. In these, the symptoms of lymphoma led to the diagnosis of coeliac disease and they had never received or had been unresponsive to a GFD given for less than 1 year. Of the 23, 8 were not given treatment for lymphoma or were diagnosed at autopsy. The prognosis of these 8 (3 diagnosed during life) and those in group 1 (4 diagnosed during life) was very poor with average mean survival times from the diagnosis of lymphoma of 3.3 and 2.25 months, respectively. From group 2, 15 patients diagnosed during life had the lymphoma treated usually by surgery and chemotherapy. All but one of these presented as emergencies with intestinal obstruction or perforation or had an abdominal mass. The exception was a patient with diffuse gastric ulceration and B-cell nonHodgkin’s lymphoma on peripheral lymph node biopsy. Of the 15 cases, the assessment of 1 was still incomplete. Five died of lymphoma within 1 year, while 9 survived for a mean of 74 months (range lo- 196 months). Five were disease free and 3 died of other causes. Overall l-year survival was 3 1% and 5-year survival 11%. A number of chemotherapeutic regimes were used together with surgery. Gale et al. 43reported their experience of 31 patients gathered in Southamptom, United Kingdom, between 1979 and 1996. A total of 24 patients were given combination chemotherapy after diagnosis. A variety of regimes were used. Less than half of the patients completed their courses because of poor nutritional state or complications associated with the treatment such as gastrointestinal bleeding and small bowel perforation. At the time of report, 26 (84%) of the 31 patients had died and their median survival was only 7.5 months (range O-83). Five patients who were still alive and disease free had survived for 49 to 219 months after diagnosis. The actuarial I- and 5-year survival rates were 38.7% and 19.7%, respectively and 1- and 5-year failure free survival rates of 19.4% and 3.2%, respectively. The prognosis of coeliac-associated lymphoma has been considered worse than for primary gastrointestinal lymphoma 15.This has been attributed to the added debility from malabsorption or the adverse effects of immunological abnormalities that occur in coeliac disease. In the review of Domizio et al. 36however, the presence of enteropathy had no significant effect on survival of those with EATL. Bowel perforation, multiple tumours and high grade histology were noted to have an adverse effect on outlook. For low grade B-cell lymphomas, the 5-year survival was 75% but for T-cell tumours, of which 83 were high grade, the figure was 25%.
Prevention of lymphoma The treatment of lymphoma occurring in coeliac disease is unsatisfactory which makes the prognosis poor. The question arises, therefore, does adherence to a GFD reduce the risk? There are reasons to suppose that this might be the case. Hence, the cellular infiltrate in the small intestinal mucosa is reduced by a GFD so that the number of potentially malignant cells is also reduced. The integrity of the mucosa and its enzymes are restored toward normal by a GFD so that carcinogens are less likely to gain access to the body and so the malignant risk is again potentially reduced. A study of 210 patients with coeliac disease showed that, in those who had adhered to a strict GFD for 5 or more consecutive years, the overall cancer risk was not significantly increased, while there was significantly increased risk for those on a reduced gluten diet or a normal diet 5y. Excess morbidity, calculated as observed minus expected numbers of tumours divided by the person years at risk, showed a clear relationship between the amount of gluten ingested and this index. A significantly decreasing trend in excess morbidity over increasing elimination of gluten from the diet was observed. For those on a normal diet, the excess morbidity was 10.7 compared with 1.2 for those on strict GFD. Other reports support this contention. Eight lymphomas occurred in 487 patients with dermatitis herpetiformis and all were found in those who had taken a normal diet or a GFD for less than 5 years 32. Egan et al. I5 interpreted their data as reflecting the protective effect of a GFD in a population where coeliac disease is common. The rule continues to hold true in my Derby coeliac clinic. list
of abbreviations
r CT: computed tomography; limphoma; GFD: gluten-free 1 intraepithelial lymphocytes;
EATL: enteropathy-associated T-cell ’ diet; HLA: human leucocyte antigen; IEL: TCR: T-cell receptor,
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‘* Cooper BT Holmes GKT, Ferguson R, Cooke WT. Coeliac disease and malignancy. Medicine 1980;59:249-61. h3 Mathus-Vliegen EMH, van Halteren H, Tytgat GNJ. Malignant lymphoma in coeliac disease: various manifestations with distinct symptomatology and prognosis? J Intern Med 1994;236:43-9. 64 Robertson DAF, Swinson CF, Hall R, Losowsky MS. Coeliac ease, splenic function and malignancy. Gut 1982;23:666-9. 65 O’Grady JG, Stevens FM, McCarthy CF. Coeliac hyposplenism predispose to the development of ease? Am J Gastroenterol 1985;80:27-9.
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Digestive and Liver Disease and The Italian Journal of Gastroenterology (Volumes 29-33) are available on-line at the web site:
http://www.dldjournal.it Possibility of on-line subscriptions.
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