Abstract

Background: Few large studies exist on the outcome of patients treated for stage I/II mucosa-associated lymphoid tissue (MALT) lymphoma.

Patients and methods: We retrospectively reviewed the records of 77 patients consecutively treated for stage I (n = 66) or II (n = 11) MALT lymphoma at our institution. Progression-free survival (PFS), freedom from treatment failure (FFTF), and overall survival (OS) were calculated using the Kaplan–Meier method.

Results: The median follow-up time was 61 months (range 2–177 months). Fifty-two patients (68%) received local radiation therapy (RT) alone, 17 (22%) had surgery followed by adjuvant RT, five (6%) had surgery alone, two (3%) had surgery and chemotherapy, and one patient had chemotherapy alone. The median RT dose was 30 Gy (range 18–40 Gy). The 5-year PFS, FFTF, and OS rates were 76%, 78%, and 91%, respectively. The 5-year PFS (79% versus 50%; P = 0.002) and FFTF (81% versus 50%; P = 0.0004) rates were higher for patients who received RT as compared with patients who did not.

Conclusions: The prognosis following treatment of stage I/II MALT lymphoma is excellent. RT improves PFS and FFTF and has an important role in the curative treatment of patients with localized disease.

introduction

Extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT) is an indolent B-cell lymphoma that comprises ∼5%–8% of all non-Hodgkin's lymphomas [1, 2]. MALT lymphoma is most commonly found in the stomach but can involve almost any organ [3]. Because MALT lymphomas have a tendency to involve multiple mucosal sites, approximately one-third of patients present with disseminated disease [4–6].

With the identification of Helicobacter pylori infection as a stimulus for the formation of gastric MALT lymphoma, antibiotics have become the first-line therapy for H. pylori-associated gastric MALT lymphoma and have been shown to result in high rates of disease regression [7–10]. The optimal treatment of patients with nongastric MALT lymphomas, however, remains undefined. Surgery, radiotherapy (RT), chemotherapy, or a combination thereof have all been used with favorable results [6, 11–14], and some investigators have proposed observation as a reasonable approach for the management of orbital or conjunctival MALT lymphomas [15, 16].

There are few large studies of the treatment outcome for patients with localized MALT lymphoma. We previously published the results of treatment at our institution for patients with MALT lymphoma of all stages [4]. In this study, we focus on the outcome following treatment of patients with stage I/II disease in a larger cohort of patients with updated follow-up.

patients and methods

We retrospectively reviewed the records of 77 consecutive patients with biopsy-proven clinical stage (CS) I or II MALT lymphoma treated with curative intent at the Brigham and Women's Hospital, Dana-Farber Cancer Institute, and Beth Israel Deaconess Medical Center from 1986 to 2005. The study was carried out in accordance with an institutional review board-approved protocol. As part of our prior study [4], all pathology reports were reviewed by the study pathologist, and pathology slides were retrieved and reviewed in uncertain cases to confirm the diagnosis of MALT lymphoma. New cases added to the current series since 2002 were all reviewed at our institution at the time of diagnosis but were not rereviewed for the purposes of the current study. Review of the medical records showed that all cases arose in extranodal sites. Staging work-up included a bone marrow aspirate and biopsy in 38 patients (49%), chest X-ray in 16 (21%), computed tomography (CT) of the chest in 71 (92%), abdominal/pelvic CT in 70 (91%), gallium scan in 14 (18%), and positron emission tomography (PET) using 18-fluoro-2-deoxyglucose (FDG) in 10 (13%).

patient characteristics

The baseline patient characteristics and the distribution of the initial sites of disease involvement are summarized in Table 1. Fifty-one (66%) of the 77 patients were female. The median patient age was 55 years (range 16–82 years). Sixty-six patients (86%) had CS I disease and 11 patients (14%) had CS II disease. Forty-eight patients (62%) had an International Prognostic Index (IPI) score of zero, 25 patients (32%) had an IPI of one, three (4%) had an IPI of two, and one (1%) had an IPI of three. Sixty-six patients (86%) had one site of involvement and 11 patients (14%) had two sites of involvement.

Table 1.

