18F-FDG PET Versus CT for the Detection of Enteropathy-Associated T-Cell Lymphoma in Refractory Celiac Disease
==============================================================================================================

* Muhammed Hadithi
* Maarten Mallant
* Joost Oudejans
* Jan-Hein T.M. van Waesberghe
* Chris J. Mulder
* Emile F.I. Comans

## Abstract

Refractory celiac disease (RCD) can evolve into enteropathy-associated T-cell lymphoma (EATL). 18F-FDG PET has been reported to discriminate between RCD and EATL. Because prospective data are lacking, we designed a prospective study to evaluate the potential of 18F-FDG PET for detection of EATL in patients with RCD and compared the results with those obtained using abdominal CT in a referral center. **Methods:** Between April 2003 and April 2005, 8 consecutive patients (median age, 66 y; range, 52−89 y) with EATL and 30 patients (median age, 61 y; range, 44−71 y) with RCD were included. CT and 18F-FDG PET were performed on all patients. Histologic evidence of EATL was identified in tissue samples obtained during upper gastrointestinal endoscopy or surgical resection. **Results:** Villous atrophy was found in all patients with RCD and all (except 1) patients with EATL in nontumoral mucosa. Histologic examination of 1 patient with EATL localized in the duodenum showed intraepithelial lymphocytosis only. 18F-FDG PET could reveal sites histologically proven to be EATL in all 8 patients, whereas CT showed normal findings in 1 patient with EATL. 18F-FDG PET detected unsuspected extraintestinal sites affected by EATL in 2 patients. CT showed abnormalities such as a thickened small-bowel wall or lymphadenopathy in 14 patients with RCD lacking evidence of EATL at follow-up. 18F-FDG PET findings were positive in 3 and equivocal in another 3 patients with RCD. 18F-FDG PET was more sensitive and specific than CT (100% vs. 87% and 90% vs. 53%, respectively). **Conclusion:** Our data show that 18F-FDG PET is more sensitive in detecting EATL in patients with RCD than is CT. 18F-FDG PET, in addition to conventional CT, is recommended for evaluating patients with RCD.

*   refractory celiac disease
*   enteropathy-associated T-cell lymphoma
*   computed tomography
*   positron emission tomography

Refractory celiac disease (RCD), a disease of malabsorption due to persisting villous atrophy despite a gluten-free diet for at least 12 mo (*1,2*), can evolve into enteropathy-associated T-cell lymphoma (EATL) (*3–5*). RCD is reported to occur in 5%−30% of patients with celiac disease (*6*). The relative risk of EATL is 20−30 times higher in patients with celiac disease than in the general population (*7,8*).

Although the value of CT has been retrospectively assessed in patients with celiac disease (*9,10*), its role in detecting EATL has been reported in case reports only (*11*). Moreover, the role of radiologic imaging may be limited in patients with RCD and EATL because the neoplastic changes may be restricted to the epithelial layer of the small bowel even when the lymphoma diffusely affects the whole small intestine (*12*).

18F-FDG PET has become a well-accepted method for diagnosis, staging, and follow-up of patients with malignant lymphomas (*13–16*), with the exception of extranodal marginal-zone B-cell lymphoma of the mucosa-associated lymphoid tissue lymphoma (*17*). 18F-FDG PET seems to discriminate between RCD and EATL (*18*), although data are limited to case reports (*19*) or retrospective analysis of single patients with EATL and RCD (*12*).

Because prospective data are lacking, we designed this longitudinal study to evaluate the potential of 18F-FDG PET for detecting EATL in patients with RCD and compared the results with those obtained by abdominal CT.

## MATERIALS AND METHODS

### Patients

Between April 2003 and April 2005, 41 consecutive patients were referred to the Department of Gastroenterology for evaluation of RCD and EATL. Three patients were excluded because of normal findings on duodenal histology, 18F-FDG PET, and abdominal CT. Therefore, 38 patients were included in the study; their clinical characteristics are summarized in Table 1. 

