HOMO SAPIENS DISEASES - MARGINAL ZONE LYMPHOMAS (MZL) OF THE MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT)-TYPE LYMPHOMAS (MALTOMAS)

Table of contents :

Aetiology : the interaction of bacterial or viral antigens with host T-cells and antigen-presenting cells leads to a complex cascade resulting in clonal B-cell or plasma cell expansion. Although all immune responses are in effect clonal, MALT lymphomas are the result of immune responses gone awry^ref, in which persistence of the antigen leads eventually to an autonomous clonal proliferation. The pathogenesis of malignant lymphoma is a multi-step process that recapitulates many aspects of the normal immune response and of normal lymphocyte development. The patterns of spread of lymphomas reflect the homing patterns of normal lymphocytes, both microscopically, within lymph nodes, and macroscopically, at a clinical level. Thus, the site of presentation provides insight into the cellular origin of the neoplastic process. MALT lymphomas are primarily extranodal in distribution, retaining the phenotypic and functional properties of the mucosa-associated lymphoid system. Thus, MALT lymphomas are post-germinal center–derived B-cell lymphomas that arise in and home to mucosa-associated sites that have acquired lymphoid tissue as a consequence of a chronic inflammatory process^ref. Although MALT lymphomas arising in different organ systems share many pathologic and clinical similarities, there are also important differences. A successful immune response requires a delicate balance among antigen drive, lymphocyte proliferation, and lymphocyte apoptosis. In MALT lymphomas, unchecked proliferation of autoreactive B-cells can lead to both autoimmune disease, e.g., Sjogren’s syndrome or Hashimoto’s disease, and lymphoma^ref. In a parallel fashion, defective immunoregulation of responding T cells following chronic EBV infection may result in a cytokine storm, leading to a hemophagocytic syndrome and, rarely, to T-cell lymphomas^ref. In the above examples of lymphoma pathogenesis, defective immunoregulation characterized by either excess lymphocyte activation and proliferation or defective apoptosis leads ultimately to clonal expansion and lymphoma. An unanswered question is how chronic antigenic stimulation in the presence of H. pylori or C. psittaci infection leads not only to chronic B-cell proliferation but also to the specific translocations that characterize most MALT lymphomas^ref. In 2005 Bende et al. analyzed the structure of antigen receptors of a comprehensive panel of mature B non-Hodgkin's lymphomas (B-NHLs) by comparing, at the amino acid level, their immunoglobulin (Ig)V_H-CDR3s with CDR3 sequences present in GenBank. Follicular lymphomas, diffuse large B cell lymphomas, Burkitt's lymphomas, and myelomas expressed a CDR3 repertoire comparable to that of normal B cells. Mantle cell lymphomas and B cell chronic lymphocytic leukemias (B-CLLs) expressed clearly restricted albeit different CDR3 repertoires. Lymphomas of mucosa-associated lymphoid tissues (MALTs) were unique as 8 out of 45 (18%) of gastric- and 13 out of 32 (41%) of salivary gland-MALT lymphomas expressed B cell antigen receptors with strong CDR3 homology to rheumatoid factors (RFs). Of note, the RF-CDR3 homology without exception included N-region–encoded residues in the hypermutated IgVH genes, indicating that they were stringently selected for reactivity with auto-IgG. By in vitro binding studies with 10 MALT lymphoma–derived antibodies, we showed that 7 of these cases, of which 4 with RF-CDR3 homology, indeed possessed strong RF reactivity. Of one MALT lymphoma, functional proof for selection of subclones with high RF affinity was obtained. Interestingly, RF-CDR3 homology and t(11;18) appeared to be mutually exclusive features and RF-CDR3 homology was not encountered in any of the 19 pulmonary MALT lymphomas studied^ref. In HIV⁺ patients, MALT lymphoma is most commonly described in children. In an original case of HIV⁺ MALT lymphoma with bronchial, conjuctival and laryngeal involvement clinical and histopathological remission has been obtained with HAART alone^ref.
