The value of double-balloon enteroscopy in patients with refractory celiac disease

OBJECTIVE: Patients with refractory celiac disease can develop enteropathy-associated T-cell lymphoma (EATL) or ulcerative jejunitis. Double-balloon enteroscopy allows examination of the small bowel. We prospectively assessed the value of this technique in patients with refractory celiac disease in a tertiary referral center. METHODS: Small bowel enteroscopy was performed in a total of 21 consecutive patients for lesions like ulcerations (high risk). Biopsy specimens were taken from such lesions and from examined small bowel at three different levels of scope insertion depth. Tissue specimens were evaluated for the modified Marsh classification and for the presence of EATL. RESULTS: Twenty-four procedures were successfully performed without complications. EATL was found in five patients (24%, 95% CI 10-45%) as circumferential, discrete, or confluent ulcerations. In three of them, Marsh III was found while in the other two patients with EATL Marsh I was found. Another two patients (9%, 95% CI 2-28%) had ulcerative jejunitis in the absence of EATL and histology was compatible with Marsh III. In the remaining 14 patients (54%, 95% CI 35-73%), no high-risk lesions were found. Double-balloon enteroscopy could exclude the presence of EATL in four patients that was suggested by abdominal computerized tomography. CONCLUSIONS: Complications of refractory celiac disease like ulcerative jejunitis or EATL could efficiently be detected or excluded by double-balloon enteroscopy. This technique should be reserved for patients with refractory celiac disease or patients with a past history of EATL.     

Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue

BACKGROUND: Clonal T cell receptor (TCR) gene rearrangements and loss of T cell antigens such as CD8 and TCR-beta in intraepithelial lymphocytes (IELs) may indicate the development of an enteropathy-type intestinal T cell lymphoma (EITCL) in patients with refractory sprue. AIMS: To define the diagnostic value of these markers in duodenal biopsies from patients with villous atrophy as a result of various underlying disorders. PATIENTS AND METHODS: Duodenal biopsies from eight patients with coeliac disease and five patients with villous atrophy caused by defined disorders were compared with three patients with refractory sprue evolving into overt EITCL, two patients with ulcerative jejunitis, and with eight patients with overt EITCL, for expression of CD3, CD4, CD8, and TCR-beta in IELs using immunohistochemistry and for clonal TCR-gamma gene rearrangements using polymerase chain reaction. In addition, biopsies from six consecutive patients with refractory sprue of uncertain cause were examined. RESULTS: Clonal TCR-gamma gene rearrangements were found in all resected tumours of patients with EITCL, in 3/8 duodenal biopsies of patients with EITCL, in 2/2 patients with ulcerative jejunitis, in 2/3 patients with refractory sprue evolving into overt EITCL, and in 1/6 patients with refractory sprue. No rearrangements were found in biopsies from patients with refractory sprue caused by defined disorders or those with coeliac disease. Clonality in duodenal biopsies was associated with an abnormal phenotype of IELs in all cases and in all but one case in patients with evidence of underlying coeliac disease. Specificity for detection of an EITCL using immunohistology was 77% for CD8 and for TCR-beta staining, and 100% for detection of a clonal TCR-gamma gene rearrangement. Sensitivity was 62% for staining with CD8 and clonality investigation, while sensitivity reached 100% for TCR-beta staining in all investigated patients with EITCL. CONCLUSIONS: Clonal proliferations of phenotypically abnormal IELs in refractory sprue represent an early manifestation of EITCL, for which the term "sprue-like intestinal T cell lymphoma" is proposed. This constellation is also found in duodenal biopsies from patients with an overt EITCL and is not related to other sprue syndromes, resulting in a high specificity for detection of an EITCL or refractory sprue evolving into EITCL. Overt EITCL may develop directly from coeliac disease without a precursor lesion (refractory sprue with clonal IELs) being demonstrable in duodenal biopsies or via a "sprue-like intestinal T cell lymphoma". This latter entity is a complication of coeliac disease.     