View this table:
[TABLE 1](http://jnm.snmjournals.org/content/47/10/1622/T1)

**TABLE 1** 
General and Clinical Characteristics of Patients with RCD and EATL

The diagnosis of EATL, based on histologic and immunohistochemical features (*18*) according to the recent WHO Classification of Tumors of Haematopoietic and Lymphoid Tissues (*20*), was made in 8 patients (21%; 95% confidence interval [CI], 11%–36%). EATL was newly diagnosed in 5 patients and had already been diagnosed at the referring hospital in 3 patients within a median of 4 wk (range, 3−11 wk) preceding evaluation. Histologic evidence of EATL was identified in tissue samples obtained by small-bowel resection (*n* = 1), small- and large-bowel resection (*n* = 1), small-bowel and lymph node resection (*n* = 1), and lymph node resection (*n* = 2). In 3 patients, EATL lesions were recognized in small-bowel biopsy samples obtained during upper gastrointestinal endoscopy.

Thirty patients (79%; 95% CI, 63%–88%) were considered to have RCD because symptoms of malabsorption were due to persisting villous atrophy with crypt hyperplasia and increased intraepithelial lymphocytes despite adherence to a gluten-free diet (*2*) and in the absence of histologic evidence of EATL. Surgery was performed on 2 patients with RCD (1 patient with mesenteric infiltration and 1 with abdominal lymphadenopathy), without identifiable evidence of EATL in the resectioned material.

### Methods

The diagnostic work-up included the celiac disease–specific serum antibody tests (IgA-antigliadin (*21,22*), -transglutaminase (*23,24*), and -endomysium antibodies (*23*)), human leukocyte antigen, DQ subregion 2 or 8 typing (*23,25*), and small-bowel histologic evaluation according to the modified Marsh classification (*26,27*). Suspected sites of lymphoma were sampled during small-bowel enteroscopy or surgery for histologic examination when indicated.

All candidates underwent abdominal CT and 18F-FDG PET as part of the diagnostic work-up. The CT examinations were performed with a Somatom volume zoom Sensations 64 (Siemens). The patients fasted overnight. A diluted solution of oral barium sulphate suspension (1,000 mL of E.Z.-CAT) was administered to the patients; it was divided into 2 doses (500 mL) administered the night before the scan and the morning of the investigation. The patients were administered additional E.Z.-CAT (200 mL) 15 min before the CT started and 100 mL of intravenous iopromide (300 mg/mL). Two experienced radiologists analyzed abdominal CT, after reaching a consensus, for bowel wall thickening (abnormal, >3 mm thick; Fig. 1), lymphadenopathy (abnormal, >10 mm in size along the short axis; Fig. 2), and mesenteric fat infiltration (Fig. 3). CT findings were considered abnormal when one or a combination of these abnormalities was found. 

![FIGURE 1. ](http://jnm.snmjournals.org/https://jnm.snmjournals.org/content/jnumed/47/10/1622/F1.medium.gif)

[FIGURE 1. ](http://jnm.snmjournals.org/content/47/10/1622/F1)

**FIGURE 1.**  
Axial abdominal CT image showing thickened small-bowel segments (arrows) in patient with EATL.

![FIGURE 2. ](http://jnm.snmjournals.org/https://jnm.snmjournals.org/content/jnumed/47/10/1622/F2.medium.gif)

[FIGURE 2. ](http://jnm.snmjournals.org/content/47/10/1622/F2)

**FIGURE 2.**  
Axial abdominal CT image showing enlarged lymph nodes (arrows) in patient with EATL.

![FIGURE 3. ](http://jnm.snmjournals.org/https://jnm.snmjournals.org/content/jnumed/47/10/1622/F3.medium.gif)

[FIGURE 3. ](http://jnm.snmjournals.org/content/47/10/1622/F3)

