A possible new role for <i>Helicobacter pylori</i> in the development of ocular adnexal lymphoma
Authors: Sarah E. Coupland
Journal: American Journal of Hematology (2010)

The ocular adnexal lymphoma (OAL), with an incidence of ∼0.18 and 0.31 per 100,000 per year, represent ∼8% of all extranodal non-Hodgkin lymphomas (NHL), and arise in the orbit, conjunctiva, eyelids and lacrimal gland [1]. The most common subtype is the extranodal marginal zone B-cell lymphoma (EMZL), representing approximately two-thirds of these tumors [2]. Although EMZL are low-grade B-cell lymphomas, which respond well to localized low-dose radiotherapy, the clinical course of the patients is often characterized by tumor recurrence, typically in other extranodal locations, and also by late systemic dissemination in up to 25% of patients [2]. Since the original description of conjunctival EMZL of "MALT type" by Wotherspoon in 1993 [3], the pathogenesis of these tumors remains enigmatic. Particular chromosomal abnormalities, including trisomy 3 and +18q as well as the translocations t(11;18) (API-2/MALT1), t(14;18) (IgH/MALT1), t(1;14) (BCL-10/IgH) and t(3;14) (FOX-P1/IgH), have been described in OAL; however, these are not specific for anatomical location and are not predictive of disease progression [4]. Recently, the presence of the A20 deletion on chromosome 6 has been found with a particular high frequency in OAL EMZL compared to other extranodal sites [5, 6]. Epigenetic changes involving this and other genes correlate with an increased rate of OAL EMZL recurrence and reduced disease free survival [5-7]. Underlying chronic inflammation has also been associated with the initiation of OAL EMZL: this is supported by molecular genetic and clinical evidence. For example, the somatic mutation pattern of the variable region of the immunoglobulin genes would suggest that there is either an endoantigen or an exoantigen driving the process of disease development [8-10]. The presence of an endoantigen (or autoantibody) is supported by an increased incidence of OAL EMZL in patients with Sjögren's syndrome, Hashimoto's thyroiditis, and other autoimmune diseases [11]. Supporting the possibility of exoantigens are the data following examination of OAL biopsies suggesting the involvement of particular infectious agents,—such as Chlamydia psittaci, Chlamydia pneumoniae, Hepatitis C and Helicobacter pylori (H. pylori)—in ocular adnexal EMZL development [7, 12-18]. According to the aforementioned chronic inflammation hypothesis, it is proposed that both endo-and exoantigens initiate a reactive lymphoid hyperplasia in the ocular adnexal tissues. Through this protracted antigenic stimulation, together with interactions with the microenvironment [particularly microorganism-specific T-helper (CD4+) and T-regulatory cells] and with the accumulation of genetic alterations resulting in aberrant NF-κB activation, it is suggested that these events ultimately lead to an uncontrolled monoclonal B-cell expansion, which is resistant to inducers of the extrinsic and intrinsic apoptosis pathways [19-21]. Recurrent tumor in other extranodal sites is thought to be caused by homing mechanisms involving chemokine receptor and ligand interactions of the lymphoma cells in the required milieu for proliferation [22, 23]. In this issue of the American Journal of Hematology, Decaudin et al. [24] have examined a large series of gastric biopsies for H. pylori in three cohorts of patients: (A) patients with OAL (n = 83); (B) patients with extra-gastric and extra-ophthalmologic lymphoma (n = 101); and (C) patients with no clinical evidence of lymphoma (controls; n = 156). Gastric H. pylori infection was investigated by means of histopathological analysis and H. pylori-specific polymerase chain reaction (PCR) assay on gastric biopsy tissue samples, and was demonstrated in 45%, 25% and 12% of patients in groups A, B, and C, respectively. That is, a significant association between gastric H. pylori infection and OAL could be demonstrated in this study, with this association being greatest for the EMZL/lymphoplasmocytic lymphoma (LPL) group of OAL. This association with gastric H. pylori infection was not seen in other subtypes of OAL, such as follicular lymphoma or diffuse large B-cell lymphoma, or in the other extra-ophthalmologic extra-gastric NHL. Interestingly, the eight OAL tissue biopsies available for examination for H. pylori were negative. The