Malignant complications of coeliac disease

Patients with coeliac disease (CD), particularly those who are undiagnosed or do not adhere to a strict gluten free diet (GFD), are prone to develop complications. Malignant complications are the most serious and should be suspected when expected responses to GFD are not achieved or sustained. Lymphomas, mostly T-cell type, and other malignant tumours, particularly carcinoma of the small bowel, less frequently of stomach and oesophagus, are associated with CD. Loss of response to a gluten free diet (refractory coeliac disease) and ulcerative jejunitis are two recently described complications of CD that may progress to an Enteropathy-Associated T-cell Lymphoma (EATL). Coeliac disease-related lymphoma most often appears at extra-nodal sites, essentially the small bowel, although one have to realise that T-cell lymphomas arising in sites outside the small bowel could be related to coeliac disease. Workup of an EATL must include immunehistology and if necessary T-cell flow cytometry and T-cell rearrangement. Adequate imaging with CT and PET-scanning is mandatory.     

Refractory celiac disease

Celiac disease is a gluten-sensitive enteropathy, characterized by villous atrophy, which is reversed by gluten withdrawal. A minority of patients with celiac-like enteropathy are resistant to gluten-free diet, so-called refractory sprue, or unclassified sprue. Refractory sprue is a diagnosis of exclusion; all other causes of a celiac-like enteropathy must be eliminated before a diagnosis of refractory sprue can be made. Recent evidence suggests that refractory sprue comprises a heterogenous group of patients with diverse underlying causes. A small proportion of these patients seem to have an adult form of autoimmune enteropathy, characterized by the presence of antienterocyte antibodies. However, a larger group of patients with refractory sprue now seem to have a cryptic intestinal T-cell lymphoma, characterized by the presence of phenotypically abnormal, monoclonal intraepithelial lymphocytes, despite benign cytology. Current therapeutic options include nutritional support and immunosuppressive therapy, but response is variable. The prognosis of refractory sprue may be poor; patients may die of severe malabsorption, or through synchronous or metachronous development of an enteropathy-associated T-cell lymphoma. Based on this recent evidence, patients with refractory sprue should be screened for antienterocyte antibodies and have T-cell receptor and monoclonal antibody studies performed; this could facilitate identification of cases of adult-onset autoimmune enteropathy and those of cryptic T-cell lymphoma. Moreover, early recognition of the malignant nature of the intestinal infiltrate in some cases of refractory sprue could permit the development of novel chemotherapeutic regimens for this condition.     

Push enteroscopy in celiac sprue and refractory sprue.

BACKGROUND: The aim of this study was to determine in patients with sprue whether jejunal endoscopy improves the diagnostic yield or provides information that may modify management, when compared with evaluation limited to the duodenum. METHODS: From January 1994 to June 1998, a total of 31 patients (6 men, 25 women, mean age 41 years) were prospectively evaluated by push enteroscopy. They were divided into two groups: (1) celiac disease at different stages of activity (n = 23) and (2) refractory sprue (n = 8). The endoscopic and histologic findings in the duodenum and in the jejunum were compared. RESULTS: Celiac disease: In 19 patients, endoscopic and histologic findings in the duodenum and jejunum were similar; in four patients villous atrophy was more severe in the duodenum than in the jejunum. Refractory sprue: In 5 of 8 patients, enteroscopy revealed ulcerative jejunitis, whereas ulcerations were found in the duodenum in only one case. CONCLUSION: In refractory sprue, push enteroscopy with jejunal biopsies was of diagnostic value in 50% of cases demonstrating ulcerative jejunitis, whereas it did not modify the management of patients with responsive celiac disease.     

Azathioprine in refractory sprue: results from a prospective,open-label study

OBJECTIVE: Refractory sprue is a rare and severe malabsorptive disorder that mimics celiac disease but is refractory to a gluten-free diet and is without initial evidence of overt lymphoma. Treatment is largely empiric and often ineffective, with steroids and immunosuppression being the mainstream therapeutic options. The aim of this study was to evaluate prospectively the effect of azathioprine on a group of patients diagnosed with refractory sprue. METHODS: We studied seven consecutive patients (five women and two men) with a well-defined diagnosis of refractory sprue and a lack of response to oral or parenteral steroids. At diagnosis, five patients had endoscopic evidence of ulcerative jejunitis, and five underwent exploratory laparotomy for exclusion of malignancies. The characteristic monoclonal TCRgamma gene rearrangement was shown in five of six patients studied. Patients were treated for a mean of 11 months (range 8-12 months), and clinical, biochemical, molecular, and histological parameters were reassessed at the end of the trial. The study was a prospective, open-label, non-placebo-controlled study using azathioprine (2 mg/kg/ day) plus oral prednisone (1 mg/kg/day). A gluten-free diet (n = 7) as well as enteral (n = 6) and parenteral nutrition (n = 5) were administered during the trial. RESULTS: After treatment, five patients had a complete clinical remission, and biochemical and nutritional parameters were significantly improved. Steroids were tapered after the onset of azathioprine, and no patient was on steroids at the end of the trial. Intestinal histology improved significantly in all cases (normal histology in three cases and minor infiltration in the lamina propria in two). Two patients did not respond to treatment at any time and died in months 10 and 9, of an irreversible ventricular fibrillation and sepsis, respectively. No overt lymphoma was demonstrated during the follow-up. CONCLUSIONS: The present study confirms earlier anecdotal reports on the efficacy of azathioprine in refractory sprue, with clear clinical and histological improvement shown in most patients. However, monoclonality persisted after treatment. We consider that a larger number of patients should be evaluated before a definitive recommendation is adopted for use of this drug in refractory sprue.     