**FIGURE 3.**  
Axial abdominal CT image showing mesenteric fat infiltration (arrow) in patient with EATL.

Whole-body 18F-FDG PET was performed using a dedicated PET scanner (ECAT EXACT HR+; CTI/Siemens). All patients were asked to fast for at least 6 h before 18F-FDG injections and received an intravenous injection of 20 mg of *N*-butylbromide (Buscopan; Boehringer Ingelheim) for smooth-muscle relaxation 5 min before the start of the scan (*28*). This injection was repeated when necessary 45 min after the first injection. Emission and transmission scans of 5 and 4 min per bed position (ETTE mode) were performed 60 min after injection of 370 MBq of 18F-FDG (555 MBq when body weight was >85 kg) from the neck to the pelvic floor. All emission scans were corrected for decay, scatter, randoms, and attenuation and were reconstructed using ordered-subset expectation maximization with 2 iterations and 16 subsets followed by smoothing of the reconstructed image using a gaussian filter of 5 mm in full width at half maximum. Transmission data were smoothed by a 1-dimensional filter in the axial direction and were segmented, and attenuation correction factors were calculated by forward projection. Images were reconstructed iteratively. Venous blood was withdrawn before injection for measurement of the serum glucose concentration. Two independent nuclear medicine physicians who were unaware of the clinical data and histologic findings interpreted the images. The results of 18F-FDG PET were classified as negative (when 18F-FDG uptake was compatible with physiologic biodistribution), equivocal, or positive (when 18F-FDG uptake was not compatible with physiologic biodistribution and was moderately or intensely increased; Fig. 4). No standardized uptake values were calculated because no validated methods exist for correction of the partial-volume effect of the radioactivity concentration of small volumes such as the small-intestinal wall (smaller than 2 times the resolution of the system). 18F-FDG PET results were compared with those of abdominal CT, histologic findings on biopsy or resection material, and surgical findings. 

![FIGURE 4. ](http://jnm.snmjournals.org/https://jnm.snmjournals.org/content/jnumed/47/10/1622/F4.medium.gif)

[FIGURE 4. ](http://jnm.snmjournals.org/content/47/10/1622/F4)

**FIGURE 4.**  
Intensely increased 18F-FDG PET uptake on coronal and axial images in patient with small-bowel lymphoma (A) and another patient with abdominal and extraabdominal lymphoma (B).

Informed consent was obtained from all patients, and the institutional review board of the VU University Medical Center gave permission for this study.

### Statistical Analysis

The Student paired *t* test, Mann–Whitney test, or Fisher exact test was used for data analysis when indicated. *P* values of less than 0.05 were considered statistically significant. All statistical analysis was performed using the Statistical Software Package, version 11.0 (SPSS Inc.).

## RESULTS

### Patients

Small-bowel biopsy established the presence of villous atrophy (Marsh III) in all patients with RCD and all (except 1) patients with EATL in nontumoral mucosa. In 1 patient with EATL localized in the duodenum, histologic examination showed only Marsh I changes in the mucosa. The diagnostic makeup of the study population is summarized in Table 2. Within a median follow-up period of 14 mo (range, 9−24 mo), 6 patients (75%) with EATL and 4 patients (13%) with RCD have died (*P* = 0.001). Causes of death in RCD patients were recurrent infections in malnourished patients (*n* = 3) and a metastasized squamous cell lung carcinoma (*n* = 1). Four patients with EATL received therapy consisting of cyclophosphamide, doxorubicin, vincristine, and prednisolone (*20,29*). In 1 patient with EATL, autologous peripheral stem cell transplantation was performed, and no further therapy was given to 3 patients because of their poor general condition and comorbidity. 

