Japanese Journal of Clinical Oncology Advance Access published online on June 11, 2007
Japanese Journal of Clinical Oncology, doi:10.1093/jjco/hym031
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© 2007 Foundation for Promotion of Cancer Research
Primary Ocular Adnexal MALT Lymphoma: A Long-term Follow-up Study of 114 Patients
1 Hematology and Stem Cell Transplantation Division
2 Ophthalmology Division
3 Radiation Oncology Division
4 Pathology Division, National Cancer Center Hospital and Research Institute, Tokyo, Japan
For reprints and all correspondence: Kensei Tobinai, Hematology and Stem Cell Transplantation Division, National Cancer Center Hospital, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan. E-mail: ktobinai{at}ncc.go.jp
Received October 14, 2006; accepted January 17, 2007
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Abstract |
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 TOP Abstract INTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Background: Although primary ocular adnexal MALT (mucosa-associated lymphoid tissue ) lymphoma (POAML) is a recently recognized unique entity, its natural history, prognostic factors, behavior of progression and death, and standard initial management have not been fully elucidated.
Methods: The data of 114 patients with histologically verified POAML who were treated at our institution between 1970 and 2003 were retrospectively analyzed.
Results: With a median follow-up duration of 5.7 years (0.6–34.0), estimated overall survival (OS) rate and progression-free survival (PFS) rate at 10 years was 89% and 57%, respectively. Thirteen (11%) patients died, but only three (3%) of them due to progressive lymphoma. Thirty-one (27%) patients progressed: eight who progressed at contra lateral sites were limited to those who had initially involved in the orbit (P = 0.036) and their OS and PFS were significantly longer (P = 0.035 and 0.039, respectively). Patients who initially received radiation-containing therapy were superior in PFS but not in OS to those initially treated with other modalities (P = 0.016 and 0.091, respectively). When we compared the outcomes of the observation cohort and the immediate therapy cohort, there were no significant differences in OS and PFS (P = 0.499 and 0.073, respectively).
Conclusions: The majority of patients with POAML showed the behaviors of localized and indolent diseases. Our preliminary observation that no initial therapy is an acceptable approach for selected patients was confirmed. Considering the possible heterogeneity of POAML among initial sites, further investigations are warranted.
Key Words: MALT lymphoma • heterogeneity • observation • retrospective study
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INTRODUCTION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Since the first description by Isaacson and Wright in 1983, extranodal marginal zone B-cell lymphoma of mucosa -associated lymphoid tissue (MALT lymphoma) has been recognized as a distinct entity of low-grade B-cell lymphoma; it is described in the revised European–American lymphoma (REAL) classification and also in the more recent classification by the World Health Organization (WHO) (1–3). The majority of patients with MALT lymphoma show an indolent natural history it manifests as localized diseases in two-thirds of patients (4,5).
Malignant lymphoma arising in the ocular adnexa is a rare disorder, and previous reports indicated that they account for about 8% of all extranodal lymphomas (6). Several reports indicate that the majority of lymphomas in the ocular adnexa are of MALT type (7–11). It was reported that histology according to the REAL or WHO classification can be used to accurately predict the prognosis of patients with lymphomas in the ocular adnexa, and those with MALT type have a more favorable prognosis than those with lymphomas of differing histology (8–11). Although there have been a few analyses carried out on small numbers of patients with primary ocular adnexal MALT lymphoma (POAML), its natural history and prognostic factors have not been fully elucidated (12,13).
For localized MALT lymphoma, radiotherapy is recognized as the most frequently applied management and most patients show good responses (14,15). For the initial management of POAML, especially for localized diseases, radiotherapy is a safe and effective treatment (16–21). However, several reports recently suggested that radiotherapy alone may not provide superior outcomes in patients with MALT lymphoma (22). Based on the long-term follow-up results at our institution, we previously reported that in selected patients with POAML no initial therapy might be an acceptable approach (23). The investigators in Italy reported the detection of Chlamydia psitacci DNA in 80% of POAML and the regression by C. psitacci-eradicating antibiotic therapy in some patients (24,25). However, a recent report from South Florida indicated no association of C. psitacci in 57 patients with primary ocular adnexal lymphoma (26). Thus, the optimal initial management of POAML has not been fully elucidated.