Baseline characteristics of the study cohort (n = 77)

Characteristic No. of patients %a 
Age at diagnosis, years   
    Median  55 
    Range 16–82  
Gender   
    Female 51 66 
    Male 26 34 
Ann Arbor clinical stage   
    I 66 86 
    II 11 14 
IPI   
    0 48 62 
    1 25 32 
    2 
    3 
Number of sites involved   
    1 66 86 
    2 11 14 
Site of involvement   
    Stomach 21 27.3 
    Parotid 15 19.5 
    Orbit 11 14.3 
    Conjunctiva 9.1 
    Duodenum/large bowel 7.8 
    Lung 3.9 
    Breast 2.6 
    Buccal mucosa 2.6 
    Neck 2.6 
    Thyroid 2.6 
    Bladder 1.3 
    Epidural 1.3 
    Cheek 1.3 
    Axilla 1.3 
    Nostril 1.3 
    Elbow 1.3 
Characteristic No. of patients %a 
Age at diagnosis, years   
    Median  55 
    Range 16–82  
Gender   
    Female 51 66 
    Male 26 34 
Ann Arbor clinical stage   
    I 66 86 
    II 11 14 
IPI   
    0 48 62 
    1 25 32 
    2 
    3 
Number of sites involved   
    1 66 86 
    2 11 14 
Site of involvement   
    Stomach 21 27.3 
    Parotid 15 19.5 
    Orbit 11 14.3 
    Conjunctiva 9.1 
    Duodenum/large bowel 7.8 
    Lung 3.9 
    Breast 2.6 
    Buccal mucosa 2.6 
    Neck 2.6 
    Thyroid 2.6 
    Bladder 1.3 
    Epidural 1.3 
    Cheek 1.3 
    Axilla 1.3 
    Nostril 1.3 
    Elbow 1.3 

IPI, International Prognostic Index.

a

Percentages do not sum to 100% due to rounding error.

overall treatment

Sixty-nine patients (90%) received radiation therapy (RT) as part of their initial treatment. Fifty-two patients (68%) received local RT alone. Seventeen patients (22%) had surgery and local RT. Five patients (6%) underwent surgical resection alone. One patient had surgical resection followed by chemotherapy and another received four cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) followed by surgery. One patient received chemotherapy alone. For those patients who received RT, the median dose was 30 Gy (range 18–40 Gy). The chemotherapy regimens used included CHOP in two patients and chlorambucil alone in one.

treatment by site

stomach.

A total of 21 patients presented with gastric involvement by MALT lymphoma. All had CS I disease. One patient was treated with antibiotics followed by subtotal gastric resection and five cycles of CHOP chemotherapy. Six patients had persistent disease after initial treatment with antibiotics and went on to receive local RT alone. Two patients underwent surgical resection alone; one patient had a subtotal gastrectomy and the other had a total gastrectomy. Two patients underwent subtotal gastrectomy followed by RT. The remaining 10 patients received RT alone without prior antibiotic therapy. For those who were treated with RT, the median dose was 30.6 Gy (range 29.75–36.25 Gy) delivered generally in 1.75 or 1.8 Gy daily fractions.

Most patients underwent CT-based radiation planning with oral contrast given before the time of simulation. A three- or four-field technique was utilized to encompass the entire stomach and perigastric nodes while sparing the kidneys as much as possible.

parotid gland.

Among the 15 patients who presented with parotid gland involvement, two patients had bilateral disease. Four patients had CS II disease. Ten patients underwent superficial or subtotal parotidectomy. Eight of these 10 patients also received RT. Two patients received no further therapy after surgery. Five patients were treated with RT alone. The median dose for the 13 patients who received RT as part of their treatment was 30 Gy (range 25.2–40 Gy). Treatment was delivered daily in fraction sizes of 1.8 or 2.0 Gy. Beam arrangements used were typically anterior-posterior (AP)/posterior-anterior or paired, wedged beams.

conjunctiva/orbit.

All 18 patients with conjunctival or orbital disease received RT alone as their primary treatment. Three of the seven patients with conjunctival MALT lymphoma had bilateral involvement and two of the 11 patients with orbital MALT lymphoma had bilateral disease. The median RT dose for both conjunctival and orbital MALT lymphomas was 30 Gy (range 18–37.28 Gy). Most patients were treated with daily doses of 1.8 or 2.0 Gy per day. All patients except for one received a minimum total dose of 28 Gy. One patient with a history of Sjogren's syndrome terminated treatment early after 18 Gy because of the development of a corneal ulcer after nine fractions of 2 Gy delivered using an en face 9-MeV electron beam. Patients with conjunctival MALT lymphoma were generally treated with a single, en face electron or photon field with 0.5–1.0 cm of tissue equivalent bolus and a lens block. Patients with orbital MALT lymphoma were treated with a variety of techniques including AP, wedge pair, or AP/opposed lateral beam arrangements.

duodenum/large bowel.