Pathogenesis :

• MALT1 / MALT-lymphoma-associated translocation (MLT) / paracaspase gene on chromosome 18q21 (for which 2 alternatively spliced transcript variants encoding different isoforms have been described)
• trisomy 18
• rearranged in chromosomal translocation with 3 other genes :
• the amino terminal of the API1 / baculoviral inhibitor of apoptosis (IAP) repeat-containing protein 2 (BIRC2) / c-IAP2 / HIAP1 / MIHC (wrongly named API2 in the first works) on chromosome 11q21 => t(11;18)(q21;q21)^{ref1, ref2, ref3, ref4, ref5} : found at highest frequencies in MALT lymphomas from the lung (38-41%; associated with aberrant nuclear BCL10 expression) and stomach (24%), and at moderate frequencies in those from the conjunctiva (19%) and orbit (14%). It results in the API2-MALT2 chimeric fusion transcript that is associated with enhancement of NF-kB transcription factor activity, which, in turn, repressed p53, inhibiting cell death, and several cell apoptosis inhibitors^ref
• immunoglobulin heavy chain (IGH) locus^ref => t(14;18)(q32;q21) is a rare but recurrent translocation in MALT lymphoma^ref. It was absent in gastric and pulmonary MALT lymphomas but was identified in cases of MALT lymphomas presenting in the conjunctiva and the lacrimal gland, as well as in some other unusual sites, such as liver and skin^ref.
• t(1;14)(p22;q32)
..., generating chimeric fusion products.
The protein encoded by this gene may play a role in NF-kB activation : evolutionarily distinct ITAM receptors in innate and adaptive immune cells use diverse adaptor proteins to engage selectively the conserved Bcl10–Malt1 module^ref

Intriguingly, although the details of the translocations differ among the various target organ systems, most of the molecular changes observed in MALT lymphomas involve a final common pathway. Nevertheless, MALT lymphomas with the more common t(11;18) translocation manifest increased nuclear staining of BCL10 and overexpression of MALT1^ref. BCL10 and MALT1 cooperate in a final common cascade of events leading to increased activity of the NF-kB signaling pathway^ref. It is not surprising that the critical NF-kB pathway should be involved in MALT lymphomas, given that this family of transcription factors is activated by both antigenic stimulation and inflammatory cytokines. The milieu of infection and chronic inflammation provide a common background for the development of MALT lymphomas, but the specific events leading to chromosomal translocation and or mutation remain undiscovered. The oxidative stress associated with inflammation might precipitate chromosomal damage^ref.
• FOXP1 gene on chromosome 3
• trisomy 3
• t(3;14)(p14.1;q32) involving the immunoglobulin heavy chain (IGH) locus on chromosome 14, upregulating expression of the former gene. Originally seen in in a case of MALT lymphoma of the thyroid, out of. 91 MALT lymphomas, all of which were negative for the 3 known translocations, and 8 splenic and 6 NMZLs. Overall, 9 MALT lymphomas (10%) harbored t(3;14)(p14.1;q32) comprising tumors of the thyroid (3 of 5), ocular adnexa (4 of 20), and skin (2 of 20), whereas those of the stomach (n = 20), salivary gland (n = 20), and lung (n = 5) were negative as well as the SMZL and NMZLs. Most t(3;14)(p14.1;q32) + MALT lymphomas harbored additional genetic abnormalities, such as trisomy 3. Further studies revealed that the 3 known translocations and t(3;14)(p14.1;q32) are mutually exclusive^ref. Nuclear expression of FOXP1 in 20 of the 70 MALT lymphomas (nine of them featuring structural or numeric aberrations of the FOXP1 locus). FOXP1 positivity was confined to MALT lymphomas with poor clinical outcome (with impact of FOXP1 expression on relapse rate and disease-free survival). It was also found that MALT lymphomas with strong FOXP1 expression are at risk of transforming into an aggressive DLBCL of non-GC phenotype if they feature, in addition, a polymorphic histology and the presence of trisomy 3 and 18^ref
• somatic mutations in FAS also have been identified^ref similarly to autoimmune lymphoproliferative syndrome (ALPS)

• primary stomach MALT lymphoma / MALT gastric lymphoma (MGL / GML)

Epidemiology : after age 50
Aetiology : paradoxically most MALT lymphomas arise in the stomach, which normally contains no organized lymphoid tissue. Gastric MALT lymphomas appear to arise in MALT acquired as a reaction to infection of the stomach by Helicobacter pylori (60-90%)^ref : H. pylori-associated follicular gastritis invariably preceeds MGL^ref. Subsequently, Isaacson et al. showed that MALT lymphomas are antigen-driven clonal B-cell lymphomas^ref and that eradication of H. pylori with antibiotic therapy could lead to lymphoma regression, at least in its early stages, prior to additional genetic events^ref
Pathogenesis : t(11;18)(q21;q21) [API2;MALT1] is detected in 30% of low-grade cases, more frequent in H. pylori-negative patients and in stage IIE tumors. Somewhat surprisingly, it has been shown that B-cell proliferation in gastric MALT lymphoma is directed at auto-antigens, and not at H. pylori^ref.