Although the prognosis of the majority of patients with POAML is thought to be favorable, disease progression and/or death occurs in a fraction of patients. To our knowledge, there have been few analyses on its behavior of progression and death focusing on patients with POAML (12,13). Therefore, we analyzed the long-term follow-up results of 114 patients with POAML at our institution. The objective of this study was to analyze its natural history, behavior of progression and death, initial managements and prognostic factors.
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PATIENTS AND METHODS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Selection of Patients
We utilized the database of the National Cancer Center Hospital, Japan. Criteria for selection included patients who developed lymphoma in the ocular adnexa as the primary lesion, and were initially diagnosed or reviewed as POAML and managed at our institution. Their diagnosis of MALT lymphoma was established by biopsy or surgical resection sample in the primary lesion. For all patients, the histopathologic diagnosis of MALT lymphoma was reviewed according to the REAL or the WHO classification by two hematopathologists (Y.M., A.M-M.).
Preliminary clinical data of 36 patients with POAML who had been followed up with no initial therapy were published separately (23), and they were included in the present study for the all cohorts regardless of initial management.
Clinical Features
In patients with the confirmed diagnosis of POAML, the following clinical data were analyzed based on the medical charts; sex, age, clinical stage, involved site and laterality, performance status (PS) according to the Eastern Cooperative Oncology Group scale and the serum lactate dehydrogenase (LDH) value at initial presentation. The involved sites were anatomically classified according to Knowles et al. (27). Physical examination, chest X-ray, computed tomography of the head/eye, neck, chest, abdomen and pelvis, gallium scintigraphy, bone marrow and peripheral blood examination were performed. The clinical stages were determined according to the Ann Arbor staging classifications. International prognostic index (IPI) (28) was calculated based on these data.
Prognostic Factors and Initial Management Analyses
All patients were followed up exclusively at the National Cancer Center Hospital. If patients were lost to follow-up for more than one year, we contacted via telephone for information regarding survival, progression and treatment. Overall survival (OS) was defined as time period from the date of diagnosis until the date of death due to any cause or until the date of the last follow-up for patients who were alive. Progression-free survival (PFS) was defined as time period from the date of the diagnosis until the date of first progression, or the date of last follow-up, or the date of death due to any cause, whichever occurred earlier. In the univariate and multivariate analyses of prognostic factors influencing OS and PFS, we compared sex (male versus female), age (<60 versus 
60), clinical stage (I versus II–IV), the value of serum LDH at initial presentation (
normal value versus > normal value), anatomical involved site (orbit versus the remaining sites) and laterality (unilateral versus bilateral).
After diagnosis, we informed therapeutic options to all patients. Patients received one of four kinds of initial management, including radiation alone, chemotherapy alone, radiation combined with chemotherapy and observation with no initial therapy. We compared OS and PFS among the initial management cohorts.
Behavior of Progression and Death
In all patients who progressed, the following clinical data were extracted; sex, age, involved site at initial and progression, laterality at initial and progression which were limited to the ocular adnexal progression, initial management, PFS, OS and cause of death. We divided patients who progressed into the following three categories according to the site of progression; category A, distant disease at progression; category B, contra lateral site at progression; category C, the same lateral site at progression. We compared the clinical factors among these three categories to elucidate the character in association with progression.
In all patients who died, clinical data at initial presentation were extracted to elucidate the character in association with death.
Statistical Analysis
OS and PFS were calculated by the Kaplan–Meier method. In the univariate and multivariate analyses of prognostic factors and initial managements influencing OS and PFS, we compared them using the log-rank test and multiple Cox regression models (backward stepwise selection of variables). Analyzing the correlations of the three categories at progression, we assessed each clinical factor by cross tabulation and Fisher's exact test. OS and PFS were compared by student's t-test among these three categories. All statistical analyses were performed using the software package SPSS for Windows, version 13.0 (SPSS Inc, Chicago, IL).
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RESULTS |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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Patients' Characteristics
One hundred and fourteen patients between 1970 and 2003 were included for this retrospective analysis. The characteristics of the patients are shown in Table 1. The median age was 57.5 years (range, 15–90 years), with 43 female and 71 male patients. Fifty-one patients (45%) were 60 years of age or older. The site most frequently involved was orbit (59%). In 97 patients (85%), the disease was located in a unilateral ocular adnexal region, whereas 17 patients (15%) had the disease in bilateral regions. One hundred and seven (94%) patients had stage I disease, whereas only seven (6%) had stage II–IV disease. In 15 (13%) patients, their LDH values were elevated. One hundred patients (88%) had low risk according to IPI. No patient exhibited the coexistence of MALT lymphoma and other types of lymphoma.