Three patients had duodenal involvement at presentation and three patients had disease in the large bowel. All three patients with duodenal MALT lymphoma had persistent disease after initial treatment with antibiotics and went on to receive RT alone. Of the three patients with large bowel involvement, one patient had MALT lymphoma in both the cecum and rectum and underwent a partial ileocolectomy followed by 36 Gy of RT to the rectum. The other two patients had rectal involvement only and received RT alone without surgery. The median RT dose for all six patients was 30 Gy (range 29.75–36 Gy) given in 1.75 or 2.0 Gy daily fractions.

other sites

The remaining 17 patients had miscellaneous sites of involvement including lung (three), buccal mucosa (two), epidural (one), bladder (one), breast (two), axilla (one), elbow (one), neck (two), nostril (one), cheek (one), and thyroid (two). Among the three patients with lung involvement, one was treated with chlorambucil alone, another received four cycles of CHOP with minimal response followed by a left lower lobectomy, and the other underwent a wedge resection followed by RT to a dose of 28 Gy. One patient with bilateral breast involvement had surgical resection alone and another patient with unilateral breast disease had surgery followed by 30 Gy of whole-breast RT. One patient with thyroid MALT lymphoma underwent a partial thyroidectomy followed by adjuvant RT. The other patient with thyroid MALT lymphoma had a total thyroidectomy and adjuvant RT. The remaining patients received RT alone. The median dose for patients receiving RT was 30 Gy (range 25.2–40 Gy). The most common fraction sizes were 1.8 or 2.0 Gy per day.

statistical analysis

The Fisher's exact test was used to assess whether IPI (0 versus ≥1) was associated with age at diagnosis (≤60 versus >60) and to compare the proportion of patients achieving local control between those who received RT and those who did not. Local recurrence was defined as relapse within the initially involved organ or lymph node region. Progression-free survival (PFS) was calculated as the time from the start of treatment to progression of disease or death without documented progression. Freedom from treatment failure (FFTF) was calculated as the time from the start of treatment to progression of disease, but death without disease progression was censored. Overall survival (OS) was defined as the time from the start of treatment to death from any cause censored at the time of last contact. PFS, FFTF, and OS rates were estimated using the Kaplan–Meier method. The two-tailed log-rank test was used to assess differences in the PFS, FFTF, and OS when stratified by CS (I versus II), IPI (0 versus ≥1), age (≤60 versus >60), and treatment with or without RT.

results

staging

Seventeen of 70 patients (24%) who underwent CT imaging of the abdomen and pelvis had positive scans while five of the 71 patients (7%) who had chest CTs had positive findings. The chest X-ray was positive in only one out of the 16 patients who had had a chest X-ray. Eleven of the 14 gallium scans (79%) demonstrated gallium-avid disease. Among the 10 patients who had a PET scan before treatment, nine (90%) showed FDG uptake at the site of disease. The sites that demonstrated FDG-avid disease included stomach (three), parotid (one), orbit (one), lung (one), neck (one), and thyroid (two). The patient with the negative PET scan had a gastric MALT lymphoma that was resistant to antibiotics and only had a PET carried out following treatment with antibiotics. The PET did not detect the presence of persistent disease despite multiple biopsies demonstrating active lymphoma.

PFS, FFTF, and OS

The median follow-up time for all patients was 61 months (range 2–177 months). As illustrated in Figure 1, the 5-year PFS, FFTF, and OS rates for all patients were 76%, 78%, and 91%, respectively. The corresponding 10-year estimates were 57%, 67%, and 78%, respectively. Overall, nine deaths have occurred, five with active lymphoma and four from other causes. When analyzed by stage at presentation, the 5-year PFS rate was 76% for patients with CS I disease and 79% for patients with CS II disease (P = 0.33). There was no difference in 5-year FFTF between patients with CS I disease and those with CS II disease (P = 0.28). The 5-year OS rates were 89% and 100% for those with CS I disease and CS II disease, respectively (P = 0.96).

Figure 1.

Kaplan–Meier estimates of (a) progression-free survival (PFS), (b) freedom from treatment failure (FFTF), and (c) overall survival (OS) of the 77 study patients.

Figure 1.

Kaplan–Meier estimates of (a) progression-free survival (PFS), (b) freedom from treatment failure (FFTF), and (c) overall survival (OS) of the 77 study patients.