authors propose that gastric H. pylori infection results in the initial malignant transformation of the lymphocytes and that these neoplastic B-cells subsequently migrate to the ocular adnexa, here forming "ectopic lymphoma." The migration process is suggested to be as a result of cellular homing mechanisms with chemotactic agents being released by localised chronic inflammation in the ocular adnexal tissues (e.g., due to autoimmune disease or Chlamydia infection), attracting the neoplastic B-cells to this niche. It would have been of interest to know the incidence of Chlamydia infection or autoimmune disease in the examined OAL cohort; however, it appears that these details were not available to the investigators. To support their hypothesis, however, the authors point out the frequent bilateral involvement of OAL EMZL [25-27] and a relatively high incidence of blepharitis in patients with gastric H. pylori [23]. Decaudin et al. [24] also propose that, like the autoantigen H(+)K(+)-ATPase, expressed by the gastric epithelium, the lacrimal gland and the gastric may share common epitopes, which could be targets for autoimmune disease. Animal models for OAL, which have yet to be established, would be of use in understanding the interplay of these inflammatory processes. Another merit of the paper by Decaudin et al. [24] is represented by the attempt to correlate gastric H. pylori infection with the clinical features of the OAL—i.e., the location and Ann Arbor Stage of the tumor, the International Prognostic Index score and the clinical course. The data would suggest that the gastric H. pylori infection detected at the initial diagnosis of lymphoma had no impact on disease-free survival and the overall survival of the OAL and extra-ophthalmologic lymphoma patients. It would have been of interest here to have details to the treatment modalities of the OAL patients, which is known to vary considerably between centers. The data presented here by Decaudin et al. [24] would suggest that OAL patients should be examined for gastric H. pylori infection following lymphoma diagnosis, and that, if positive, antibacterial treatment for Helicobacter could possibly result in the disappearance of an OAL EMZL if treated early enough, as seen in gastric MALT lymphomas. A validatory multicentre prospective trial, possibly using the newly-proposed TNM-based staging system for OAL [28], which allows for better definition of tumor size and location within the ocular adnexa, would be required to test this hypothesis. In turn, the authors suggest that patients with H. pylori-induced gastritis should be followed for the potential development of an OAL. Interestingly, many patients who have gastric H. pylori infection never develop lymphoma, likely due to other oncogenetic factors, such as host response, and polymorphism susceptibilities. It remains to be seen if such host genetic factors also play a role in the susceptibility to developing EMZL OAL. In conclusion, the work of Decaudin et al. [24] remind us that at least two pathways appear to be involved in the development of EMZL OAL, and in doing so, also propose a third mechanism. The first lymphoma genetic pathway involves chronic inflammation (autoimmune disease or bacterial infections) at the affected site, resulting in an uncontrolled chronic stimulation of B-cells, favoring the occurrence of as yet poorly-understood secondary genetic and epigenetic alterations. The second pathway appears to be independent of bacterial infection and involves the development of specific chromosomal changes, possibly "de novo," presumably also at the affected site. Both the first and second pathways interlink at the level of NF-KB dysregulation. Decaudin's third pathway is an interplay between a bacterial inflammation at one extranodal site resulting in the development of a neoplastic clone, which does not "take nest" at this parent site, rather it becomes dissociated and is attracted to the ocular adnexa, possibly compromised by chronic inflammation, where it develops into an "ectopic lymphoma." The steps involved resulting in this "dissociation" and remote tumor establishment are as yet unclear. Following these data and observations of Decaudin et al. [24], it appears that a more thorough investigation of all OAL EMZL patients is required, if we are to better understand the development of these tumors, and to treat them more successfully reducing any associated morbidity.