Is Complicated Celiac Disease or Refractory Sprue an Intestinal Intra-Epithelial Cryptic T-Cell Lymphoma?

To the Editor:

We have read with interest the report by Carbonnel et al1which suggests that complicated celiac disease (CD) is a form of cryptic T-cell lymphoma in four patients. We have recently published a similar study of six patients with complicated CD, which we classified as refractory sprue,2 in which we not only suggested a possible T-cell lymphomatous origin, but also showed that the clonal population was derived from intra-epithelial lymphocytes (IEL), based on the following observations:

(1) Histological analysis showed that the lymphoid infiltrate predominated in the surface epithelium of the duodenal biopsy specimens, as in classical CD. There was a marked increase in the number of IEL (105 ± 27 IEL per 100 epithelial cells v18 ± 3 IEL per 100 epithelial cells in normal), but these were morphologically normal with no cytological evidence of malignancy.

(2) The immunophenotype was abnormal, insofar as the IEL expressed cytoplasmic (cCD3) but not surface CD3 (sCD3) and were negative for TCRαβ, TCRγδ, and CD8 expression. As with normal IEL, they expressed the αEβ7 (CD103) integrin. This abnormal phenotype was confirmed by immunocytometric analysis of CD103⁺ sorted lymphocytes isolated from duodenal biopsy specimens in two patients. In contrast, lamina propria lymphocytes showed a normal CD3⁺, CD4⁺, TCRαβ⁺, CD103⁻phenotype.

(3) The clonal TCRγ configuration identified in the duodenal biopsy samples of all patients was shown in two cases to be identical to that identified in the sorted CD103⁺, sCD3⁻ IEL population.

Several of these findings have been confirmed by Carbonnel et al, thus reinforcing a probable intra-epithelial origin for the clonal T-lymphoid population. In fact, the histological lesions described by Carbonnel et al in the duodenal biopsy specimens are identical to those observed by us, being similar to those of classical CD. These include subtotal or total villous atrophy, an increase in IEL, crypt hyperplasia, and lamina propria inflammation. Both studies also describe ulcerated lesions in either the duodenum (one case) or jejunum (three patients). Ulcerative jejunitis is recognized to occur in complicated CD and has been suggested to represent a prelymphomatous (T) state.3 The immunophenotype (cyt CD3⁺, CD103⁺, CD8⁻, CD4⁻) described by Carbonnel in one case is also virtually identical to that described by us but differs in the expression of TCR αβ, which we did not detect, using the βF1, TCRβ-specific, monoclonal antibody. Most normal IEL and lamina propria lymphocytes express TCRαβ. The immunohistochemical study of Carbonnel did not differentiate these two lymphoid populations; TCRαβ expression may reflect the nontumoral lymphoid population associated with lymphomatous cells. Therefore, the phenotype of the abnormal cells may be identical in both studies. This abnormal phenotype differs from that observed in active, classical CD, when the majority of T lymphocytes are cCD3⁺, CD8⁺.2 The persistence and the intestinal dissemination of the clonal population described by Carbonnel was also a frequent finding in our patients.2 

Given the virtually identical clinical, histological, immunological, and molecular features in the two series, it is probable that both describe the same pathogenic entity. However, the clinical evolution of the patients differed somewhat, insofar as three of the four patients described by Carbonnel developed evident lymphoma within 4 to 31 months of diagnosis and none of our six patients had done so, with a median follow-up of 5 years (range, 1 to 11 years). In a more extensive series (Cellier et al: manuscript in preparation), we have also observed evolution to frank lymphoma in 3 of 20 patients with refractory sprue. Therefore, it is clear that the identification of an immunologically abnormal, clonal T-lymphoid population may, in some patients, preceed development of lymphoma by several years. However, it is important to note that, even in the absence of overt lymphoma, the prognosis is poor in this category of patient. In the 10 patients of the two series, 5 are resistant to a gluten-free diet, 3 responded only temporarily and are steroid dependant, and 7 of the 10 have died within 10 years of diagnosis, 3 from lymphoma and 4 from malnutrition. Therefore, it is important to identify this group, independently of the risk of malignant transformation.

Carbonnel et al suggested that molecular analysis of TCRγ gene configuration represents a useful method of identification of cases with complicated CD/refractory sprue. Although our data are in keeping with this, we suggest that immunohistological identification of abnormal CD3⁺, CD8⁻ IEL on frozen or paraffin-embedded material4 may represent a simple, rapid alternative that can be applied prospectively or retrospectively. Parallel analysis of a large series by both immunological and molecular techniques, which we are currently undertaking, will determine which represents the most reliable, predictive, and cost-effective strategy.

In conclusion, the entity described by Carbonnel as complicated CD is probably identical to our series of refractory sprue and corresponds to a group of patients with a poor prognosis due either to development of T-cell lymphoma or to complications of malabsorption. Early identification of this group by immunological or molecular techniques will allow more appropriate therapy and improved understanding of the pathogenic mechanisms underlying this disorder.