The 5-year PFS (82% versus 64%; P = 0.04) and OS (98% versus 73%; P = 0.005) rates were higher for patients with an IPI of zero than for patients with an IPI ≥1, but FFTF was not significantly different between the groups (82% versus 74%, P = 0.38). Similarly, patients ≤60 years of age had higher PFS (82% versus 58%, P = 0.01) and OS (98% versus 71%, P = 0.002) rates than older patients, but no statistically significant difference was seen in FFTF (82% versus 69%, P = 0.2). There was, however, a high degree of correlation between age ≤60 years and an IPI of zero (P < 0.001, Fisher's exact test).

As shown in Figure 2, when analyzed by treatment with or without RT, the 5-year FFTF was 81% for those who received RT and 50% for those who did not (P = 0.0004). Patients who received RT as a component of their initial therapy also had higher PFS than those who did not (79% versus 50%; P = 0.002), but there was no statistically significant difference in OS between the two groups (94% versus 75%, P = 0.74).

Figure 2.

Kaplan–Meier estimates of freedom from treatment failure (FFTF) of the 77 study patients when stratified by treatment with or without radiotherapy (RT).

Figure 2.

Kaplan–Meier estimates of freedom from treatment failure (FFTF) of the 77 study patients when stratified by treatment with or without radiotherapy (RT).

relapse outcome

Table 2 summarizes the sites of initial presentation, initial treatment, sites of relapse, salvage therapy, and clinical outcome of the 17 patients who relapsed. Four relapses were local and 13 were distant. Among the 17 patients who relapsed, the median time to relapse was 25 months (range 0–123 months). Four relapses (24%) occurred >5 years following initial treatment. Among those who relapsed, five deaths have occurred, all related to lymphoma.

Table 2.

Outcome of patients with relapsed disease

Initial site Initial treatment Time to relapse (months) Relapse type Site of relapse Salvage therapy Status Time to death (months) 
Stomach RT (30.5 Gy) Distant Chest, GI tract None DCD 
Stomach RT (35 Gy) 32 Distant Right orbit RT Second relapse in sacrum treated with RT, ASD 24 months after second relapse  
Parotid RT (36 Gy) Distant Contralateral parotid RT Second relapse in breast salvaged with surgery, ASD 20 months after second relapse  
Parotid RT (40 Gy) 90 Distant Mediastinum None DCD 93 
Orbit RT (28 Gy) 65 Distant Supraclavicular node (transformed to DLCL) CHOP + IF-RT ASD 102 months after first relapse  
Rectum RT (30 Gy) 58 Distant Mediastinum (transformed to DLCL) CHOP ACD undergoing chemotherapy for first relapse  
Buccal mucosa RT (30.6 Gy) 25 Distant Stomach RT ASD 71 months after first relapse  
Epidural RT (34.6 Gy) Distant Buccal mucosa RT ASD after multiple relapses  
Bladder RT (40 Gy) 49 Distant Axilla, mediastinum, groin (transformed to mantle cell lymphoma) CVP + rituximab ASD after multiple relapses (maintenance rituximab)  
Cecum, rectum Surgery + RT (30 Gy) 28 Distant Oropharynx, nasopharynx Debulking surgery + CHOP ASD 30 months after first relapse  
Breast Surgery (excisional biopsy) + RT (30 Gy) Distant Neck, hilum, mediastinum, retroperitoneum, bone marrow (transformed to DLCL) CHOP + rituximab DCD 20 
Left lung Chlorambucil Local Left lung CVP DCD 44 
Stomach Surgery (partial gastrectomy) 54 Distant Conjunctiva Surgery + RT ASD 84 months after first relapse  
Parotid Surgery (superficial parotidectomy) Distant Thigh (transformed to DLCL) CHOP + IF-RT DCD 49 
Bilateral breasts Surgery (excisional biopsy) 24 Local Left breast RT ASD after multiple relapses (maintenance rituximab)  
Stomach Surgery (partial gastrectomy + CHOP) 124 Local Stomach Antibiotics + RT ASD 54 months after first relapse  
Left lung CHOP + surgery (lobectomy) 11 Local Left lung RT ASD 119 months after first relapse  
Initial site Initial treatment Time to relapse (months) Relapse type Site of relapse Salvage therapy Status Time to death (months) 
Stomach RT (30.5 Gy) Distant Chest, GI tract None DCD 
Stomach RT (35 Gy) 32 Distant Right orbit RT Second relapse in sacrum treated with RT, ASD 24 months after second relapse  
Parotid RT (36 Gy) Distant Contralateral parotid RT Second relapse in breast salvaged with surgery, ASD 20 months after second relapse  
Parotid RT (40 Gy) 90 Distant Mediastinum None DCD 93 
Orbit RT (28 Gy) 65 Distant Supraclavicular node (transformed to DLCL) CHOP + IF-RT ASD 102 months after first relapse  
Rectum RT (30 Gy) 58 Distant Mediastinum (transformed to DLCL) CHOP ACD undergoing chemotherapy for first relapse  
Buccal mucosa RT (30.6 Gy) 25 Distant Stomach RT ASD 71 months after first relapse  
Epidural RT (34.6 Gy) Distant Buccal mucosa RT ASD after multiple relapses  
Bladder RT (40 Gy) 49 Distant Axilla, mediastinum, groin (transformed to mantle cell lymphoma) CVP + rituximab ASD after multiple relapses (maintenance rituximab)  
Cecum, rectum Surgery + RT (30 Gy) 28 Distant Oropharynx, nasopharynx Debulking surgery + CHOP ASD 30 months after first relapse  
Breast Surgery (excisional biopsy) + RT (30 Gy) Distant Neck, hilum, mediastinum, retroperitoneum, bone marrow (transformed to DLCL) CHOP + rituximab DCD 20 
Left lung Chlorambucil Local Left lung CVP DCD 44 
Stomach Surgery (partial gastrectomy) 54 Distant Conjunctiva Surgery + RT ASD 84 months after first relapse  
Parotid Surgery (superficial parotidectomy) Distant Thigh (transformed to DLCL) CHOP + IF-RT DCD 49 
Bilateral breasts Surgery (excisional biopsy) 24 Local Left breast RT ASD after multiple relapses (maintenance rituximab)  
Stomach Surgery (partial gastrectomy + CHOP) 124 Local Stomach Antibiotics + RT ASD 54 months after first relapse  
Left lung CHOP + surgery (lobectomy) 11 Local Left lung RT ASD 119 months after first relapse  