Microscopic anatomy : destruction of glandular epithelium and lymphatic follicles; centrocyte-like cells and lymphoepithelial lesions
Differential diagnosis :
• metastases of lymphoma : intermediate sized cells, clear cytoplasm, irregular nuclei, plasma cell differentiation
• florid gastritis (neither lymphoepithelial lesions nor monoclonal lymphocytes)
• composite DLBCL with residual MALT lymphoma (DLCLML)
Therapy : eventual regression after Helicobacter pylori infection eradication using a triple regimen mainly depends on apoptosis of neoplastic cells in absence of promoting factors and lasting for up to several years^{ref1, ref2}. Extragastric MALT lymphoma regression after eradication has been reported despite H. pylori organisms were not detected in the lymphoma tissue by PCR. Endoscopic US- and CT-staged gastric MALT stage IE tumors will achieve a complete response with this approach in approximately 60-90% of patients (the more superficial the tumor, the better the response). Patients with tumors that are T4 N⁺ Musshoff stage IIE1 and IIE2 or tumors with adverse cytogenetics should receive radiotherapy or gastrectomy with or without radiotherapy. Tumors with a significant high-grade component or large cell tumors with a minor low-grade MALT component should receive CHOP-based chemotherapy. Oral alkylating agents (cyclophosphamide 100 mg/day for 12 to 18 months and chlorambucil 6 mg/m²/day for 14 days/month for 12 months) have been shown to be effective in 60% to 75% of patients with this condition. Surgery as first-line therapy for gastric MALT lymphomas was replaced by attempts at organ preservation. In the past, margin-free surgical excision or tumor debulking followed by radiation therapy and chemotherapy has been highly effective for gastric MALT lymphomas. Although surgery was once considered central to diagnosis, staging, and treatment of gastric lymphoma, most patients can now have a diagnosis established by endoscopic biopsy and are candidates for chemotherapy and adjuvant radiation. The risks of fatal hemorrhage and perforation have probably been vastly overestimated and appear to be equal or less than the mortality associated with surgery. In addition, the long-term effects of gastric resection on quality of life have been almost completely ignored.
Prognosis : the rate of remission after eradication is 60-80%. Perigastric lymph nodes and deep gastric wall tumoral infiltration are negative predictors of tumoral response to treatment; t(11;18) translocation is associated with a poor tumoral response to H. pylori eradication (<5%)^ref and oral alkylating agents
• non-gastric MALT lymphomas :
• primary GALT lymphoma (differential diagnosis with primary gastrointestinal Hodgkin's disease)
• primary oral cavity MALT lymphoma
• primary salivary gland MALT lymphoma (SGML)
• primary parotid gland lymphoma
• intraoral MALT lymphoma of the minor salivary gland in a 70-year-old woman with Sjogren's syndrome. Unexpectedly, a spontaneous clinically and histologically confirmed regression occurred 1 month after the tumor biopsy for diagnosis. Considering that salivary MALT lymphoma is associated with Sjogren's syndrome and that the chronic inflammation caused by Sjogren's syndrome persisted, it is hypothesized that the tumor clone might be present in the regressed lesion. Minimal residual tumor clone identical with the primary lesion was detected using PCR clonality assay for IgH rearrangement. No recurrence was clinically evident 38 months after the diagnosis. Spontaneous regression of MALT lymphoma should be examined at the molecular level in addition to clinical and histological evaluations. When minimal residual disease is detected, close follow up is necessary for early detection of the tumor relapse^ref.
