Mucosal Healing and Risk of Lymphoproliferative Malignancy in Celiac Disease Outcomes

Celiac disease (CD) is associated with an increased risk of lymphoproliferative malignancy (LPM). It is unknown whether this risk is affected by the results of the follow-up intestinal biopsy, performed to document mucosal healing. We aimed to quantify the risk of LPM in those patients with CD who had persistent villous atrophy and those patients who had mucosal healing on follow-up biopsy.

Using a population-based database that included all pathology departments in Sweden (n=28), we identified all patients with CD (equal to villous atrophy, Marsh histopathology stage 3) who had a follow-up biopsy between six months and five years after initial diagnosis, and compared the risk of LPM to that of the general population using expected rates based on age, gender, and calendar year. We used Cox regression to compare the rate of LPM in those with persistent villous atrophy to those with mucosal healing.

Among 7,625 patients with CD and a follow-up biopsy, persistent villous atrophy was present in 3,308 (43%). LPM developed in 53 (0.7%) patients, with a median time to LPM of 4.9 years after follow-up biopsy. The overall risk of LPM was increased compared to the general population (Standardized incidence ratio, SIR 2.81; 95% CI 2.10-3.67), but this increase was limited to those with persistent villous atrophy (SIR 3.78; 95% CI 2.71-5.12) with no significant increased risk among those with mucosal healing (SIR 1.50; 95% CI 0.77-2.62). Persistent villous atrophy compared to mucosal healing was associated with an increased risk of LPM (Hazard ratio, HR 2.26; 95% CI 1.18-4.34). This risk was primarily observed for T cell lymphoma (HR 3.51; 95% CI 0.75-16.34), with no association for B cell lymphoma (HR 0.97; 95% CI 0.21-4.49). Patients with subtotal or total villous atrophy on follow-up biopsy had a greater increase in LPM risk (HR 3.96; 95% 1.65-9.50) compared to those with partial villous atrophy (HR 1.90; 95% CI 0.70-5.19).

The increased risk of LPM in CD is markedly influenced by the results of the follow-up biopsy; those with mucosal healing have an LPM risk similar to that of the general population. The increased risk of LPM among those with persistent villous atrophy is mainly for T cell lymphoma. Follow-up biopsy can effectively stratify CD patients regarding subsequent LPM risk.

Benjamin Lebwohl1, 2, Fredrik Granath2, Anders Ekbom2, Karin E. Smedby2, Joseph A. Murray3, Alfred I. Neugut1, Peter H. Green1, Jonas F. Ludvigsson2

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