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Natural History
With a median follow-up duration of 5.7 years (range, 0.6–34.0 years), the estimated median OS was 18.4 years. The proportion of patients alive at 5, 10 and 15 years was 96, 92 and 71%, respectively (Fig. 1). The estimated median PFS was 11.0 years. The proportion of patients who were alive and progression-free at 5, 10 and 15 years was 77, 57 and 39%, respectively (Fig. 2).
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Initial Managements
After the various therapeutic options were carefully explained to patients, most patients agreed with their physicians' recommendations. One hundred and fourteen patients were initially managed with the following four kinds of therapy; 58 (51%) patients receiving radiation alone, 15 (13%) chemotherapy alone, 5 (4%) radiation combined with chemotherapy and 36 (32%) observation as watchful waiting. The total dose of radiation ranged from 30 to 40 Gy, and the rate of achieving complete response was 83%. The radiation management was generally well tolerated, however, the clinical manifestation of cataract development was documented in four of the 63 patients who received radiation. Several kinds of chemotherapy were performed; most patients were treated with cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP) or cyclophosphamide, procarbazine, vincristine and prednisolone (C-MOPP) regimen. The overall rate of complete response in the chemotherapy alone cohort was 67%. As we discussed in our previous report (23), reasons for no initial therapy varied; seven patients (19%) selected no initial therapy when informed of various therapeutic options, 28 (78%) accepted no initial therapy according to physicians' suggestions and one (3%) because of advanced age.
The results of the univariate analysis of initial managements affecting OS and PFS are shown in Table 2. There were no significant differences in OS among the initial management cohorts (P = 0.284). However, the radiation cohort showed a trend toward superior PFS to those initially treated with other modalities (P = 0.053). To analyze the efficacy of radiation as the initial management, we compared the radiation-containing cohort (radiation alone or radiation combined with chemotherapy) and the radiation-non-containing cohort (observation or chemotherapy alone). Figures 3 and 4 show that patients who received radiation-containing therapy were superior in PFS but not in OS to those who received other modalities (P = 0.016 and 0.091, respectively).
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To confirm the acceptability of observation as an initial management, we compared the observation cohort and the immediate therapy cohort. As shown in Table 2 and Fig. 5, there were no significant differences in OS (P = 0.499), although the slightly superior tendency of the immediate therapy cohort in PFS (P = 0.073) was recognized.
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Behavior of Progression and Death
Thirty-one (27%) patients progressed after the initial management. Among them, only two (2%) patients showed the histology of transformed high-grade lymphoma. One patient died of progressive lymphoma, while the other was salvaged by chemotherapy after initial radiotherapy. Table 3 lists the clinical features of the 31 patients who showed progression. The most frequent sites of progression were the same as the initial sites: seven (6%) patients progressed at distant diseases (category A), eight (7%) at contra lateral sites (category B), and 16 (14%) at the same sites (category C). All eight patients who belonged to the category B were limited to those who had involved initially in the orbit (P = 0.036) and their OS and PFS were significantly longer than those who belonged to the remaining categories (P = 0.035 and P = 0.039, respectively). When we analyzed the relationship between the sites of progression and the initial managements, patients who were initially managed with observation progressed more frequently at the same sites than those who were treated with other modalities (P = 0.016).
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Table 4 lists the clinical features of 13 patients (11%) who died. Six (5%) patients showed progressive diseases and three of them died of lymphoma progression. The remaining 10 (9%) patients died of the following various causes: pancreatic cancer (n = 2), lung cancer (n = 2), esophageal cancer (n = 1), cerebral infarction (n = 1), heart failure (n = 1), renal failure (n = 1), pneumonia (n = 1) and unclear (n = 1).
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Prognostic Factors
The results of the univariate analysis of the prognostic factors affecting OS and PFS are shown in Table 5. No clinical factors affected OS except for age. No factors significantly affected PFS. Because we considered that the choice of no initial therapy might have been related to selection biases, we analyzed prognostic factor affecting PFS in the immediate therapy cohort only. However, no factor affected PFS (data not shown). In the multivariate analysis of the factors affecting OS or PFS, there were also no significant factors (data not shown).