Epidemiology : male-female ratio = 1:5, with a median age of 61 years.
Aetiology :
• Sjoegren syndrome (SS) (46%)
• HCV^ref (23% : 61% of the patients express the V_H1-69 gene which recognizes E2^ref)
• no case had both SS and HCV^ref.
Anyway HCV is known to be sialotropic^ref and chronic lymphocytic sialadenitis due to salivary gland infection by HCV maybe a presentation symptom of HCV and may simulate SS^ref.
Therapy : treatment of HCV with peginterferon and ribavirin^ref
• primary esophageal MALT lymphoma
• primary liver MALT lymphoma
• primary intestinal MALT lymphoma (8%)
• primary orbital adnexa MALT lymphoma (OAL) (24%)^{ref1, ref2, ref3, ref4}
• primary conjunctival MALT lymphoma
Epidemiology : interestingly, the incidence of ocular adnexal lymphomas is growing^ref. During 1992-2001 in the 12 SEER areas, ocular (i.e., eye and adnexa) NHL rates per 100 000 person-years for both sexes were highest among Asians/Pacific Islanders, lower in whites, and lower still in blacks. Incidence increased with advancing age and showed little difference by sex, in contrast to other (extranodal and nodal) NHLs, which occurred predominantly in males. From 1975-2001, there was a rapid and steady increase in incidence of ocular NHL, with annual increases of 6.2% and 6.5% among white males and females, respectively, with no evidence of peaking. By contrast, other NHLs showed evidence of peaking in recent years. The distinctive patterns of ocular NHL call for further studies to identify risk factors and mechanisms, including the potential role of C. psittaci or other infections^ref. Notably, this increase in incidence is substantially higher than that reported for systemic lymphomas^ref and does not seem to be biased by demographic or reporting artifacts or by variations in diagnostic criteria^ref. There was a 71% increase in the number of ocular adnexal lymphoma cases diagnosed at San Raffaele H Scientific Institute between 1994–1997 and 1998–2001. These epidemiologic trends may be related to unrecognized pathogenic factors, among which infectious agents could be included.
Aetiology :
• Chlamydophila psittaci (DNA detected in 80% of 40 cases^ref). The strength of the association between C. psittaci infection and ocular adnexal lymphoma is also supported by the statistically significantly higher prevalence of C. psittaci infection detected in ocular adnexal lymphoma patients than in the general population^ref. Unlike C. pneumoniae, which has a broad diffusion worldwide^ref, C. psittaci infection is a rare condition in European countries^ref. Although data for the prevalence of C. psittaci DNA detection in blood samples from the general population are lacking, serology data indicate that only 3% of elderly individuals in Northern Europe are C. psittaci IgG-seropositive^ref. Serology assays, however, are not an adequate method to detect C. psittaci infection, because they are severely limited by high cross-reactivity among different Chlamydiae species and between Chlamydiae and other microorganisms^ref. In fact, LPS, the antigen used in available serologic tests, is a common molecule found among several microorganisms. Moreover, in some geographic areas, the seroprevalence of C. pneumoniae has been reported to range from 40% to 80%^ref, limiting the value of serologic screening for C. psittaci. Thus, it is important to emphasize that DNA detection by PCR analysis is the current gold standard for chlamydial infection recognition ^{ref1, ref2}. Chlamydial infections have also been associated with neoplastic diseases^{ref1, ref2, ref3}. In fact, Chlamydiae species are known to establish persistent infections, to be mitogenic in vitro^ref, to induce polyclonal cell proliferations in vivo^ref, and to cause resistance to apoptosis in infected cells^ref. Nevertheless, any association between C. psittaci and cancer has not been convincingly demonstrated thus far. The possibility that C. psittaci infections may be underdiagnosed^ref, however, highlights the need for research on the potential contribution of this microorganism to tumor development in humans. Indeed, chronic ocular infections by C. psittaci could be more common than previously recognized^{ref1, ref2, ref3}. If this is the case, then the parallelism between the association of gastric lymphomas with H. pylori–related chronic gastritis^ref and the potential pathogenic link between chronic conjunctivitis related to chlamydial infection and ocular adnexal lymphomas appears to be worthy of analysis. Chronic persistence of infectious agents causes prolonged direct antigen stimulation, which is thought to play an important role in the clonal expansion of some lymphomas (e.g., follicular and B-cell MZLs), as indicated by the presence of SHM Ig genes with a pattern of ongoing mutations^ref. The presence of SHMs in clonally rearranged Ig H-chain variable genes in B-cell MZLs of the ocular adnexa shows a molecular similarity with the normal properties of B cells positively selected by a cognate antigen within the GC^ref. In particular, the mutation rates observed in Ig-variable genes of ocular adnexal lymphomas are similar to those reported for gastro-intestinal