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Nongastric Marginal-Zone B-Cell MALT Lymphoma: Prognostic Value of Disease Dissemination

^a Division of Hematology and ^c Department of Pathology, IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy; ^b Division of Hematology, Ospedali Riuniti, Bergamo, Italy; ^d Division of Hematology, Niguarda Ca’ Granda Hospital, Milano, Italy; ^e Department of Hematology, and ^f Azienda Ospedaliera S. Andrea, University "La Sapienza," Roma, Italy; ^g Division of Hematology, Azienda Ospedaliera S. Giovanni Battista, Torino, Italy; ^h Division of Hematology, Policlinico "S. Maria alle Scotte", University of Siena, Siena, Italy; ⁱ Department of Hematology, S. Bortolo Hospital, Vicenza, Italy; ^j Department of Hematology, Catholic University Medical School, Rome, Italy; ^k Division of Hematology, University of Udine, Udine, Italy

Key Words. MALT lymphoma • Prognosis • Marginal zone • Dissemination

Correspondence: Luca Arcaini, M.D., Division of Hematology, IRCCS Policlinico San Matteo, University of Pavia, Viale Golgi 19, 27100 Pavia, Italy. Telephone: 39-0382-503595; Fax: 39-0382-502250; e-mail: luca.arcaini{at}unipv.it

Received November 9, 2005; accepted for publication January 24, 2006.

	LEARNING OBJECTIVES

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After completing this course, the reader will be able to:

1. Discuss the different modalities of disease dissemination in nongastric marginal-zone B-cell MALT lymphoma.
   
2. Explain the rationale for using extensive staging in nongastric marginal-zone B-cell MALT lymphoma.
   
3. Assess the clinical features helpful to detect patients with nongastric marginal-zone B-cell MALT lymphoma who have a poor prognosis.
   

	ABSTRACT

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The aim of this study is to describe the clinical features and define the prognostic significance of disease dissemination in a large series of nongastric marginal-zone B-cell mucosa-associated lymphoid tissue (MALT) lymphomas. We studied 208 patients with nongastric marginal-zone B-cell MALT lymphoma diagnosed and treated from 1991 to 2004. Ninety percent of the patients had a single site of MALT involvement—skin (26%), salivary glands (18%), orbit (14%), Waldeyer’s ring (13%)—and 39% and 28% had nodal involvement and bone marrow involvement, respectively. After a median follow-up of 2.7 years, the median event-free survival (EFS) time was 2.4 years, and the median overall survival (OS) time was not reached. On univariate analysis, the features significantly associated with longer EFS and OS times were the following: single MALT site involvement (OS), localized disease (EFS and OS), no nodal disease (EFS and OS), skin and orbit lymphoma (OS), and stage IV disease without bone marrow involvement (OS). On multivariate analysis, both bone marrow and nodal involvement were associated with shorter OS. This study describes the clinical features and the natural history of nongastric marginal-zone lymphomas and highlights that the dissemination to lymph nodes and bone marrow is associated with a poorer outcome.

	INTRODUCTION

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Marginal-zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) are extranodal low-grade lymphomas that represent 8% of all non-Hodgkin’s lymphomas (NHLs) [1–3]. MALT lymphomas are indolent disorders that typically affect patients of middle and advanced age, predominantly women [2–6].

Although traditionally considered a localized type of lymphoma, dissemination at diagnosis has been reported in 34% of all MALT lymphomas (including gastric lymphoma) [5]. The disease may disseminate within the MALT (diffuse involvement of a single MALT site or multiple mucosal localizations) or may spread outside the MALT (lymph nodes and bone marrow involvement) as a result of the loss of the mucosal homing properties [5, 6]. According to these findings, the traditional concept of MALT lymphoma as a localized disease does not seem appropriate, indicating the need for extensive staging in all patients [7].

However, the percentage of disseminated disease in nongastric MALT lymphomas remains a controversial issue: in the Lyon series, 52% of patients had advanced disease and 25% had bone marrow involvement [8], while in the International Extranodal Lymphoma Study Group (IELSG) study, the percentages were lower (27% and 14%, respectively) [6]. Moreover, whether dissemination has a prognostic value is still debatable: the Lyon researchers found a median progression-free survival time of 5 years for all patients without any difference between those with localized and disseminated disease [8]. The IELSG, in contrast, found that advanced disease with bone marrow and nodal involvement was associated with shorter survival [6].