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DISCUSSION |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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POAML is recognized as a distinct entity of low-grade B-cell lymphoma and is thought to be localized and indolent diseases (7–13). However, in most of the previous analyses the nature of POAML may have been masked, because various histopathological entities of lymphoma occurring in the ocular adnexa were analyzed together. In the present study, to elucidate its clinical behaviors, we analyzed 114 patients with POAML who were treated at our institution for more than 30 years follow-up.
As shown in Table 1, the majority of patients with POAML in the present series show the behaviors of localized diseases and having low IPI. These results are similar to those by other investigators (7,9–13).
In the present analysis, we confirmed that POAML was an indolent disease because the proportions of patients alive at 5, 10 and 15 years were 96, 92 and 71%. However, the proportions of patients who were alive and progression-free at 5, 10 and 15 years were 77, 57 and 39%, respectively. It was suggested that nearly half of POAML patients might progress during the long-term follow-up period. Because there was a difference between OS and PFS rates, it was suggested that even if progression occurred, disease control of POAML is possible by the subsequent therapy and progression does not directly affect a patient's survival.
As shown in Table 2, this study suggests that radiation is superior to other modalities as initial management in especially PFS. However, this superiority is obscure in OS among all the cohorts. Because the majority of the previous studies analyzed the radiation cohort alone, there were few comparative studies regarding OS or PFS between the radiation-containing cohort and the radiation-non-containing cohort (16–21). We recently reported the results of our preliminary observation that no initial therapy might be acceptable in selected patients with POAML (23). When we compared the outcomes of the observation cohort and the immediate therapy cohort in the present study, there were no significant difference in OS and PFS (P = 0.499 and 0.073, respectively). We therefore consider that observation approach with no initial therapy for selected patients was further confirmed in this study for the all cohorts. Because various treatment modalities were principally based on physicians' choices, however, there might be some biases affecting prognoses. Thus, the efficacy of each treatment modality in POAML should be evaluated by prospective studies in future, for example, by a randomized control trial comparing local radiotherapy and watch-and-waiting for asymptomatic patients with localized diseases.
There has been no previous analysis, to our knowledge, focusing on progression behavior of POAML. Partly because very few patients developed histological transformation (2%), the OS rate was excellent with long-term follow-up. Although the radiation-containing cohort was superior in disease control of the initial sites, the majority (88%) of progression in the radiation-containing cohort occurred in the distant sites or contra lateral sites, in contrast with the frequent same initial sites in the observation cohort, as shown in Table 3.
According to the sites in progression, we divided patients with POAML into three categories. As shown in Table 3, we found that patients who belonged to the category B had a unique character compared to those who belonged to the remaining categories. We recently found that patients with POAML having trisomy 18 might have unique clinicopathological characteristics (29). Other investigators reported that some ocular adnexal lymphomas were related to C. psittaci infection and the involvement of this agent might partly explain the heterogeneity of POAML (24,25).
When we analyzed the prognostic factors affecting PFS, there was no clinical factor significantly affecting its prognosis. A few previous analyses indicated that there were several prognostic factors (8–11). However, most of these analyses included several different histopathological entities of malignant lymphomas occurring in the ocular adnexa. We recently showed that in POAML, patients with trisomy 18 had worse PFS than those without (29). Other investigators reported that patients with t(11;18) had a significantly longer median time to relapse than those without (22). Further analyses of genetic and histopathological features are warranted to predict the prognosis of each patient with POAML more accurately.
In conclusion, the majority of patients with POAML showed the behavior of localized and indolent disease, although a fraction of them slowly progressed. Our previous observation was further confirmed in this study that no initial therapy is an acceptable approach for selected patients with POAML. Considering the possible heterogeneity of POAML suggested in the present study and the genetic heterogeneity revealed by our and other studies, further investigations on POAML are warranted.
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Conflict of interest statement |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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None declared.
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Acknowledgment |
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This study was supported by a Grant-in-Aid for Cancer Research from the Ministry of Health, Labor and Welfare, Japan (15–11).
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References |
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TOPAbstractINTRODUCTIONPATIENTS AND METHODSRESULTSDISCUSSIONConflict of interest statementReferences |
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