RT, radiation therapy; GI, gastrointestinal; DCD, dead with disease; ASD, alive without disease; DLCL, diffuse large cell lymphoma; CHOP, cyclophosphamide, doxorubicin, vincristine, prednisone; IF, involved field; ACD, alive with disease; CVP, cyclophosphamide, vincristine, prednisone.

The crude local control rate for the 69 patients who received RT as a component of their initial therapy was 100% as compared with 50% for the eight patients who did not (P < 0.001, Fisher's exact test). Eleven (16%) of the 69 patients who received RT relapsed at distant sites. Among the five patients treated initially with surgery alone, one patient relapsed locally and two relapsed at other sites. All three patients who were initially treated with chemotherapy alone or chemotherapy and surgery relapsed locally.

Salvage therapies included RT alone in seven patients, chemotherapy alone in four, chemotherapy followed by RT in two, surgery followed by chemotherapy in one, and surgery followed by RT in another. Two patients received no additional therapy at the time of relapse. All 10 patients who received RT as part of their salvage therapy achieved local control although five of these patients did go on to relapse distantly. Both patients who received no further treatment have died of their lymphoma.

disease transformation

Fourteen patients had pathologic documentation of disease recurrence. Four were found to have transformation to diffuse large B-cell lymphoma (DLBCL) and one was found to have transformation to mantle cell lymphoma. The times between treatment start and disease transformation were 6, 8, 49, 58, and 65 months. In four patients with documented disease transformation, the number of large cells was not found to be significantly increased in the original diagnostic biopsies. One patient with a MALT lymphoma of the parotid gland, however, did have a minor component of large cells in her original biopsy material and later developed a thigh mass 6 months after initial treatment. The mass was excised and found to be DLBCL.

The patients with transformation to DLBCL received salvage CHOP chemotherapy either alone (one), with RT (two), or with rituximab (one). One patient who received CHOP with RT was successfully salvaged and remains free of disease. The patient receiving CHOP plus rituximab is currently undergoing therapy. The other two patients have died of complications related to their lymphoma. The patient with transformation to mantle cell received several courses of salvage cyclophosphamide, vincristine, and prednisone plus rituximab after multiple relapses and is now free of disease on maintenance rituximab therapy.

discussion

In this report, we describe the treatment outcome of a large cohort of patients with localized gastric and nongastric MALT lymphoma. The majority of the patients (90%) received RT as a component of their initial therapy and the most common sites of involvement were the stomach, parotid gland, and orbit/conjunctiva. We found that the prognosis of these patients is very favorable with an estimated 5-year OS of 91%. Younger age and the absence of IPI risk factors were associated with improved PFS and OS. The use of moderate-dose RT as part of initial therapy resulted in higher PFS and FFTF rates as compared with treatment without RT. RT was also an effective salvage therapy as all patients who received salvage RT achieved local control at the site of relapse.