A consensus on the prognostic assessment of nongastric MALT lymphoma has not yet been reached: in the IELSG series, 17% of the patients ranked in the intermediate-high and high International Prognostic Index (IPI) risk groups, with a shorter progression-free survival time on multivariate analysis [6], while in the Lyon study, only elevated ß₂-microglobulin was an adverse predictive factor for shorter overall survival [8].

We carried out a collaborative study on nongastric marginal-zone MALT lymphomas to study the clinical features at presentation, the patterns of disease dissemination, and the prognostic value of disease dissemination.

	MATERIALS AND METHODS

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We studied 208 patients with nongastric marginal-zone B-cell MALT lymphoma diagnosed and treated from 1991 to 2004. The study was conducted in accordance with institutional guidelines established for retrospective studies.

In order to be included in the study, patients were required to have had a histological diagnosis of MALT lymphoma in accordance with the World Health Organization classification [9]. The immunophenotypic profile was used to exclude other indolent low-grade B-cell lymphomas with extranodal localization. Patients had to have shown main disease manifestation in an extranodal site. HIV-positive cases were excluded from the study.

All patients underwent complete staging procedures, including bone marrow examination. Extranodal disease was defined as bulky when the largest dimension was = 10 cm. We defined nodal involvement as locoregional, distant, or diffuse (both locoregional and distant). The IPI and the Follicular Lymphoma International Prognostic Index (FLIPI) were calculated according to published criteria [10, 11].

Numeric variables are summarized by their medians and ranges, while categorical variables are described by counts and relative frequencies. Associations were tested using Fisher’s exact test (for 2 x 2 tables) or using the ² approximation for larger tables. The Kaplan-Meier product-limit method was used to compute survival curves, and the log-rank test was used to compare different groups of patients. The overall survival (OS) time was calculated as the time between the date of diagnosis and the date of death, or last follow-up for censored cases; the event-free survival (EFS) time was calculated as the time from the first line of therapy until the event (treatment after an initial watch-and-wait policy, relapse or progression, death from any cause). The Cox proportional-hazard model was used to perform a multivariate survival analysis.

	RESULTS

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Patient Characteristics
The characteristics of the 208 patients at diagnosis are summarized in Table 1. The median age at diagnosis was 64.4 years (range, 23–91), while 126 of the patients were women and 82 were men (ratio, 1.5). In 188 patients (90%), a single extranodal mucosal site was involved; the remaining 20 patients (10%) had multiple sites of MALT involvement (two or three). The primary sites of lymphoma were as follows: skin (26%), parotid gland and minor salivary glands (18%), orbit and ocular adnexa (lachrymal glands and conjunctiva) (14%), Waldeyer’s ring (13%), lung and pleura (9%), small intestine and colon (4%), breast (3%), and other sites (3%). The primary sites of MALT lymphomas are summarized in Table 2. The ratio of localized disease (stage I–II) to advanced disease (stage III–IV) was 1.2. Eighty-one patients (39%) had nodal involvement (54% locoregional, 11% distant, and 35% diffuse): among them, 32% had a single nodal site, 22% had two nodal sites, and 46% had more than two nodal sites. Nineteen (9%) had mild spleen enlargement (14 with bone marrow involvement, four with liver involvement). Eight patients (4%) had liver involvement, and in four of them, the liver represented the primary and only site of lymphoma. One hundred thirty-three patients (64%) had only one extranodal site, which was the primary site of lymphoma, while 75 patients (36%) had more than one extranodal site. The IPI score was applicable to 138 patients: 38 (28%) ranked in the low-risk group, 49 (35%) were in the low-intermediate risk group, 34 (25%) were in the intermediate-high risk group, and 17 (12%) were in the high-risk group. The FLIPI score was applicable to 150 patients: 42 (28%) ranked in the low-risk group, 69 (46%) were in the intermediate-risk group, and 39 (26%) were in the high-risk group.

Treatment
First-line treatment consisted of chemotherapy alone in 94 patients (45%), surgery in 44 patients (21%), and radiotherapy in 40 patients (19%). A watch-and-wait policy was adopted in 30 cases (15%). Chemotherapy varied from a single alkylating agent in 45 patients to combination chemotherapy with anthracyclines in 36 patients and without anthracyclines in 10 patients, and to fludarabine-based regimens in three patients. In five cases, anti-CD20 monoclonal antibody was added to chemotherapy. Surgical treatments consisted of surgery alone in 29 patients, surgery followed by chemotherapy in seven patients, surgery followed by radiotherapy in seven patients, and surgery followed by radiotherapy and chemotherapy in one patient. Radiotherapy alone was used in 22 cases, while radiotherapy combined with chemotherapy was used in 18. In one case, anti-CD20 monoclonal antibody was added to radiotherapy.