View this table:
[TABLE 2](http://jnm.snmjournals.org/content/47/10/1622/T2)

**TABLE 2** 
The Celiac Disease Makeup of Patients with RCD and EATL

### 18F-FDG PET Versus Abdominal CT

In all 8 patients with EATL, 18F-FDG PET identified enhanced abdominal 18F-FDG uptake (100%; 95% CI, 67%–100%), whereas abdominal CT findings were abnormal in 7 of these 8 patients (87%; 95% CI, 52%–97%). Abnormal CT findings in patients with evidence of EATL included lymphadenopathy (*n* = 4), a thickened small-bowel wall (*n* = 7), and mesenteric fat infiltration (*n* = 2). Small-bowel thickening, whether duodenal (*n* = 2), jejunal (*n* = 1), jejunal and ileal (*n* = 3), or diffuse (*n* = 1), ranged from 8 to 15 mm on CT slices. The abdominal sites of enhanced 18F-FDG uptake were proven to be EATL by histologic examination of samples obtained by surgery or endoscopy. CT did not show any abnormality in 1 patient with EATL proven by surgical resection of the small bowel. In 2 patients with EATL, additional sites of focal 18F-FDG accumulation were shown in the superior mediastinum on 18F-FDG PET images. Mediastinal lymphadenopathy was verified by thoracic CT. Mediastinoscopy and lymph node resection proved the presence of EATL in these 2 patients.

In patients with RCD, 18F-FDG PET findings were positive in 3 (10%; 95% CI, 3%–25%) and CT findings were abnormal in 14 (46.6%; 95% CI, 30%–63%). Of the patients with RCD and positive 18F-FDG PET results, the findings on abdominal CT were normal in 1 and abnormal in 2 patients (1 patient with a 6-mm thickened jejunal wall and 1 patient with a 7-mm thickened jejunal and ileal wall). All patients underwent small-bowel enteroscopy. No histologic evidence of EATL was found. The first 2 patients are alive and in good condition. The third patient died after recurrent chest infections.

In addition, 18F-FDG PET showed equivocal findings in 3 patients (10%; 95% CI, 3%–25%) with RCD. In these patients, the findings on abdominal CT were normal in 1 and abnormal in 2 patients (1 patient with lymphadenopathy and 1 patient with lymphadenopathy and a 10-mm thickened jejunal and ileal wall). The first patient could not undergo further invasive diagnostic examinations because of a poor general condition requiring long-term clinical admission. The other 2 patients underwent small-bowel enteroscopy. No evidence of EATL was found in any of multiple small-bowel histology specimens. Both patients are alive and in good general condition.

Of the patients with normal 18F-FDG PET findings, 10 had abnormal abdominal CT findings. CT showed lymphadenopathy in 3, a thickened small bowel (7−11 mm) in 7, and infiltrated mesenteric fat in 1 patient. Surgical resection of enlarged lymph nodes in 1 patient and mesenteric fat in 1 patient did not show evidence of EATL.

The CT and 18F-FDG PET findings in patients with RCD and those with EATL are summarized in Table 3. Abdominal CT results were concordant with the results of 18F-FDG PET in 7 patients (87.5%) who had EATL and in 18 patients (60%) with RCD. CT results did not match the results of 18F-FDG PET in 1 patient (12.5%) with EATL and 12 patients (40%) with RCD. Table 4 summarizes the sensitivity, specificity, and positive and negative likelihood ratios for CT and 18F-FDG PET. When equivocal 18F-FDG PET findings were scored as positive in the analysis (*n* = 6 [20%]; 95% CI, 9–37), the specificity declined to 80% but remained higher than that of CT (*P* = 0.008). 

View this table:
[TABLE 3](http://jnm.snmjournals.org/content/47/10/1622/T3)

**TABLE 3** 
Abdominal CT and 18F-FDG PET Scan Findings in Patients With and Without EATL

View this table:
[TABLE 4](http://jnm.snmjournals.org/content/47/10/1622/T4)

**TABLE 4** 
Diagnostic Value of CT vs. 18F-FDG PET in Detecting EATL in Patients with RCD

## DISCUSSION

The results of this prospective cohort demonstrated that 18F-FDG PET revealed sites affected by EATL as confirmed on biopsy in all patients, whereas CT was false negative in 1 patient. Conversely, CT showed abnormalities such as a thickened small-bowel wall or lymphadenopathy in 14 patients with RCD lacking evidence of EATL after a follow-up period of at least 1 y, rendering CT less specific than PET, even when equivocal 18F-FDG PET findings were considered positive. Finally, 18F-FDG PET could unravel extraintestinal sites affected by EATL.

