Chlamydia or Not Chlamydia , That Is the Question: Which Is the Microorganism Associated With MALT Lymphomas of the Ocular Adnexa?

In the mid-1990s, the demonstration that Helicobacter pylori infection is a risk factor for gastric marginal-zone B-cell lymphoma of MALT type (MALT lymphoma) and the finding that eradication of these bacteria can result in histological lymphoma regression in most patients made this tumor a popular model of antigen-driven lymphomagenesis ( 1 ) . The association of H. pylori with gastric MALT lymphoma led to the hypothesis that the microorganism provides an antigenic stimulus that sustains the growth of the lymphoma in the stomach, and today it is generally accepted that administration of antibiotics to eradicate H. pylori should be the sole initial treatment of gastric MALT lymphoma that is confined to the gastric wall. This approach has been validated in more than 20 reported studies ( 2 ) . These advances in the understanding and treatment of gastric MALT lymphoma prompted a search for microorganisms responsible for the growth of MALT lymphomas outside the stomach. Although Borrelia burgdorferi and Campylobacter jejuni have been associated with marginal-zone lymphomas arising in the skin and small intestine, respectively ( 3 , 4 ) , results implicating particular infectious microorganisms in nongastric lymphomas have often been elusive.

In 2004, Ferreri et al. ( 5 ) reported in this journal that Chlamydia psittaci DNA was detected in 87% of lymphomas arising in the ocular adnexa (orbital soft tissue, lachrymal glands, and conjunctiva), and therefore, it has been proposed that C. psittaci infection may be a cause of these lymphomas. Furthermore, a very recent epidemiologic paper has shown a possible real increase in the incidence of ocular adnexal lymphomas, suggesting C. psittaci or another microorganism as possible causative agents ( 6 ) . However, subsequent to the report of Ferreri et al., other groups analyzed the prevalence of C. psittaci in these lymphomas, and overall, the reported data did not confirm a strong link between C. psittaci infection and ocular adnexal MALT lymphomas ( Table 1 ). Thus, our understanding of the role of C. psittaci is far from complete.

In this issue of the Journal, Ferreri et al. ( 7 ) report the results of a prospective trial in which patients affected by marginal-zone B-cell lymphoma of the ocular adnexa were treated for 3 weeks with the oral antibiotic doxycycline, with the intent of eradicating C. psittaci. The endpoints of the study were the rate of objective lymphoma response to antibiotic treatment and the presence or absence of C. psittaci DNA in peripheral blood mononuclear cells, the latter endpoint serving as a measure of C. psittaci eradication. Twenty-seven patients were enrolled and evaluated for response to treatment, 15 of them were newly diagnosed with ocular adnexal lymphoma and 12 had relapsed after previous therapies. Three patients had lymphoma involving regional lymph nodes and five had bilateral MALT lymphomas. Preliminary results in the first nine cases of the study have previously been published ( 8 ). C. psittaci was detected, using, as in the previous studies, a touchdown enzyme time release polymerase chain reaction ( 5 , 7 – 8 ) in 11 of 27 or 41% of lymphoma biopsies, a percentage lower than in the first report from the same investigators ( 5 ) and somewhat more consistent with other published series ( Table 1 ). An objective lymphoma response following doxycycline therapy was seen in 48% of the 27 treated patients, with six complete and seven partial remissions. A prolonged period (up to 36 months) was required to document the lymphoma remission after the antibiotic therapy, similar to what was observed in treatment of patients with gastric lymphomas for H. pylori infection ( 1 – 2 ) , and the data in the present report ( 7 ) suggest that the remission rate might increase after a longer follow-up. Information about the future outcome of the seven patients who were unresponsive to antibiotics but failure free (i.e., with apparently stable disease) at the time of analysis may clarify the long-term effect of this therapeutic approach.

Of great interest was the finding that some lymphomas with no evidence of C. psittaci infection regressed after doxycycline treatment. This contrasts with results in the better studied gastric MALT lymphoma, where H. pylori –negative patients are generally unresponsive to the antibiotic treatment ( 1 – 2 , 9 ) . The responses of C. psittaci –negative patients may have two alternative explanations. First, as noted by Ferreri et al. ( 7 ) , the current techniques to detect the presence of C. psittaci are not optimal (in contrast to the situation in gastric MALT lymphomas where there are a variety of tools available for detection of the infectious agent). Moreover, in detection of C. psittaci , false-negative results may be, in part, due to unknown previous antibiotic administration. A second possible explanation for the unexpected response to treatment of patients who did not test positive for C. psittaci is that other doxycycline-sensitive microorganisms are linked with the lymphoma.

The efficacy of the detection system for C. psittaci would also affect the second endpoint of the study, the eradication of C. psittaci as indicated by the presence of the bacterium in peripheral blood mononuclear cells before and after treatment. The peripheral blood cells of only four patients tested positive before therapy, rendering the study inconclusive as to the effectiveness of the antibiotic in eliminating C. psittaci.

In conclusion, the study by Ferreri et al. ( 7 ) shows that therapy with doxycycline might induce an objective response in about half of orbital adnexal lymphomas, and it provides further support to the model of antigen-driven MALT lymphomas. Still, many questions remain unanswered: What is the best method for detection of C. psittaci ? Is this bacterium a causative agent? Are there any other microorganisms that can induce orbital adnexal MALT lymphomas? Is there a role of hepatitis C virus or other viral infections? Do chromosomal aberrations such as the translocation t(14;18)(q32;q21) (IgH/MALT1) [relatively frequent in orbital adnexal MALT lymphomas ( 10 ) ] affect the response to doxycycline treatment? While doxycycline appears to be an easy-to-implement therapeutic approach, we strongly encourage all physicians to enroll patients in clinical prospective trials to help answer these questions. The IELSG-27 trial, launched by the International Extranodal Lymphoma Study Group ( 11 ) , is aimed to investigate the possible infectious causes of ocular adnexal lymphomas with particular reference to Chlamydia species and the effects of tetracycline treatment. Such a study can be indeed worthy of consideration for patients with orbital adnexal MALT lymphoma and a good opportunity as well for the scientific community.

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