After first-line therapy, 73% of patients achieved complete response (CR) and 17% achieved partial response (PR), for an overall response rate (ORR) of 90%. The ORR was 65% in patients receiving chemotherapy, 76% in patients treated with radiotherapy, and 90% in those who underwent surgery. Among the patients receiving chemotherapy, the CR rate was not influenced by the use of anthracyclines. The comparison between localized and disseminated disease demonstrated a significant difference in achieving a CR/PR (p = .05) (ORR, 94% vs. 83%). When the analysis was performed on all patients, those receiving chemotherapy had a lower CR/PR rate than those undergoing surgery or receiving radiotherapy (p = .03).

Sixty-two patients experienced relapse (46) or progression (16) after a median of 18 months (range, 6–96) from response. In 30 cases, the relapse/progression occurred at the original site of disease. Of the 30 patients who did not receive initial treatment, eight progressed at the original location after a median of 14 months, and 22 remained stable after a median follow-up of 12 months (range, 6–53).

Outcome
The median duration of follow-up was 2.7 years. A median OS time was not reached, and the median EFS time was 2.4 years. The estimated 5-year OS and EFS rates were 83% (95% confidence interval [CI], 76%–90%) and 37% (95% CI, 28%–46%), respectively (Fig. 1). The 5-year OS rates for stage I–II and stage III–IV patients were 94% (95% CI, 88%–100%) and 69% (95% CI, 55%–83%), respectively (p = .001) (Fig. 2).

View larger version (8K): [in this window] [in a new window]   Figure 1. Overall survival (OS) and event-free survival (EFS) of 208 patients with nongastric mucosa-associated lymphoid tissue lymphoma.

View larger version (10K): [in this window] [in a new window]   Figure 2. Overall survival of 208 patients with nongastric mucosa-associated lymphoid tissue lymphoma according to Ann Arbor stage (stage I–II vs. stage III–IV).

View larger version (12K): [in this window] [in a new window]   Figure 3. Overall survival of 208 patients with nongastric mucosa-associated lymphoid tissue lymphoma according to the presence of nodal disease.

We divided patients into two groups: patients with at least one adverse feature of disease dissemination (bone marrow involvement, more than one MALT site, distant/diffuse nodal involvement) and patients with none. The group of patients with at least one sign of disease dissemination had a shorter OS time (p = .0005) and a shorter EFS time (p = .01).

On multivariate analysis, the features significantly associated with shorter OS were: bone marrow involvement (p = .004), distant/diffuse nodal involvement (p = .01), ECOG score =2 (p = .007), Hb < 11 g/dl (p = .04), and the presence of a monoclonal component (p = .04). On multivariate analysis, only bone marrow involvement had a negative influence on EFS (p = .03).

	DISCUSSION

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In nongastric marginal-zone MALT lymphomas, disease dissemination may involve the MALT (diffuse involvement of a single MALT site or multiple mucosal localizations) or may extend into bone marrow and lymph nodes after the loss of mucosal homing properties [5, 6]. In the present study, 44% of patients had advanced disease, which is similar to the figure reported by the Lyon group (52%) [8] and higher than that reported by the IELSG (27%) [6]. The percentage of patients with bone marrow involvement in our series (28%) is similar to that reported in the Lyon series (25%) [8] and slightly higher than in the IELSG series (14%) [6]. According to these findings, the traditional concept of MALT lymphoma as a localized disease does not seem appropriate, and this confirms the need for extensive staging in all patients [7].

The survival analysis confirms the indolent nature of nongastric MALT lymphomas, with some heterogeneity, depending on the MALT site of origin; in our series, orbit and skin lymphomas had the most favorable outcomes. Similarly, Tanimoto et al. [12] recently reported that patients with stage I ocular adnexal MALT lymphomas have a long overall survival time even when untreated. Aside from primary MALT site localization, patients with advanced disease had worse outcomes, as previously reported by the IELSG [6].

Because of the retrospective nature of our survey, the therapeutic approaches were quite different, since patients were treated according to the policy of each institution. The overall response rate for all the series was 90% but was inferior (65%) for patients treated with chemotherapy. Interestingly, the comparison between localized and disseminated disease demonstrated a significant difference in response.