In a previous publication, we observed 100% local control in a cohort of 35 patients with localized disease treated with RT [4]. In the current study, treatment with 30 Gy resulted in 100% local control in an updated cohort containing an additional 34 patients treated in a similar manner. The excellent local control achieved with the use of moderate-dose RT is consistent with the results of other studies. Tsang et al. [17] published on the outcome of 103 patients treated for stage I/II MALT lymphoma; among 85 patients treated with RT alone to a median dose of 30 Gy, the crude local control rate was 95%. Le et al. [18] also reported a 100% local control rate among 31 patients with orbital MALT lymphoma treated with a mean dose of 34 Gy. Other investigators have reported similarly high rates of local control achieved with 30 Gy in patients with MALT lymphoma of the orbit and ocular adnexa [19–22].

The management of gastric MALT lymphoma has evolved because of the identification of H. pylori infection as a stimulus for its development. Treatment with antibiotics and acid-reducing medications has become the standard first-line therapy for H. pylori-associated gastric MALT lymphoma with reported remission rates of 55%–95% [7–10]. Wündisch et al. [10] reported on a prospective trial of 120 patients with early-stage H. pylori-positive gastric MALT lymphoma treated with H. pylori-eradicating medical regimens. With a median follow-up of 75 months, 80% of the study patients achieved a complete histologic remission and 80% of those patients remained in continuous complete remission [10]. Consequently, the use of moderate-dose RT, which has been shown in numerous series to be effective in controlling gastric MALT lymphoma is now generally recommended for the treatment of antibiotic resistant or non-H. pylori-associated gastric MALT lymphoma. Schechter et al. [23] observed that 30 Gy was sufficient to achieve 100% local control in a group of 17 patients with localized gastric MALT lymphoma.

In our study, 17 patients (22%) experienced a relapse, typically in sites that commonly harbor MALT lymphomas. While Tsang et al. [17] noted a tendency for recurrences to occur in paired organs, we observed only one relapse in a contralateral untreated parotid gland. We also noted that relapses could occur as late as 123 months following initial treatment with a median time to relapse of 25 months among those who recurred. Raderer et al. [24] reported that among 86 patients achieving a complete remission following initial therapy, 37% relapsed between 14 and 307 months after remission with a median time to relapse of 47 months. This finding highlights the importance of continued follow-up of these patients who have a high rate of long-term survival, given the indolent nature of this disease and the efficacy of salvage therapies.

Because of the affinity of MALT lymphoma to involve multiple mucosal sites it is possible that some relapses may in fact represent progression of untreated disease that was not initially detected at the time of presentation. Dabaja et al. [25] retrospectively studied 36 patients who underwent esophagogastroduodenoscopy (EGD) as part of staging for nongastric MALT lymphoma and found that 12 had occult gastric involvement. Based on these findings, the authors concluded that EGD should be part of routine initial staging work-up of nongastrointestinal MALT lymphoma. In our study, only one patient with nongastrointestinal MALT relapsed in the stomach. The high rate of relapse, however, in other mucosa-associated sites seen in our study as well as others may reflect the need for more accurate staging to improve patient selection for local therapy with curative intent.

Imaging with FDG-PET is commonly used in the management of patients with aggressive non-Hodgkin's lymphoma for staging, treatment, and follow-up. On the basis of early, small studies, the sensitivity of PET for MALT lymphoma had previously been thought to be low [26, 27]. In a larger study by Beal et al. [28], among 42 patients who underwent PET scanning for MALT lymphoma at Memorial Sloan-Kettering Cancer Center, 34 (81%) were, however, found to have FDG-avid disease in verified tumor sites. Although a minority of patients in our study had a PET scan as part of initial staging, of the 10 patients who did, nine were found to have FDG uptake at the site of disease supporting the ability of PET to detect these indolent lymphomas. The one patient with a negative PET study had previously been treated with antibiotics; however, biopsies did demonstrate the presence of persistent disease at the time of the PET scan. Further prospective studies are needed to define the role of PET in the staging of patients with MALT lymphoma and in assessing response to treatment.

