DISCUSSION

This is the first report of extranodal DLBCL of the stomach in a patient receiving nataliziumab therapy for MS. No other nodal or extranodal presentations of DLBCL have been reported in the population of MS patients treated with natalizumb.

In other treatment groups, an individual with Crohn’s disease was diagnosed with DLBCL over 6 months after completing natalizumab therapy.6 PCNSL and one case of peripheral T-cell lymphoma have both been described in patients with MS receiving natalizumab.7,8


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Interestingly, the majority of reported cases had no identified EBV-driven etiology. Studies have shown that patients with MS do not have a predilection for the development of NHL.9 Histologically, DLBCL reflects moderate to higher grade disease activity and is often associated with a more aggressive initial presentation.

In a recent study of extranodal NHL, approximately 50% of cases were DLBCL.10 The most common extranodal site is the gastrointestinal tract with involvement of the stomach composing the majority of cases.11

The overall incidence of primary extranodal NHL of the gastrointestinal tract is approximately 1 per 100,000 individuals.1 A singlecenter review identified 371 primary gastrointestinal NHL cases over a 4-year period of which 74.8% of cases were confined to the stomach.11 The incidence of extranodal gastrointestinal NHL appears to be increasing with H. pylori infection implicated in the majority of gastric MALT cases.10

Frequent symptoms prompting clinical evaluation include abdominal pain, nausea, and weight loss although clinical presentations of extranodal NHL vary. Genetic studies have revealed differences in lymphomagenesis between nodal and extranodal DLBCL that suggest the two diseases merit consideration as separate entities.12

The use of concurrent natalizumb in the presented case raises questions regarding a possible relationship between VLA-4 inhibition and the development of extranodal DLBCL.

Outside of its inhibitory effects on lymphocyte transportation into the CNS, natalizumab appears to decrease the migratory capacity of circulating immune cells and alter expression of genes involved in B-cell activation and differentiation.13

Although impaired immune surveillance with natalizumab appears possible mechanistically, further confirmatory studies are needed to better understand the clinical implications of this phenomenon. It is difficult to establish a direct causal association between natalizumab use and the development of extranodal DLBCL of the stomach on the basis of one reported case.

However, it is important to document this event in the available literature given prior questions regarding natalizumab use and the development of other rare lymphoproliferative disorders such as PCNSL and peripheral T-cell lymphoma.

As long-term use of natalizumab increases, heightened clinical suspicion remains imperative given the potential unanticipated complications from this potent method of immunosuppression.

AUTHOR CONTRIBUTIONS

Wrote the first draft of the manuscript: JYL. Contributed to the writing of the manuscript: JYL. Jointly developed the structure and arguments for this paper: JYL, HVN. Made critical revisions and approved final version: JYL, DWK, AS, HVN. All authors reviewed and approved of the final manuscript.