If a targeted therapy for infection-driven, marginal-zone lymphoproliferation is not indicated [13, 14], clinicians should select treatment taking into account the specific MALT lymphoma localization and disease dissemination.

In our series, 30% of the patients experienced relapse or progression after a median of 18 months from response, and nearly half of the relapses/progressions occurred at the original disease sites. These findings partially agree with previous data: Raderer et al. [15] reported a high relapse rate for nongastric MALT lymphoma, but the majority of relapses occurred in other MALT organs.

Despite the indolent nature of these neoplasms, a reliable prognostic assessment could be useful in the treatment choice, considering their high relapse rate [15] and the possibility of using new therapeutic approaches, including immunotherapy [16], proteasome inhibitors [17], and oxaliplatin [18]. The IPI has been validated and employed in aggressive NHL [10] and applied in MALT lymphomas [6]. In the IELSG series, 17% of the patients ranked in the intermediate-high risk and the high-risk IPI groups and had a shorter progression-free survival time [6]. In our study, we found a higher proportion of patients at high risk according to IPI score. We also applied the FLIPI score, proposed for follicular lymphoma [11], and 26% of our patients ranked in the high-risk group. On multivariate analysis, neither the IPI nor the FLIPI score maintained a statistically significant influence on OS and EFS. Therefore, we tried to find some simple clinical parameters to detect those patients with a worse prognosis. We found that at least one sign of widespread disease (bone marrow involvement and/or more than one MALT site and/or distant/diffuse nodal involvement) was associated with shorter overall and event-free survival times. The prognostic value of disease dissemination, although not validated as a prognostic tool, appears clinically useful.

In conclusion, this study describes the clinical features and natural history of nongastric marginal-zone MALT lymphoma in a large series and underlines that dissemination to lymph nodes and bone marrow is associated with a poorer outcome.

	DISCLOSURE OF POTENTIAL CONFLICTS OF INTEREST

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The authors indicate no potential conflicts of interest.

	APPENDIX

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The following institutions and investigators participated in the study: Division of Hematology, IRCCS Policlinico San Matteo, University of Pavia (Luca Arcaini, Sara Burcheri, Francesco Passamonti, Ercole Brusamolino, Ester Orlandi, Francesca Montanari, Cristiana Pascutto, Mario Lazzarino); Department of Pathology, IRCCS Policlinico San Matteo, University of Pavia (Marco Paulli, Emanuela Boveri, Umberto Magrini); Division of Hematology, Ospedali Riuniti Bergamo (Andrea Rossi, Sergio Cortelazzo); Division of Hematology, Niguarda Ca’ Granda Hospital, Milano (Alfredo Molteni, Enrica Morra); Department of Hematology, University "La Sapienza", Rome (Alessandro Pulsoni, Natalia Frattarelli, Robin Foa); Azienda Ospedaliera S. Andrea, University "La Sapienza", Rome (Maria Christina Cox, Sergio Amadori); Division of Hematology, Azienda Ospedaliera S. Giovanni Battista, Torino (Lorella Orsucci, Umberto Vitolo); Division of Hematology, Policlinico "S. Maria alle Scotte", University of Siena (Alberto Fabbri, Francesco Lauria); Department of Hematology, S. Bortolo Hospital, Vicenza (Maurizo Frezzato, Francesco Rodeghiero); Department of Hematology, Catholic University Medical School, Rome (Maria Teresa Voso, Annalaura Di Febo, Giuseppe Leone); Division of Hematology, University of Udine (Francesco Zaja, Renato Fanin); Division of Hematology, University of Verona (Achille Ambrosetti, Maura Colosio, Giovanni Pizzolo); Division of Oncology, National Cancer Institute, Aviano (Michele Spina, Umberto Tirelli); Division of Hematology, Brescia (Alessandra Tucci, Giuseppe Rossi); Division of Hematology, University "Federico II", Napoli (Amalia De Renzo, Bruno Rotoli); Division of Haematology, University of Ancona (Mauro Montanari, Pietro Leoni); Department of Haematology, General Hospital S. Maurizio, Bolzano (Atto Billio, Paolo Coser); Division of Hematology, S. Croce Hospital, Cuneo (Roberta Calvi, Silvia Tavera, Andrea Gallamini); and Division of Hematology, University of Parma (Monica Crugnola, Vittorio Rizzoli).

	ACKNOWLEDGMENT

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We thank Ms. Ziggy Kennell for linguistic review of the manuscript.

	REFERENCES

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