Multiple cerebral lesions in a patient with refractory celiac disease: A case report

BACKGROUNDEnteropathy-associated T cell lymphoma (EATL) is an aggressive intestinal T cell lymphoma derived from intraepithelial lymphocytes, which occurs in individuals with celiac disease (CD). Cerebral involvement is an extremely rare condition and as described so far, lymphoma lesions may present as parenchymal predo-minantly supratentorial or leptomeningeal involvement. We describe a case of EATL with multifocal supra- and infratentorial brain involvement in a patient with refractory celiac disease (RCD).CASE SUMMARYA 58-years old man with known CD developed ulcerative jejunitis and was diagnosed with RCD type II. Six months later he presented with subacute cerebellar symptoms (gait ataxia, double vision, dizziness). Cranial magnetic resonance imaging (MRI) revealed multifocal T2 hyperintense supra- and infratentorial lesions. Laboratory studies of blood and cerebrospinal fluid were inconspicuous for infectious, inflammatory or autoimmune diseases. ¹⁸F-fluorodeoxyglucose-positron emission tomography/computed tomography (¹⁸FDG-PET/CT) scan showed a suspect hypermetabolic lesion in the left upper abdomen and consequent surgical jejunal resection revealed the diagnosis of EATL. During the diagnostic work-up, neurological symptoms aggravated and evolved refractory to high-dosage cortisone. Recurrent MRI scans showed progressive cerebral lesions, highly suspicious for lymphoma and methotrexate chemotherapy was initiated. Unfortunately, clinically the patient responded only transiently. Finally, cerebral biopsy confirmed the diagnosis of cerebral involvement of EATL. Considering the poor prognosis and deterioration of the performance status, best supportive care was started. The patient passed away three weeks after diagnosis.CONCLUSIONEATL with cerebral involvement must be considered as a possible differential diagnosis in patients with known RCD presenting with neurological symptoms.     

Enteropathy-associated T-cell lymphoma: clinical and histological findings from the international peripheral T-cell lymphoma project

Few large, international series of enteropathy-associated T-cell lymphoma (EATL) have been reported. We studied a cohort of 62 patients with EATL among 1153 patients with peripheral T-cell or natural killer (NK)-cell lymphoma from 22 centers worldwide. The diagnosis was made by a consensus panel of 4 expert hematopathologists using World Health Organization (WHO) criteria. Clinical correlations and survival analyses were performed. EATL comprised 5.4% of all lymphomas in the study and was most common in Europe (9.1%), followed by North America (5.8%) and Asia (1.9%). EATL type 1 was more common (66%) than type 2 (34%), and was especially frequent in Europe (79%). A clinical diagnosis of celiac sprue was made in 32.2% of the patients and was associated with both EATL type 1 and type 2. The median overall survival was only 10 months, and the median failure-free survival was only 6 months. The International Prognostic Index (IPI) was not as good a predictor of survival as the Prognostic Index for Peripheral T-Cell Lymphoma (PIT). Clinical sprue predicted for adverse survival independently of the PIT. Neither EATL subtype nor other biologic parameters accurately predicted survival. Our study confirms the poor prognosis of patients with EATL and the need for improved treatment options.     

Refractory sprue

Celiac disease is a T cell-mediated disorder that results from intolerance to gluten. The major cause of failure to respond to a gluten-free diet is continuing gluten ingestion. In poorly responsive patients diagnosis of refractory sprue can be established after exclusion of a limited number of conditions. Refractory sprue may occur after an initial response to the diet or without evidence of preexisting celiac disease. The detection of aberrant, clonally expanded, intraepithelial lymphocytes has led to better definition and classification of patients with refractory sprue. Only a few series of patients with well-characterized refractory sprue have been reported in the literature. The prognosis is poor, though some patients respond to corticosteroids and immunosuppressive agents. The presence of an aberrant clonal intraepithelial T-cell population has led to the designation of refractory sprue as a cryptic intestinal T-cell lymphoma.     