Our results confirm earlier conclusions that 18F-FDG PET can detect EATL in patients with RCD (*12*), in contrast to the limited diagnostic role of 18F-FDG PET in mucosa-associated lymphoid tissue lymphoma (*17*). This confirmation indicates that 18F-FDG PET efficacy varies with the histologic type (*30*). However, false-positive 18F-FDG PET readings were made in patients with RCD in the absence of histologic evidence of EATL. It has been reported that false-positive results may be due to inflammation (*31*) or increased uptake in nonrelaxed muscles such as the gut (*30*). In this study, even though we tried, by the routine use of Buscopan, to diminish the effect of small-bowel peristalsis on images obtained during 18F-FDG PET, instances of false-positive findings occurred. Therefore, 18F-FDG PET cannot be a substitute for histologic examination in the diagnosis of EATL. However, 18F-FDG PET can be helpful tool in directing biopsy.

CT abnormalities that have been reported in patients with celiac disease include jejunoileal fold-pattern reversal (*9*), small-bowel intussusception (*32*), lymphadenopathy (*33*), and bowel wall thickening (*10*). Mesenteric nonneoplastic, histologically proven lymphadenopathy or fat infiltration was seen in 2 patients with RCD, suggesting that such findings can accompany RCD without necessarily being specific for T-cell lymphoma (*18*). Moreover, disappearance of benign mesenteric lymph node enlargement and cavitation after a gluten-free diet has been described (*34,35*).

Recently, hybrid PET/CT devices have been introduced as a powerful tool to facilitate fusion of the functional information of PET with the anatomic information of CT (*36*). Further, PET/CT as a combined modality may contribute substantially to lesion characterization and staging in patients with lymphoma (*37*). Whether combined PET/CT improves the diagnostic distinctions described for patients with EATL needs to be further investigated.

To our knowledge, this study was the largest series of patients with RCD and EATL being investigated by 18F-FDG PET for detection or exclusion of EATL. The relatively limited number of patients may be considered a confounding factor to the main outcome of the study. However, the prospective nature of the study and the available follow-up data validate, in our opinion, the reported results. The selection bias inherent in this study because of the strict inclusion criteria might lead to an overestimation of the performance of 18F-FDG PET. Therefore, the generalizability of the study results remains to be elucidated.

## CONCLUSION

18F-FDG PET seems a more sensitive method than CT for detecting EATL in patients with RCD. This technique is recommended in addition to conventional CT for evaluating patients with RCD. Positive PET results in patients with RCD should be pursued vigorously by examining histologic samples from areas with high uptake.

## Footnotes

*   COPYRIGHT © 2006 by the Society of Nuclear Medicine, Inc.

## References

1.  1. Mulder CJ, Wahab PJ, Moshaver B, Meijer JW. Refractory coeliac disease: a window between coeliac disease and enteropathy associated T cell lymphoma. Scand J Gastroenterol Suppl. 2000;(232):32–37.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=11232488&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

2.  2. Wahab PJ, Meijer JW, Goerres MS, Mulder CJ. Coeliac disease: changing views on gluten-sensitive enteropathy. Scand J Gastroenterol Suppl. 2002;(236):60–65.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=12408506&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

3.  3. Wright DH. The major complications of coeliac disease. Baillieres Clin Gastroenterol. 1995;9:351–369.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/0950-3528(95)90035-7&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=7549031&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=A1995RE98000010&link_type=ISI) 

4.  4. Cellier C, Delabesse E, Helmer C, et al. Refractory sprue, coeliac disease, and enteropathy-associated T-cell lymphoma. French Coeliac Disease Study Group. Lancet. 2000;356:203–208.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/S0140-6736(00)02481-8&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10963198&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000088179100011&link_type=ISI) 

5.  5. Daum S, Weiss D, Hummel M, et al. Frequency of clonal intraepithelial T lymphocyte proliferations in enteropathy-type intestinal T cell lymphoma, coeliac disease, and refractory sprue. Gut. 2001;49:804–812.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjg6IjQ5LzYvODA0IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

6.  6. Howdle PD, Blair GE. Molecular biology and coeliac disease. Gut. 1992;33:573–575.
    