Our study has several limitations related to its retrospective methodology. First, although the majority of the patients in our study received RT there was heterogeneity in the manner in which the patients were treated. Secondly, as we demonstrated, late relapses do occur, and longer follow-up will be necessary to confirm the durability of the responses seen in this study. Thirdly, many of the patients in this study did not undergo extensive staging evaluation at the time of presentation. Although most did have CT scans, only 49% underwent bone marrow biopsy and aspirate. Thus, it is possible that a proportion of these patients who received local therapy only may have had occult disseminated disease.

In conclusion, the prognosis following treatment of patients with localized MALT lymphoma is excellent, especially for younger patients or those with an IPI score of zero. Treatment with local RT to a dose of 30 Gy achieves local control and appears to improve PFS and FFTF compared with treatment without RT. Future directions for investigation include improving the accuracy of staging of patients with MALT lymphoma to optimize patient selection for local therapy and evaluating the efficacy of lower doses of RT.

The authors would like to thank Dongyun Kim for her assistance in preparing the figures. This study was presented at the 48th Annual Meeting of the American Society for Therapeutic Radiology and Oncology, 5–9 November 2006, Philadelphia, PA.

References

1.
Armitage
JO
Weisenburger
DD
New approach to classifying non-Hodgkin's lymphomas: clinical features of the major histologic subtypes. Non-Hodgkin's Lymphoma Classification Project
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
2780
-
2795
)
2.
A clinical evaluation of the International Lymphoma Study Group classification of non-Hodgkin's lymphoma
The Non-Hodgkin's Lymphoma Classification Project
Blood
 , 
1997
, vol. 
89
 (pg. 
3909
-
3918
)
3.
Zucca
E
Bertoni
F
Roggero
E
Cavalli
F
The gastric marginal zone B-cell lymphoma of MALT type
Blood
 , 
2000
, vol. 
96
 (pg. 
410
-
419
)
4.
Hitchcock
S
Ng
AK
Fisher
DC
, et al.  . 
Treatment outcome of mucosa-associated lymphoid tissue/marginal zone non-Hodgkin's lymphoma
Int J Radiat Oncol Biol Phys
 , 
2002
, vol. 
52
 (pg. 
1058
-
1066
)
5.
Thieblemont
C
Berger
F
Dumontet
C
, et al.  . 
Mucosa-associated lymphoid tissue lymphoma is a disseminated disease in one third of 158 patients analyzed
Blood
 , 
2000
, vol. 
95
 (pg. 
802
-
806
)
6.
Zucca
E
Conconi
A
Pedrinis
E
, et al.  . 
Nongastric marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue
Blood
 , 
2003
, vol. 
101
 (pg. 
2489
-
2495
)
7.
Bayerdorffer
E
Neubauer
A
Rudolph
B
, et al.  . 
Regression of primary gastric lymphoma of mucosa-associated lymphoid tissue type after cure of Helicobacter pylori infection. MALT Lymphoma Study Group
Lancet
 , 
1995
, vol. 
345
 (pg. 
1591
-
1594
)
8.
Montalban
C
Manzanal
A
Boixeda
D
, et al.  . 
Treatment of low-grade gastric MALT lymphoma with Helicobacter pylori eradication
Lancet
 , 
1995
, vol. 
345
 (pg. 
798
-
799
)
9.
Fischbach
W
Goebeler-Kolve
ME
Dragosics
B
, et al.  . 
Long term outcome of patients with gastric marginal zone B cell lymphoma of mucosa associated lymphoid tissue (MALT) following exclusive Helicobacter pylori eradication therapy: experience from a large prospective series
Gut
 , 
2004
, vol. 
53
 (pg. 
34
-
37
)
10.
Wundisch
T
Thiede
C
Morgner
A
, et al.  . 
Long-term follow-up of gastric MALT lymphoma after Helicobacter pylori eradication
J Clin Oncol
 , 
2005
, vol. 
23
 (pg. 
8018
-
8024
)
11.
Thieblemont
C
Bastion
