© 2006 European Society for Medical Oncology
‘Blind’ antibiotic treatment targeting Chlamydia is not effective in patients with MALT lymphoma of the ocular adnexa
Departments of 1 Medicine I, Division of Oncology, 2 Opththalmology, and 3 Pathology Medical University Vienna, Vienna, Austria
* Correspondence to: Prof. M. Raderer, MD, Department of Medicine I, Division of Oncology, Medical University Vienna, Waehringer Guertel 18–20, A-1090 Vienna, Austria. Tel/Fax: +43-1-40400-2296; E-mail: markus.raderer{at}meduniwien.ac.at
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Abstract |
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Background: Recent results have implicated Chlamydia, especially Chlamydia psittaci, in the development of ocular adnexal lymphoma in the large majority of patients. We present our experience with ex-juvantibus antibiotic treatment in patients diagnosed with MALT lymphoma of the ocular adnexa.
Patients and methods: A retrospective analysis identified a total of 11 patients (six female, five male) with MALT-lymphoma of the ocular adnexa who were given doxycyclin 200 mg p.o. daily over 3 weeks. Patients were tested also for autoimmune conditions, Helicobacter status and hepatitis along with assessment of MALT-lymphoma specific genetic changes.
Results: After a median follow-up of 9 months, none of the patients responded to ‘blind’ antibiotic treatment with doxycyclin. Only one patient with bilateral conjunctival lymphoma related a short lasting subjective improvement, but was referred to alternative therapy due to progression and worsening symptoms after 6 months.
Conclusions: In this uncontrolled series, no effect of ‘blind’ antibiotic treatment with doxycyclin could be found in our patients with MALT lymphoma of the ocular adnexa. These results are in contrast to other series and suggest a potential geographic difference in the role of Chlamydia in ocular adnexal lymphoma. Thus, antibiotic therapy without prior testing for Chlamydia should be discouraged.
Key words: antibiotic therapy, chlamydia, MALT lymphoma, ocular adnexa
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introduction |
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Chronic inflammation due to various persistent infections may play a crucial role in the development of malignancies. Amongst other agents, especially Chlamydia, which are intracellular bacteria growing in eukaryote cells with a tendency to cause persistent infections, have repeatedly been implicated as potentially oncogenic. C. trachomatis has been linked to rectal cancer [1
] and cervical carcinoma [2, 3], and C. pneumoniae to the development of lung cancer [4]. Antilla et al. [5] have reported serologic evidence for an association between Chlamydia infection and lymphomas, and it has been suggested that C. pneumoniae might play a role in the development of cutaneous T-cell lymphoma [6].
Lymphoma of the mucosa associated lymphoid tissue (MALT-lymphoma) is an antigen-driven process. Apart from the apparent association between Sjogren's syndrome (SS) and Hashimoto's thyroiditis (HT) with MALT lymphoma of the salivary glands and the thyroid, the most impressive proof of this concept is the role of Helicobacter pylori (HP) in gastric MALT lymphoma. This association has resulted in early attempts to use antibiotic eradication of the bacteria to treat gastric MALT lymphoma [7], and early successes could consistently be reproduced by large-scale trials. Patients with localized gastric MALT lymphoma achieve an objective tumor response in up to 80% when treated with antibiotics [8–10], and HP-eradication is now considered standard therapy for early stage gastric, HP-associated MALT lymphoma.
In analogy to these data, other attempts to eliminate the source of chronic antigenic stimulation have been published in MALT lymphomas of various origins. Roggero et al. [11] have reported regression of cutaneous MALT lymphomas with eradication of Borrelia burgdorferi, while two lymphomas closely related to MALT lymphoma, i.e. splenic marginal zone lymphoma and immunoproliferative small intestinal disease (IPSID) have been shown to regress following elimination of hepatitis C virus [12] in the former and Campylobacter jejuni [13] in the latter.
More recently, an association between infection with C. psittaci and MALT-lymphoma of the ocular adnexa [6, 14] has been reported. C. psittaci is the etiologic agent of psittacosis, a human lung infection caused by exposure to infected birds and cats [15, 16]. Ferreri and co-workers [14] have detected C. psittaci DNA in tumour biopsies from 32 of 40 (80%) patients with ocular adnexal lymphoma, whereas none of 20 non-neoplastic orbital biopsies and only 3 of 26 (12%) reactive lymphadenopathy samples carried C. psittaci-DNA. In addition, 43% of the patients with lymphomas positive for C. psittaci also carried the respective DNA in their peripheral-blood mononuclear cells (PBMC). In an extension of these findings, Ferreri et al. again reported regression of ocular adnexal lymphoma after antibiotic therapy targeting C. psittaci. A total of nine patients with C. psittaci-positive MALT lymphomas of the ocular adnexa were treated with doxycycline 100 mg bid for 3 weeks. Two patients had a complete response and two a partial response [17].