    [FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo2OiJndXRqbmwiO3M6NToicmVzaWQiO3M6ODoiMzMvNS81NzMiO3M6NDoiYXRvbSI7czoyMzoiL2pudW1lZC80Ny8xMC8xNjIyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

7.  7. Catassi C, Fabiani E, Corrao G, et al. Risk of non-Hodgkin lymphoma in celiac disease. JAMA. 2002;287:1413–1419.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1001/jama.287.11.1413&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=11903028&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000174465000023&link_type=ISI) 

8.  8. Kavoosi M, Meijer J, Kwan E, Creagh AL, Kilburn DG, Haynes CA. Inexpensive one-step purification of polypeptides expressed in Escherichia coli as fusions with the family 9 carbohydrate-binding module of xylanase 10A from T. maritima. J Chromatogr B Analyt Technol Biomed Life Sci. 2004;807:87–94.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.jchromb.2004.03.031&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15177165&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

9.  9. Tomei E, Marini M, Messineo D, et al. Computed tomography of the small bowel in adult celiac disease: the jejunoileal fold pattern reversal. Eur Radiol. 2000;10:119–122.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1007/s003300050016&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10663727&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

10. 10. Tomei E, Diacinti D, Marini M, et al. Abdominal CT findings may suggest coeliac disease. Dig Liver Dis. 2005;37:402–406.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.dld.2004.10.016&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15893278&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

11. 11. Buess M, Steuerwald M, Wegmann W, Rothen M. Obstructive jaundice caused by enteropathy-associated T-cell lymphoma in a patient with celiac sprue. J Gastroenterol. 2004;39:1110–1113.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1007/s00535-004-1453-3&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15580407&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

12. 12. Hoffmann M, Vogelsang H, Kletter K, Zettinig G, Chott A, Raderer M. 18F-fluoro-deoxy-glucose positron emission tomography (18F-FDG-PET) for assessment of enteropathy-type T cell lymphoma. Gut. 2003;52:347–351.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiZ3V0am5sIjtzOjU6InJlc2lkIjtzOjg6IjUyLzMvMzQ3IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

13. 13. Schoder H, Meta J, Yap C, et al. Effect of whole-body 18F-FDG PET imaging on clinical staging and management of patients with malignant lymphoma. J Nucl Med. 2001;42:1139–1143.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjk6IjQyLzgvMTEzOSI7czo0OiJhdG9tIjtzOjIzOiIvam51bWVkLzQ3LzEwLzE2MjIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

14. 14. Segall GM. FDG PET imaging in patients with lymphoma: a clinical perspective. J Nucl Med. 2001;42:609–610.
    
    [FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiRlVMTCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjg6IjQyLzQvNjA5IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

15. 15. Tucker R, Coel M, Ko J, Morris P, Druger G, McGuigan P. Impact of fluorine-18 fluorodeoxyglucose positron emission tomography on patient management: first year's experience in a clinical center. J Clin Oncol. 2001;19:2504–2508.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6MzoiamNvIjtzOjU6InJlc2lkIjtzOjk6IjE5LzkvMjUwNCI7czo0OiJhdG9tIjtzOjIzOiIvam51bWVkLzQ3LzEwLzE2MjIuYXRvbSI7fXM6ODoiZnJhZ21lbnQiO3M6MDoiIjt9) 