Coeliac disease and (extra)intestinal T-cell lymphomas: definition, diagnosis and treatment

Intestinal lymphomas encompass those lymphomas with a dominant or only localized occurrence in the intestinal tract. Coeliac disease is highly associated with enteropathy-associated T-cell lymphomas (EATLs). Coeliac disease-related lymphomas can appear at nodal or extranodal sites. EATL is often multifocal with ulcerative lesions, which explains the high perforation rate at presentation or during chemotherapy. Staging includes ear-nose-throat examination and CT scan of the chest and abdomen. Positron emission tomography (PET) scanning may be valuable. Accurate diagnosis based on endoscopic biopsies is preferable; if necessary, full thickness laparoscopic small-bowel biopsies are mandatory. Refractory coeliac disease (RCD) with aberrant T cells carries a high risk of development of EATLs. There is no satisfactory treatment for EATL, the only possibility of preventing EATL development in RCD being autologous bone marrow transplantation. EATLs can present in 20% of patients as extra-small-bowel T-cell lymphomas; such as subcutaneous panniculitis-like lymphoma, hepatosplenic gamma/delta lymphoma, nodal as well as sinus, gastric or colon disease and extraintestinal T-cell lymphomas. The majority of EATLs present as large cell lymphoma CD3+, CD8-, CD30+; however, they also present as small cell lymphoma CD3+, CD8+, CD30-. Sometimes gamma/delta lymphomas in CD are recognized. Work-up of EATL must include immunohistology, T-cell flow cytometry, T-cell rearrangement and adequate imaging with CT and PET scanning.     

Coeliac disease and malignancy

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, however 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, case-finding 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.     

Free perforation of the small intestine in collagenous sprue

A 67-year-old man with celiac disease developed recurrent diarrhea, profound weakness and weight loss, with evidence of marked protein depletion. His clinical course was refractory to a strict gluten-free diet and steroid therapy. Postmortem studies led to definition of unrecognized collagenous sprue that caused ulceration and small intestinal perforation. Although PCR showed identical monoclonal T-cell populations in antemortem duodenal biopsies and postmortem jejunum, careful pathological evaluation demonstrated no frank lymphoma. Rarely, overt or even cryptic T-cell lymphoma may complicate collagenous sprue, however, small intestinal ulcers and perforation may also develop independently. The dramatic findings here may reflect an underlying or early molecular event in the eventual clinical appearance of overt T-cell lymphoma.     

Endoscopic Findings of Enteropathy-Associated T-Cell Lymphoma Type II: A Case Series

Enteropathy-associated T-cell lymphoma (EATL) is a rare extranodal T-cell lymphoma arising from the intestine. Two types of EATL have been reported. In contrast to the classic EATL type I, EATL type II occurs sporadically, is unrelated to celiac disease, and comprises 10% to 20 % of all EATL cases. A total of five cases of EATL type II were diagnosed at our clinic from January 2009 to September 2012. Four of the five patients were diagnosed with the help of endoscopy. Among the four patients, two of the cases involved both the small and large intestines, whereas in the other two patients, EATL was limited to the small intestine. Common endoscopic findings included innumerable fine granularities (also called mosaic mucosal patterns) and diffuse thickening of the mucosa with a semicircular shallow ulceration in the lesions of the small bowel. In contrast, the endoscopic findings of the colon were nonspecific and could not distinguish EATL type II from other diseases. There are only few published reports regarding the representative endoscopic findings of EATL. Here, we present the clinical and endoscopic findings of four cases of EATL type II diagnosed by endoscopy.     

Refractory celiac disease

Refractory celiac disease (RCD) affects patients who have failed to heal after 6–12 months of a strict gluten-free diet (GFD) and when other causes of symptoms (including malignancy) have been ruled out. It may also occur in patients who previously had responded to a long-term GFD. RCD may be categorized as RCD1 (normal immunophenotype) and RCD2 (aberrant immunophenotype). RCD1 usually responds to a continued GFD, nutritional support, and therapeutic agents such as corticosteroids. In contrast, clinical response in RCD2 is incomplete and prognosis is often poor. RCD (particularly RCD2) is associated with serious complications, such as ulcerative jejunitis and enteropathy-associated T-cell lymphoma (EATL). Strict clinical and laboratory criteria should be used to diagnose RCD and specialized tests for aberrancy and clonality should be interpreted in the context of their sensitivity and specificity. Adequate nutritional support and anti-inflammatory treatment may even allow patients with RCD2 to attain a clinical remission.     