MZLs^ref, whose association with chronic antigenic stimulation by H. pylori is well established^ref. The possibility that ocular adnexal lymphomas arise in the context of chronic inflammation has also been recently suggested^ref; however, the source of the putative antigen or antigens presumably involved in this process is still unknown. Chlamydia psittaci may, indeed, provide such an antigenic stimulus, thus contributing to the pathogenesis of ocular adnexal lymphomas. C. psittaci infection was more common among patients with B-cell MZLs and other low-grade lymphomas (88%) than among those with DLBCLs (60%), indicating that there may be different pathways leading toward lymphomagenesis, similar to what has been reported for gastric MALT lymphomas^ref. However, the fact that DLBCLs were more often negative for C. psittaci DNA than were B-cell MZLs is consistent with the possibility that a proportion of C. psittaci⁺ MZLs may evolve toward a more aggressive histotype (i.e., DLBCLs), which is no longer responsive to (and dependent on) the antigenic stimulation provided by the microorganism. Of note, 38% of the patients in this study who had C. psittaci⁺ lymphomas had a prior history of chronic conjunctivitis. Nevertheless, a more thorough characterization of the association between ocular adnexal lymphoma and C. psittaci is presently limited, most importantly by the facts that sequencing of the C. psittaci genome has not been completed and that reagents suitable to specifically investigate the expression of bacterial proteins in lymphoma tissues are lacking. These limitations need to be overcome to identify candidate bacterial peptides to be used in ex vivo functional assays aimed at demonstrating whether C. psittaci is able to provide stimuli that promote lymphoma cell growth. This is the first study to demonstrate the presence of C. psittaci DNA in PBMCs of humans. In fact, C. psittaci DNA was observed in the PBMCs of half of patients with chlamydia⁺ lymphomas at diagnosis. Thus, these data suggest that infection of PBMCs by C. psittaci persists over time in a high proportion of case patients. In fact, 3 of the 4 chlamydia⁺ PBMC samples collected > 5 years after the lymphoma diagnosis were collected concomitantly with a disease recurrence, further supporting the possible involvement of C. psittaci in sustaining long-term lymphoma cell growth. These findings are similar to recent observations^ref, which demonstrated the presence of C. pneumoniae DNA in circulating cells of humans, and support the previously reported^ref hypothesis that a prolonged C. psittaci infection in PBMCs could favor continuous reinfections that could, in turn, chronically trigger antigenic stimulation. IHC data suggest that monocyte/macrophage system components may play a critical role in such a scenario. Although mononuclear cells immunoreactive for anti-chlamydia antibodies were not found within blood vessel lumina in the ocular adnexal lymphoma samples studied, available immunohistoIHCchemical data do not allow the distinction between these cells being resident or circulating elements. In conclusion, although only a limited number of lymphoma patients were treated with antibiotics specific for chlamydia infection, observation of lymphoma regression after C. psittaci eradication with doxycycline treatment provides additional evidence for a role of C. psittaci infection in the development of ocular adnexal lymphomas. Similar to findings observed in gastric MZLs^ref, in which H. pylori eradication was followed by an objective response in 70–80% of case patients, 2 out of 4 of case patients with ocular adnexal lymphoma and measurable disease showed objective regression after antibiotic treatment. These data should, however, be interpreted with caution, given the small number of treated patients. Nevertheless, the findings deserve to be confirmed in a phase I/II prospective trial to conclusively assess whether C. psittaci–eradicating antibiotics may constitute a new therapeutic strategy against ocular adnexal lymphomas^ref. In parallel with the gastric MALT lymphoma story, the risk for lymphomatous complications appears to be both species- and strain-specific^{ref1, ref2}. Thus, DNA sequences of Chlamydia trachomatis or pneumoniae were not identified in any of the ocular adnexal lymphomas studied by Ferreri et al. Interestingly, Chlamydia species share many features with H. pylori, because they too are associated with chronic persistent infection; induce a polyclonal lymphoid infiltrate in extranodal mucosa-associated sites^ref; and have been implicated as cofactors in the development of both carcinoma and lymphoma^{ref1, ref2}. These common threads may prove to be part of the fabric of MALT lymphoma pathogenesis. Anyway in 57 South Florida patients with OALs, no specimens harbored Chlamydia psittaci DNA^ref. Gastric Helicobacter pylori infection, even if common among OAL patients, does not influence clinical presentation. Hp-eradicating antibiotic therapy is not active against OAL. C. psittaci-eradicating antibiotic therapy with doxycycline induces lymphoma remission irrespectively of the persistence of Hp infection^ref.