These findings suggest that the large majority of cases of MALT lymphomas arising in the ocular adnexa might be related to chlamydial infection, as 80% of patients investigated by Ferreri tested positive. Thus, one might speculate that a high percentage of patients could benefit from antibiotic therapy, suggesting that patients could be treated upfront without exhaustive testing for chlamydial infection. We present our experience with an unselected group of patients undergoing ex-juvantibus antibiotic treatment for MALT lymphoma of the ocular adnexa, who were given doxycycline following the initial report by Ferreri and co-workers [17].
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patients and methods |
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A total of 11 patients with MALT lymphoma of the ocular adnexa undergoing antibiotic therapy for initial management were retrospectively identified. Three patients were referred to our institution after initial antibiotic treatment, while the remaining eight cases had been given antibiotics as primary treatment at our department. All patients were treated with doxycycline at a dose of 200 mg daily for 3 weeks.
Histologic diagnosis of MALT lymphoma was (re)established by a reference hematopathologist (A.C.) in all cases according to the criteria outlined in the WHO-classification of lymphoid malignancies. Immunologic phenotyping on paraffin sections was done for demonstration of light-chain restriction and the phenotype CD20+CD5-CD10-cyclinD1- which, in context with the microscopic appearance, is consistent with MALT-lymphoma.
All patients underwent staging for assessment of extent of disease and to rule out additional manifestations outside of the ocular adnexa. Staging at our institution included MRI/sonography of the orbit/oculat adnexa, MRI or sonography of the salivary glands, sonography of cervical lymph nodes, gastroscopy with multiple biopsies, endo-sonography of the upper GI-tract, computed tomography (CT) of thorax and abdomen and a bone marrow biopsy.
In addition, all patients were screened for the presence of an underlying autoimmune condition, i.e. Sjogren's syndrome (SS) and Hashimoto's thyroiditis (HT). The diagnosis of SS was based on characteristic clinical symptoms, i.e. presence of mouth- and/or eye-dryness as well as additional features such as a positive lip biopsy or serologic changes as required in the recently updated US-EU criteria [18]. Routine evaluation of TSH, T3, T4 and thyroid auto-antibodies was performed for assessment of HT. In addition, patients also were tested for the presence of hepatitis, and HP-status was assessed histologically as well as by breath test and serology.
Paraffin-embedded biopsy samples were tested for MALT-lymphoma specific genetic aberrations including t(11;18) (q21;q21), t(14;18) (q32;q21) involving IGH and MALT1, t(1;14) (p22;q32), t(3;14) (q14;q32) involving FOXP1 and IGH and trisomies 3 and 18. T(11;18) (q21;q21) involving API2 and MALT1 was assessed by reverse transcriptase polymerase chain reaction, t(14;18) (q32;q21) involving IGH and MALT1, t(1;14) (p22;q32) involving BCL10 and IGH, t(3;14) (q14;q32) involving FOXP1 and IGH and trisomies 3 and 18 were investigated by fluorescence in situ hybridization as previously published [19].
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results |
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For detailed patients' characteristics see Table 1. Six patients were female, and five were male, with the median age being 63 years (range; 40–83). Primary location of the lymphoma was the conjunctiva in three patients and in the lachrymal gland in another three cases, four had orbital lymphoma, while one patient had lymphoma involving both orbit and conjunctiva. Bilateral manifestations were present in four cases (two patients with bilateral conjunctival lymphoma, and one patient each with bilateral lachrymal and orbital involvement).
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All 11 patients underwent antibiotic treatment with doxycyclin 200 mg p.o. daily. After a median follow up of 9 months (range; 7–14), none of the patients responded to ‘blind’ antibiotic treatment. Only one patient with bilateral conjunctival lymphoma related a short-lasting subjective improvement. He was, however, referred to alternative therapy due to progression and worsening symptoms after 6 months. All patients developed a complete remission following radiation or chemotherapy after initial failure of antibiotic treatment.
Assessment for hepatitis was positive in only one patient with orbital lymphoma, who was found to be positive for hepatitis C, and four patients displayed evidence of HP-infection. In terms of autoimmune disease, 4 of 11 patients (36%) were found to suffer from an underlying autoimmune condition. One patient with a bilateral orbital involvement had long-standing severe chronic polyarthritis, one patient with both orbital and conjunctical involvement had SS, one patient with lymphoma of the conjunctiva had Hashimoto's thyroiditis and one with orbital lymphoma suffered from Lupus erythematosus (for details, see Table 1).