Y
Berger
F
, et al.  . 
Mucosa-associated lymphoid tissue gastrointestinal and nongastrointestinal lymphoma behavior: analysis of 108 patients
J Clin Oncol
 , 
1997
, vol. 
15
 (pg. 
1624
-
1630
)
12.
Tsang
RW
Gospodarowicz
MK
Pintilie
M
, et al.  . 
Stage I and II MALT lymphoma: results of treatment with radiotherapy
Int J Radiat Oncol Biol Phys
 , 
2001
, vol. 
50
 (pg. 
1258
-
1264
)
13.
Jager
G
Neumeister
P
Brezinschek
R
, et al.  . 
Treatment of extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue type with cladribine: a phase II study
J Clin Oncol
 , 
2002
, vol. 
20
 (pg. 
3872
-
3877
)
14.
Zinzani
PL
Stefoni
V
Musuraca
G
, et al.  . 
Fludarabine-containing chemotherapy as frontline treatment of nongastrointestinal mucosa-associated lymphoid tissue lymphoma
Cancer
 , 
2004
, vol. 
100
 (pg. 
2190
-
2194
)
15.
Matsuo
T
Yoshino
T
Long-term follow-up results of observation or radiation for conjunctival malignant lymphoma
Ophthalmology
 , 
2004
, vol. 
111
 (pg. 
1233
-
1237
)
16.
Tanimoto
K
Kaneko
A
Suzuki
S
, et al.  . 
Long-term follow-up results of no initial therapy for ocular adnexal MALT lymphoma
Ann Oncol
 , 
2006
, vol. 
17
 (pg. 
135
-
140
)
17.
Tsang
RW
Gospodarowicz
MK
Pintilie
M
, et al.  . 
Localized mucosa-associated lymphoid tissue lymphoma treated with radiation therapy has excellent clinical outcome
J Clin Oncol
 , 
2003
, vol. 
21
 (pg. 
4157
-
4164
)
18.
Le
QT
Eulau
SM
George
TI
, et al.  . 
Primary radiotherapy for localized orbital MALT lymphoma
Int J Radiat Oncol Biol Phys
 , 
2002
, vol. 
52
 (pg. 
657
-
663
)
19.
Hasegawa
M
Kojima
M
Shioya
M
, et al.  . 
Treatment results of radiotherapy for malignant lymphoma of the orbit and histopathologic review according to the WHO classification
Int J Radiat Oncol Biol Phys
 , 
2003
, vol. 
57
 (pg. 
172
-
176
)
20.
Lee
JL
Kim
MK
Lee
KH
, et al.  . 
Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue-type of the orbit and ocular adnexa
Ann Hematol
 , 
2005
, vol. 
84
 (pg. 
13
-
18
)
21.
Ejima
Y
Sasaki
R
Okamoto
Y
, et al.  . 
Ocular adnexal mucosa-associated lymphoid tissue lymphoma treated with radiotherapy
Radiother Oncol
 , 
2006
, vol. 
78
 (pg. 
6
-
9
)
22.
Suh
CO
Shim
SJ
Lee
SW
, et al.  . 
Orbital marginal zone B-cell lymphoma of MALT: radiotherapy results and clinical behavior
Int J Radiat Oncol Biol Phys
 , 
2006
23.
Schechter
NR
Portlock
CS
Yahalom
J
Treatment of mucosa-associated lymphoid tissue lymphoma of the stomach with radiation alone
J Clin Oncol
 , 
1998
, vol. 
16
 (pg. 
1916
-
1921
)
24.
Raderer
M
Streubel
B
Woehrer
S
, et al.  . 
High relapse rate in patients with MALT lymphoma warrants lifelong follow-up
Clin Cancer Res
 , 
2005
, vol. 
11
 (pg. 
3349
-
3352
)
25.
Dabaja
BS
Ha
CS
Wilder
RB
, et al.  . 
Importance of esophagogastroduodenoscopy in the evaluation of non-gastrointestinal mucosa-associated lymphoid tissue lymphoma
Cancer J
 , 
2003
, vol. 
9
 (pg. 
321
-
324
)
26.
Hoffmann
M
Kletter
K
Diemling
M
, et al.  . 
Positron emission tomography with fluorine-18-2-fluoro-2-deoxy-D-glucose (F18-FDG) does not visualize extranodal B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT)-type
Ann Oncol
 , 
1999
, vol. 
10
 (pg. 
1185
-
1189
)
27.
Hoffmann
M
Kletter
K
Becherer
A
, et al.  . 
18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET) for staging and follow-up of marginal zone B-cell lymphoma
Oncology
 , 
2003
, vol. 
64
 (pg. 
336
-
340
)
28.
Beal
KP
Yeung
HW
Yahalom
J
FDG-PET scanning for detection and staging of extranodal marginal zone lymphomas of the MALT type: a report of 42 cases
Ann Oncol
 , 
2005
, vol. 
16
 (pg. 
473
-
480
)