Conflicting evidences :
• no evidence of C. psittaci DNA was seen in 7 MALT-type ocular adnexal lymphomas, 4 non-MALT ocular lymphomas, 1 Langerhans histiocytosis, and 5 reactive lymphoproliferations. Several possible reasons that would cause failure to find C. psittaci DNA, including the presence of PCR inhibitors, inadequate template DNA, and sequence diversity in the target region in C. psittaci were eliminated. The positive data were based primarily on patients from Italy, while our study involved only patients living in the Northeastern USA. This would suggest possible geographic differences in the etiology of ocular adnexal lymphomas^ref.
• no evidence for the presence of C. psittaci DNA was found in a cohort of ocular adnexal MZBLs from the Netherlands^ref
• absence of Chlamydia psittaci in ocular adnexal lymphoma from Japanese patients^ref. Southern hybridization of the PCR product using the C. psittaci-specific probe failed to detect  C. psittaci, although three samples appeared to be positive by ethidium bromide staining. This indicates that technical approach for detecting  C. psittaci infection in ocular adnexal lymphoma might be an essential in disclosing this association^ref
• the presence of C. psittaci, C. trachomatis, C. pneumoniae, HSV1, HSV2, and adenovirus 8 and 19 (ADV8, ADV19) was assessed separately by PCR in 142 ocular adnexal MALT lymphomas, 53 non-MZLs, and 51 ocular adnexal biopsies without a lymphoproliferative disorder (LPD), from 6 geographical regions. C. psittaci was detected at similar low frequencies in non-LPD and non-MZL groups from different geographical regions (0-14%). Overall, the prevalence of C. psittaci was significantly higher in MALT lymphomas (22%) than in non-LPD (10%, p = 0.042) and non-MZL cases (9%, p = 0.033). However, the prevalence of C. psittaci infection in MALT lymphoma showed marked variation among the six geographical regions examined, being most frequent in Germany (47%), followed by the East Coast of the USA (35%) and the Netherlands (29%), but relatively low in Italy (13%), the UK (12%), and Southern China (11%). No significant differences in the detection of C. pneumoniae, C. trachomatis, HSV1, HSV2, ADV8, and ADV19 were found between lymphomas and controls from different geographical regions. C. psittaci, but not C. pneumoniae, C. trachomatis, HSV1, HSV2, ADV8 or ADV19, is associated with ocular adnexal MALT lymphoma and that this association is variable in different geographical areas^ref.