HP-status was available for all patients. A total of four patients (36%) had evidence of HP-infection. Among those found positive, one had bilateral conjunctival lymphoma, one an orbital lymphoma and two a lachrymal lymphoma, one of the two bilateral (see Table 1).
Due to the small biopsy samples in some cases, sufficient material for analysis of chromosomal aberrations was available from only 7 of 11 patients (64%). Among these patients, genetic aberrations were detected in two (29%; for details see Table 1). One case was found positive for t(14;18) (q32;q21) involving IGH/MALT1. Trisomy 3 along with IGH-FOXP1 could be detected in the other case.
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discussion |
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TopAbstractintroductionpatients and methodsresultsdiscussionReferences |
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Recent data have suggested C. psitacci as a potential causative agent in the development of MALT lymphoma in the ocular adnexa [14
, 17]. In fact, treatment with doxycycline has consequently been shown to result in lymphoma regression in 2 of 4 [14] and in 7 of 9 [17] patients, including two cases of complete remission. The time to response was between 1–8 months in six patients, while only one took 31 months to best response. Responses were seen both in untreated, but also in previously treated patients who had developed relapse. As opposed to this, none of the 11 patients responded to treatment with doxycycline at an identical dose and schedule. All of our patients were therapy naïve and had been given antibiotic therapy as initial treatment.
Our results are markedly different from the data reported by Ferrei [14, 17] and we cannot offer a definite explanation for these divergent results. One of the major differences is the fact that none of our patients had been analyzed for Chlamydia-infection, and our analysis is a retrospective evaluation, while only patients who tested positive for C. psittaci had been treated prospectively in the Italian series [17]. However, given the initial findings that 80% of all lymphoma patients tested had evidence of C. psittaci-infection [14], one would expect a high rate of regression with ‘blind’ eradication even without prior testing.
Another explanation might be that the follow-up time had simply been too short to observe a significant response. In fact, follow-up time plays a crucial role in gastric MALT-lymphoma, where regression might take up to 18 months after successful HP-eradication. The median follow-up in our series was 9 months (range; 6–14), which is within the range where best response had been achieved in the Italian series. Thus, a bias caused by an insufficient follow-up time can be ruled out with some certainty.
These data clearly demonstrate that antibiotic treatment with doxycycline was not effective in an unselected Austrian population with MALT lymphoma of the ocular adnexa. They do not, however, necessarily conflict with a potential role of C. psittaci in the development of ocular MALT lymphoma as seen by Ferreri [14, 17]. As has been suggested by Zucca and Bertoni [20], pronounced geographic differences might exist in terms of causative agents and MALT lymphoma. Even when no testing for chlamydial-DNA was performed on our patients, the divergent clinical results obtained in our unselected Austrian cohort, and an Italian patient-cohort [14, 17], suggest that this might indeed be the case, and that chlamydial infection does probably not play a crucial role in ocular MALT lymphoma in the Austrian population. This notion that Chlamydia might not play a ubiquitous role in ocular adnexal MALT lymphoma is substantiated by recent data investigating ocular adnexal lymphoma in South Florida [21]. In this most extensive analysis so far, 57 tumor specimens were investigated for C. psittaci, but none of them tested positive for C. psittaci -DNA.
Of note is the fact that 4 of 11 patients (36%) suffered from an underlying autoimmune disease. No information is available from the Italian series in terms of autoimmune-status of the patients investigated. One might, however, speculate that autoimmune diseases might negatively affect the efficacy of antibiotic treatment in ocular adnexal lymphoma, as has indeed been demonstrated in patients with gastric MALT lymphoma undergoing HP-eradication [21]. Such a hypothesis nevertheless would only partly explain the absence of efficacy in our series, as the remaining seven patients did not suffer from autoimmune diseases. While the number of patients available for analysis in our series is small, the available genetic data do not suggest an impact of MALT-lymphoma specific translocations, as neither patients with nor without chromosomal imbalances responded to treatment.
Taken together, our findings demonstrate that extrapolation of a causative role of C. psittaci in ocular MALT lymphoma has to be done with extreme caution when applied to a different geographic region, and that antibiotic treatment without prior testing for Chlamydia-infection should not be done in the clinical practice. Further investigations are clearly needed to define the various potential causative agents in MALT lymphoma in different geographic areas.
Received for publication September 18, 2005. Accepted for publication October 4, 2005.
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