Refractory coeliac disease

A small proportion of coeliac disease (CD) patients fail to improve after a gluten-free diet (GFD) and may be considered as atypical regarding their outcome (refractory coeliac disease). The aim of this study is to diagnose and manage patients with CD who fail to improve after a GFD. Refractory coeliac disease (RCD) is a malabsorption syndrome defined by persisting villous atrophy with, usually, an increase of intraepithelial lymphocytes (IELs) in the small bowel in spite of a strict GFD and comprises a heterogenous group of diseases. Some of these diseases have to be excluded and can be treated by specific therapies like antibiotics in tropical sprue and giardiasis and immune globulin substitution in common variable immunodeficiency, while other malabsorption syndromes are less well defined and may require immunosuppressive therapy. Standardized treatment, however, has not been evaluated in such patients so far. In a subgroup of patients with RCD, an abnormal intraepithelial lymphocyte (IEL) population may be observed with the lack of surface expression of usual T-cell markers (CD3-CD8 and/or the T-cell receptor (TCR)) on IELs associated with T-cell clonality pattern suggest the presence of an early enteropathy-associated T-cell lymphoma (EATL) in a subgroup of patients with RCD. This hypothesis has been supported by studies, which revealed progression into overt intestinal T-cell lymphomas in a subgroup of RCD. Steroid treatment has been reported effective even in patients with underlying early EATL. However, long-term results are unsatisfactory in most of these patients with RCD and parenteral nutrition has to be applied in some of these cases. First results with more aggressive chemotherapies and use of cytokines are under way. Due to the difficulty of diagnostic and therapeutic regimens patients should be referred to tertiary centres for coeliac disease.     

Enteropathy-associated intestinal t-cell lymphoma without celiac disease

Type II enteropathy-associated T-cell lymphoma (EATL) is an uncommon intestinal lymphoma. We report the case of a 73-year-old man with diarrhea and weight loss. Duodenal biopsy showed atrophy and infiltration of irregular lymphocytes. Immunohistochemistry was positive for CD3, CD8, and CD56 with monoclonal TCR rearrangement. The HLA-DQ genotype was DQ5/DQ9. The Epstein-Barr virus RNA test was negative. Before specific chemotherapy could be administered, the patient was admitted to hospital for a respiratory infection and died from a cause unrelated to his lymphoma. The differential diagnosis of CD56-positive lymphoproliferative processes include type II EATL, primary T-cell/natural killer-cell intestinal lymphoma and hepatosplenic T-cell lymphoma. The patient had CD8 y CD56+ markers that allowed type I EATL to be excluded. The HLA-DQ genotype did not correspond to celiac disease and the biopsy showed proliferation of lymphocytes with atypia. The primary intestinal T-cell/natural killer-cell lymphoma was characterized mainly by the absence of CD8 and monoclonal reassortment of the TCR present in this case.     

Refractory sprue syndrome with clonal intraepithelial lymphocytes evolving into overt enteropathy-type intestinal T-cell lymphoma

INTRODUCTION: Recently, patients with refractory sprue have been shown to contain a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes in their intestine. Whether this signifies early enteropathy-type intestinal T-cell lymphoma (EITCL) or a reactive condition is not clear. We report on a patient presenting with the findings of refractory sprue who subsequently developed overt EITCL. MATERIAL AND METHODS: Duodenal biopsies from 1997 (refractory sprue) and duodenal and jejunal biopsies from 1998 (intestinal T-cell lymphoma) were compared by immunohistochemistry and PCR for the detection of T-cell receptor (TCR)-gamma gene rearrangements. Clonal PCR products were sequenced. RESULTS: The duodenal biopsies from both 1997 and 1998 and the jejunal tumor biopsy showed villus atrophy and an increase of intraepithelial lymphocytes with an abnormal immunophenotype (CD3+, CD4-, CD8- and TCR-beta-). In all duodenal specimens including the one from 1997, and the jenunal tumor biopsy, an identical clonal amplificate was detected by enzymatic amplification of the TCR-gamma gene. CONCLUSION: These data suggest that refractory sprue containing a clonal proliferation of phenotypically abnormal intraepithelial lymphocytes may represent an early manifestation of EITCL. The detection of immunohistochemical negativity for several antigens normally found on intraepithelial lymphocytes such as CD8 or the TCR-beta chain in combination with clonal T-cell populations by PCR may be helpful in identifying refractory sprue with a malignant transformation.     