• no C.psittaci omp1 and omp2 genes were amplified from a series of 30 OALs^ref
• HCV seropositivity is present in 13% of OAL of MALT-type. Concomitant HCV infection is associated with more disseminated disease and aggressive behavior in OAL, with a consequent potential negative impact in patients managed with radiotherapy alone^ref
Symptoms & signs : may simuate thyroid orbitopathy, but superior oblique enlargement and involvement of the levator superioris palpebrae muscle are both suggestive of a non-thyroid pathology^ref
Laboratory examinations : PET/CT should be considered as a new method of diagnosing, staging, and restaging patients with orbital lymphomas^ref
Therapy^{ref1, ref2} : Ferreri et al. looked in a very limited way at clinical responses to antibiotic therapy for Chlamydia and observed an evaluable response in 2 of 4 patients. If gastric MALT lymphoma is an applicable model system to understand the sequence of events from infection to clonal B-cell proliferation and ultimately autonomous growth^ref, then cytogenetic or molecular genetic studies of ocular adnexal lymphomas may show a correlation between absence of a response to antibiotic therapy and presence of a translocation. In another series, 4 patients underwent antibiotic therapy for subconjunctival MALT lymphomas, and 3 of whom were evaluable for response to treatment. Complete evaluations for systemic disease (including CT scans of neck, chest, abdomen, pelvis, PET scans, and bone marrow examination) were all negative. Serologic tests for antibodies to Chlamydia psittaci were negative in all 4 individuals. Patients were 58, 74, 76 and 79 years of age with 2 males and 2 females. Treatment of 1 patient was with a Prevpac^R (lansoprazole 30 mg capsule, amoxicillin 500 mg capsules, and clarithromycin 500 mg tablets BID) x 14 days, while 3 received doxycycline 100 mg daily for 1 month. Of the 3 patients evaluable to date for response, all demonstrated prompt and sustained responses (2 CR and 1 PR) with followup of 38 months, 12 months, and 7 months respectively^ref. In a following study 9 patients with C psittaci⁺ marginal-zone B-cell lymphoma of the ocular adnexa at diagnosis or relapse were treated with doxycycline 100 mg, bid orally, for 3 weeks. The presence of C psittaci DNA in peripheral-blood mononuclear cells (PBMCs) was also assessed before and after treatment in 7 patients. Objective lymphoma regression was assessed 1, 3, and 6 months after therapy conclusion and every 6 months during follow-up. All patients completed antibiotic therapy with excellent tolerability. At 1 month from doxycycline assumption, chlamydial DNA was no longer detectable in PBMCs of all 4 positive patients. Objective response was complete in 2 patients, partial response (> 50%) was observed in 2 patients, and minimal response (< 50%) was observed in 3 patients. Duration of response in the 7 responders was 12+, 29+, 31+, 8+, 7+, 2+, and 1+ months, respectively. C psittaci-eradicating antibiotic therapy with doxycycline is followed by objective response in patients with ocular adnexal lymphoma, even after multiple relapses of the disease. A confirmatory, large, phase II trial is warranted to confirm whether this fast, cheap, and well-tolerated therapy could replace other more aggressive strategies as first-line treatment against ocular adnexal lymphomas^ref. After a median follow-up of 9 months, none of 11 patients (6 female, 5 male) with MALT-lymphoma of the ocular adnexa who were given doxycyclin 200 mg p.o. daily over 3 weeks responded to this 'blind' antibiotic treatment^ref. In a prospective trial, 27 OAL patients (15 newly diagnosed and 12 having experienced relapse) were given a 3-week course of doxycycline therapy. Objective lymphoma response was assessed by computerized tomography scans or magnetic resonance imaging at 1, 3, and 6 months after the conclusion of therapy and every 6 months during follow-up. Cp infection in patients was determined by touchdown enzyme time-release polymerase chain reaction (TETR-PCR). Statistical tests were 2-sided. 