16. 16. Weihrauch MR, Dietlein M, Schicha H, Diehl V, Tesch H. Prognostic significance of 18F-fluorodeoxyglucose positron emission tomography in lymphoma. Leuk Lymphoma. 2003;44:15–22.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=12691138&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000179243000003&link_type=ISI) 

17. 17. Hoffmann M, Kletter K, Diemling M, et al. Positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose (F18-FDG) does not visualize extranodal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type. Ann Oncol. 1999;10:1185–1189.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NjoiYW5ub25jIjtzOjU6InJlc2lkIjtzOjEwOiIxMC8xMC8xMTg1IjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

18. 18. Daum S, Cellier C, Mulder CJ. Refractory coeliac disease. Best Pract Res Clin Gastroenterol. 2005;19:413–424.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/j.bpg.2005.02.001&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15925846&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

19. 19. Honemann D, Prince HM, Hicks RJ, Seymour JF. Enteropathy-associated T-cell lymphoma without a prior diagnosis of coeliac disease: diagnostic dilemmas and management options. Ann Hematol. 2005;84:118–121.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1007/s00277-004-0953-9&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15452669&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

20. 20. Harris NL, Jaffe ES, Diebold J, Flandrin G, Muller-Hermelink HK, Vardiman J. Lymphoma classification: from controversy to consensus—the R.E.A.L. and WHO classification of lymphoid neoplasms. Ann Oncol. 2000;11(suppl 1):3–10.
    
    [FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6MzoiUERGIjtzOjExOiJqb3VybmFsQ29kZSI7czo2OiJhbm5vbmMiO3M6NToicmVzaWQiO3M6NjoiMTEvMS8zIjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

21. 21. Rostami K, Kerckhaert J, Tiemessen R, von Blomberg BM, Meijer JW, Mulder CJ. Sensitivity of antiendomysium and antigliadin antibodies in untreated celiac disease: disappointing in clinical practice. Am J Gastroenterol. 1999;94:888–894.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1111/j.1572-0241.1999.983_f.x&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10201452&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000079505700013&link_type=ISI) 

22. 22. Rostami K, Mulder CJ, van Overbeek FM, et al. Should relatives of coeliacs with mild clinical complaints undergo a small-bowel biopsy despite negative serology? Eur J Gastroenterol Hepatol. 2000;12:51–55.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10656210&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

23. 23. Csizmadia CG, Mearin ML, Oren A, et al. Accuracy and cost-effectiveness of a new strategy to screen for celiac disease in children with Down syndrome. J Pediatr. 2000;137:756–761.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1067/mpd.2000.110421&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=11113830&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000165876300006&link_type=ISI) 

24. 24. Schweizer JJ, von Blomberg BM, Bueno-de Mesquita HB, Mearin ML. Coeliac disease in The Netherlands. Scand J Gastroenterol. 2004;39:359–364.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1080/00365520310008503&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15125468&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000220616500009&link_type=ISI) 

25. 25. Crusius JBA. *The Immunogenetics of Chronic Inflammatory and Autoimmune Disease* [dissertation]. Amsterdam, The Netherlands: Immunogenetics, VU University Medical Center, Vrije Universiteit; 2002.
    
    

26. 26. Rostami K, Kerckhaert J, von Blomberg BM, Meijer JW, Wahab P, Mulder CJ. SAT and serology in adult coeliacs, seronegative coeliac disease seems a reality. Neth J Med. 1998;53:15–19.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1016/S0300-2977(98)00050-3&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=9718937&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000075266600004&link_type=ISI) 

27. 27. Wahab PJ, Meijer JW, Mulder CJ. Histologic follow-up of people with celiac disease on a gluten-free diet: slow and incomplete recovery. Am J Clin Pathol. 2002;118:459–463.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6NDoiYWpjcCI7czo1OiJyZXNpZCI7czo5OiIxMTgvMy80NTkiO3M6NDoiYXRvbSI7czoyMzoiL2pudW1lZC80Ny8xMC8xNjIyLmF0b20iO31zOjg6ImZyYWdtZW50IjtzOjA6IiI7fQ==) 