Survival in refractory coeliac disease and enteropathy-associated T-cell lymphoma: retrospective evaluation of single-centre experience

BACKGROUND: Coeliac disease may be regarded as refractory disease (RCD) when symptoms persist or recur despite strict adherence to a gluten-free diet. RCD may be subdivided into types I and II with a phenotypically normal and aberrant intraepithelial T-cell population, respectively. RCD I seems to respond well to azathioprine/prednisone therapy. RCD II is usually resistant to any known therapy and transition into enteropathy-associated T-cell lymphoma (EATL) is common. AIM: To provide further insight into RCD and the development of EATL, by reporting on long-term survival and risk of transition of RCD into EATL in a large cohort of patients with complicated coeliac disease. Design and METHODS: Retrospective comparison of responses to therapy in four groups of patients with complicated coeliac disease: 43, RCD I; 50, RCD II (total), of whom 26 with RCD II developed EATL after a period of refractoriness to a gluten-free diet (secondary EATL) and 13 were EATL patients without preceding history of complicated coeliac disease (de novo EATL). RESULTS: No coeliac-disease-related mortality was recognised in the RCD I group. The overall 5-year survival in the RCD I group it was 96%; in the RCD II (total) group was 58%; and in the RCD II group after developing EATL it was only 8%. The 2-year survival in the de novo EATL group was 20% versus 15% in secondary EATL group (p = 0.63). Twenty-eight (56%) of the 50 patients with RCD II died, 23 (46%) due to EATL, 4 due to a progressive refractory state with emaciation and 1 from neurocoeliac disease. CONCLUSION: Remarkably, no patient with RCD I developed RCD II or EATL within the mean follow-up period of 5 years (range 2-15 years). A total of 52% of the RCD II patients developed EATL within 4-6 years after the diagnosis of RCD II. More aggressive and targeted therapies seem necessary in RCD II and EATL.     

Heterogeneity of intraepithelial lymphocytes in refractory sprue: potential implications of CD30 expression

BACKGROUND: Refractory sprue is defined as primary or secondary failure to respond to a gluten free diet in patients with coeliac disease-like enteropathy and may signify cryptic or overt enteropathy associated T cell lymphoma. AIMS: To study in detail jejunal morphology and immunophenotypes in patients with refractory sprue in the search for features that might be useful to predict prognosis. PATIENTS: Seven patients are described, representing all such cases identified in our hospital over a 13 year period. METHODS: Biopsy and/or surgical resection specimens were examined by morphology, immunohistochemistry, including enzymatic and immunofluorescent detection, and molecular biology. RESULTS: All patients had phenotypically abnormal intraepithelial lymphocytes (IELs) that lacked CD8, T cell receptor alpha beta (or gamma delta), and/or expressed CD30 in addition to variable expression of the natural killer cell receptor CD94. A monoclonal T cell population was present in six cases, data from the seventh being inconclusive. Three patients had overt lymphoma with CD30+ tumour tissue intervening between intact mucosa that contained neoplastic IELs. Intriguingly, CD30+ IELs were observed both a long way away from, and in direct continuity with, the tumours in these patients. Such CD30+ cells were hardly detected in patients without tumours, two of which are in good health several years after the initial diagnosis. CONCLUSIONS: Our data suggest that abnormal IELs in patients with refractory sprue are phenotypically heterogeneous. CD30 expression by these cells may indicate a worse prognosis, including the occurrence of overt lymphoma.     

Enteropathy-associated T-cell lymphoma complicating an autoimmune enteropathy

Enteropathy-associated T-cell lymphoma (EATL) is a rare non-Hodgkin lymphoma frequently associated with celiac disease. We report a case of EATL complicating adult autoimmune enteropathy (AIE). Analysis of phenotype, rearrangements in T-cell receptor genes, and chromosome alterations by high-resolution comparative genomic hybridization identified features distinct from those described for types I and II EATL. Furthermore, EATL arose from a single T-cell clone that had been present for several years in AIE-associated, oligoclonal, intestinal T-cell infiltrate. Emerging T-cell clones should be monitored in patients with AIE who receive long-term immunosuppressive therapy.