11 patients were Cp DNA-positive and 16 were Cp DNA negative. Doxycycline was well tolerated. At a median follow-up of 14 months, lymphoma regression was complete in 6 patients, and a partial response (> or = 50% reduction of all measurable lesions) was observed in 7 patients (ORR [CR + PR] = 48%). Lymphoma regression was observed in both Cp DNA⁺ patients (7 of 11 experienced regression) and Cp DNA-negative patients (6 of 16 experienced regression) (64% versus 38%; P = .25, Fisher's exact test). The 3 patients with regional lymphadenopathies and 3 of the 5 patients with bilateral disease achieved objective response. In relapsed patients, response was observed both in previously irradiated and nonirradiated patients. The 2-year failure-free survival rate among the doxycycline-treated patients was 66% (95% confidence interval = 54 to 78), and 20 of the 27 patients were progression free. Doxycycline is a fast, safe, and active therapy for Cp DNA⁺ OAL that was effective even in patients with multiple failures involving previously irradiated areas or regional lymphadenopathies. The responses observed in PCR^- OAL may suggest a need for development of more sensitive methods for Cp detection and investigation of the potential role of other doxycycline-sensitive bacteria^ref
• rituximab 375 mg/m², 4 injections per week^ref. 8 patients with ocular adnexal MALT lymphoma were treated with rituximab, at diagnosis (n=5) or relapse (n=3). All untreated patients achieved lymphoma regression, while relapsing patients had no benefit. Four responding patients experienced early relapse. The median time to progression was 5 months. The efficacy of rituximab in ocular adnexal lymphoma is lower than that reported for gastric MALT lymphomas^ref
• primary skin MALT lymphoma / primary cutaneous B-cell lymphoma (CBCL) (12%)

Aetiology : Borrelia burgdorferi^ref
• primary pulmonary MALT lymphoma (12%)
• primary thyroid MALT lymphoma (7%; usually large cell lymphoma; originating from a Hashimoto's disease or Graves' disease or without any lymphocytic thyroiditis)

Therapy : radiotherapy, no surgical ablation due to risk to spread metastases. Remission of a primary thyroid lymphoma after methotrexate withdrawal^ref
• primary breast MALT lymphoma (PBL) (2%; 0.04 to 0.5% of breast malignancies)

Laboratory examinations : small lymphocytes, marginal zone B cells, monocytoid B cells, and plasma cells. Tumors are generally localized and indolent, but may spread or become more aggressive. Clinical presentation and imaging may suggest a benign condition
Therapy : reports of treatment vary widely. Surgical therapy has been reported to include only biopsy or extend to partial mastectomy, total mastectomy, or even radical mastectomy. Chemotherapy with various agents is often used. Radiotherapy has been used in the adjuvant setting or as primary local therapy. Immunotherapy and radioimmunotherapy have shown some promise in other lymphomas and may be useful here as well. There is no standard or consensus of treatment for PBL^ref
• primary head and neck MALT lymphoma (30%)
• primary dural MALT-type lymphoma : more favourable clinical course compared to PCNSL and may require a less aggressive treatment
• primary nasopharynx MALT lymphoma
• primary larynx MALT lymphoma
• primary genitourinary tract MALT lymphoma (1%)
• primary renal MALT lymphoma
• primary bladder MALT lymphoma^ref
• primary testicular MALT lymphoma
• primary bone MALT lymphoma

Laboratory examinations : CT detects surrounding blastic response that increases thickness of cancellous bone, while MRI is used to assess infiltration
• primary thymus MALT lymphoma (extremely rare)
Patient characteristics in the International Extranodal Lymphoma Study Group (IELSG) series of non-gastric mucosa-associated lymphoid tissue (MALT 0 lymphoma (n = 246) :
• median age : 60 yrs
• median age range : 20-92 yrs
• male : 39%
• PS (ECOG)>0 : 35%
• stage IV : 26%
• multiple MALT sites : 13%
• lymph node involvement : 16%
• bone marrow involvement : 13%
• high serum lactate dehydrogenase (LDH) (n=213) : 23%
• high ß-2 microglobulin (n=125) : 36%
• hepatitis C infection (n=135) : 16%
• B-symptoms : 7%

• B-cells
• marginal zone B-cell lymphoma of MALT type
• immunoproliferative small intestine disease (IPSID)
• T-cells
• enteropathy-associated T-cell-lymphoma-like lymphoma without enteropathy (EATCL-LLWE)
• enteropathy-associated T-cell-lymphoma (EATCL)
• high grade T cell lymphoma

• radiotherapy. Localized MALT lymphomas of the orbit, conjunctiva, salivary glands, and thyroid gland are treated successfully with radiotherapy. Surgical excision of large cell or bulky tumors of the stomach, thyroid, lung, and salivary gland, followed by adjuvant radiotherapy or chemotherapy, may still be an important consideration in selected patients. Surgery still has a role for patients with relapsed or refractory low-grade disease and life-threatening hemorrhage. Disseminated MALT lymphomas are incurable and are treated primarily with chemotherapy according to symptoms
• rituximab^ref.

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