28. 28. Stahl A, Weber WA, Avril N, Schwaiger M. Effect of N-butylscopolamine on intestinal uptake of fluorine-18-fluorodeoxyglucose in PET imaging of the abdomen. Nuklearmedizin. 2000;39:241–245.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=11189901&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

29. 29. Egan LJ, Walsh SV, Stevens FM, Connolly CE, Egan EL, McCarthy CF. Celiac-associated lymphoma: a single institution experience of 30 cases in the combination chemotherapy era. J Clin Gastroenterol. 1995;21:123–129.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=8583077&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=A1995RR98300012&link_type=ISI) 

30. 30. Burton C, Ell P, Linch D. The role of PET imaging in lymphoma. Br J Haematol. 2004;126:772–784.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1111/j.1365-2141.2004.05069.x&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15352980&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=000223895100002&link_type=ISI) 

31. 31. Kubota R, Yamada S, Kubota K, Ishiwata K, Tamahashi N, Ido T. Intratumoral distribution of fluorine-18-fluorodeoxyglucose in vivo: high accumulation in macrophages and granulation tissues studied by microautoradiography. J Nucl Med. 1992;33:1972–1980.
    
    [Abstract/FREE Full Text](http://jnm.snmjournals.org/lookup/ijlink/YTozOntzOjQ6InBhdGgiO3M6MTQ6Ii9sb29rdXAvaWpsaW5rIjtzOjU6InF1ZXJ5IjthOjQ6e3M6ODoibGlua1R5cGUiO3M6NDoiQUJTVCI7czoxMToiam91cm5hbENvZGUiO3M6Njoiam51bWVkIjtzOjU6InJlc2lkIjtzOjEwOiIzMy8xMS8xOTcyIjtzOjQ6ImF0b20iO3M6MjM6Ii9qbnVtZWQvNDcvMTAvMTYyMi5hdG9tIjt9czo4OiJmcmFnbWVudCI7czowOiIiO30=) 

32. 32. Strobl PW, Warshauer DM. CT diagnosis of celiac disease. J Comput Assist Tomogr. 1995;19:319–320.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=7890865&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 
    
    [Web of Science](http://jnm.snmjournals.org/lookup/external-ref?access_num=A1995QN28200030&link_type=ISI) 

33. 33. de Boer WA, Maas M, Tytgat GN. Disappearance of mesenteric lymphadenopathy with gluten-free diet in celiac sprue. J Clin Gastroenterol. 1993;16:317–319.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=8331266&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

34. 34. Al-Kawas FH, Murgo A, Foshag L, Shiels W. Lymphadenopathy in celiac disease: not always a sign of lymphoma. Am J Gastroenterol. 1988;83:301–303.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=3344733&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

35. 35. Arotcarena R, Hammel P, Terris B, Guth A, Bernades P, Ruszniewski P. Regression of mesenteric lymph node cavitation syndrome complicating celiac disease after a gluten free diet [in French]. Gastroenterol Clin Biol. 2000;24:579–581.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=10891750&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

36. 36. Sachelarie I, Kerr K, Ghesani M, Blum RH. Integrated PET-CT: evidence-based review of oncology indications. Oncology (Williston Park). 2005;19:481–490.
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=15934517&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

37. 37. Tatsumi M, Cohade C, Nakamoto Y, Fishman EK, Wahl RL. Direct comparison of FDG PET and CT findings in patients with lymphoma: initial experience. Radiology. 2005;237:1038–1045.
    
    [CrossRef](http://jnm.snmjournals.org/lookup/external-ref?access_num=10.1148/radiol.2373040555&link_type=DOI) 
    
    [PubMed](http://jnm.snmjournals.org/lookup/external-ref?access_num=16304117&link_type=MED&atom=%2Fjnumed%2F47%2F10%2F1622.atom) 

*   Received for publication March 15, 2006.
*   Accepted for publication June 19, 2006.