Original Article
Marginal Zone Lymphomas Factors That Affect the Final Outcome Ali Mazloom, MD1; L. Jeffrey Medeiros, MD2; Peter W. McLaughlin, MD3; Valerie Reed, MD1; Fernando F. Cabanillas, MD3; Luis E. Fayad, MD1; Barbara Pro, MD3; Graciela Gonzalez, MPH4; Puneeth Iyengar, MD, PhD1; Diana L. Urbauer, MS4; and Bouthaina S. Dabaja, MD1
BACKGROUND: A retrospective review and analysis of 275 patients with marginal zone lymphoma (MZL) was performed to determine prognostic factors. An effort was also made to establish a specific prognostic score for patients with extranodal MZL. METHODS: Patients were divided into 3 groups according to the type of MZL: extranodal, nodal, and splenic. Factors analyzed included age; gender; presence of B symptoms; Zubrod performance score; clinical stage; serum b2-microglobulin, lactate dehydrogenase, albumin, and hemoglobin levels; and presence of autoimmune disorder. RESULTS: The 5-year overall survival rates of patients with extranodal, nodal, and splenic MZL were 87%, 89%, and 93%, respectively (P ¼ .95). On multivariate analysis, splenic MZL patients had the best prognosis (hazard ratio, 0.18; P ¼ .018). An elevated serum b2-microglobulin level (P ¼ .010), B symptoms (P ¼ .021), and male gender (P ¼ .036) were found to be correlated with decreased recurrence-free survival (RFS) on multivariate analysis. Using these 3 variables, a 3-tier prognostic scoring system was created for patients with extranodal MZL: low-risk with no adverse factors, intermediate-risk with 1 adverse factor, and high-risk with 2 adverse factors. The 5-year RFS rates for the low-risk, intermediate-risk, and high-risk groups were 80%, 71%, and 44%, respectively (P ¼ .01). CONCLUSIONS: Patients with extranodal and nodal MZL have a similar prognosis, whereas patients with splenic MZL have a better prognosis despite the increased prevalence of negative prognostic indicators. With the use of 3 readily available factors, a prognostic scoring system was identified for patients with extranodal MZL. Cancer 2010;116:4291– C 2010 American Cancer Society. 8. V KEYWORDS: marginal zone lymphoma, mucosa-associated lymphoid tissue, prognostic factors, extranodal, nodal, splenic.
The current World Health Organization (WHO) classification of tumors of hematopoietic and lymphoid tissues,
updated in 2008, describes 3 types of marginal zone lymphoma (MZL): extranodal, nodal, and splenic.1-3 Although these tumors are usually clinically indolent and share many morphologic and immunophenotypic features, there are also important differences in their frequency, clinical presentation, and pathogenesis. Extranodal MZL, also known as low-grade B-cell lymphoma of mucosa-associated lymphoid tissue (or MALT lymphoma) is most common and accounts for approximately 70% of all MZLs.1,4 These neoplasms can arise at virtually any extranodal site and are commonly associated with chronic antigenic stimulation, either as a result of infection (eg, Helicobacter pylori in the stomach) or autoimmune disease (eg, Sjogren syndrome and salivary glands).1,4 Several chromosomal translocations also have been identified in extranodal MZLs, accounting in aggregate for approximately one-third of all cases.5 Splenic MZL accounts for approximately 20% of all MZLs.3,6 Patients typically present with an enlarged spleen, involvement of abdominal lymph nodes, and bone marrow disease. Liver and leukemic involvement occurs in a subset of patients. Approximately 40% to 50% of splenic MZLs are associated with deletions of chromosome 7q.3 Nodal MZL is the least common, representing approximately 10% of all MZLs.2,7 Patients with nodal MZL, by definition, have lymph node-based disease without involvement of the spleen or extranodal sites. To the best of our knowledge, the molecular pathogenesis of nodal MZL is not understood.
Corresponding author: Bouthaina S. Dabaja, MD, Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, 1515 Holcomb Blvd., Houston, TX 77030; Fax: (713) 563-2331;
[email protected] 1 Division of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 2Department of Hematopathology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 3Department of Lymphoma and Myeloma, The University of Texas M. D. Anderson Cancer Center, Houston, Texas; 4Division of Quantitative Sciences, The University of Texas M. D. Anderson Cancer Center, Houston, Texas
Presented in part at the American Society of Hematology Annual Meeting, San Francisco, California, December 6-9, 2008. DOI: 10.1002/cncr.25325, Received: December 9, 2009; Revised: February 2, 2010; Accepted: February 23, 2010, Published online June 14, 2010 in Wiley Online Library (wileyonlinelibrary.com)
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Original Article
To our knowledge, few studies to date have compared the prognosis of patients with the 3 types of MZL, and the prognostic factors that affect the outcome of MZL patients are not well understood.8,9 The aim of this study was to retrospectively analyze 275 patients with extranodal, splenic, and nodal MZL referred to The University of Texas M. D. Anderson Cancer Center (MDACC). We compared the prognosis of the 3 patient groups and determined prognostic factors that affect outcome with the intent to generate a prognostic score that may be helpful for tailoring therapy for extranodal MZL patients.
MATERIALS AND METHODS Patients were identified by searching the Institutional Lymphoma Planning Clinic Database for the time interval January 1, 1996, to December 31, 2006. This database includes all patients with lymphoma presenting initially at our institution. Eligibility criteria for inclusion in this analysis were as follows: 1) diagnosis of MZL according to the WHO classification criteria,1-3 2) no prior therapy for the MZL, and 3) diagnosis at MDACC or referral to MDACC at the time of diagnosis. For the diagnosis of nodal MZL, exclusion of concomitant extranodal or splenic disease was required. This was done as part of staging. All biopsy specimens were obtained at MDACC, or they were performed elsewhere and reviewed by hematopathologists at MDACC. The diagnosis of MZL was confirmed in all cases according to the criteria initially proposed in the Revised European-American Lymphoma (REAL) classification10 and then incorporated into the 200111 and current 2008 versions of the WHO classification of tumors of hematopoietic and lymphoid tissues.1-3 A preliminary database of 333 patients with MZL was obtained. Fifty-eight patients were excluded because they did not meet eligibility criteria, clinical data were incomplete, or there was no clinical follow-up at MDACC. This left a study group of 275 patients. These patients were reviewed retrospectively, and approval for this study was obtained from the Institutional Review Board of MDACC. The information reviewed included patient demographic characteristics, clinical symptoms, Ann Arbor clinical stage,12 anatomic site at time of initial presentation, Zubrod score, serum lactate dehydrogenase (LDH) and b2-microglobulin levels before therapy, type of treatment, response to treatment, time to failure, and survival. All patients were staged by upper endoscopy and computed tomography scans of the neck, thorax,
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abdomen, and pelvis. In addition, all patients underwent bone marrow aspiration and biopsy, either unilateral or bilateral. Serologic testing for hepatitis C virus was not performed for 36 of 37 patients with splenic MZL; therefore, this prognostic factor was not evaluated in our study. Response was classified according to the definitions recommended by the International Workshop to Standardize Response Criteria for non-Hodgkin Lymphomas.13 Complete remission (CR) was defined as the disappearance of all detectable clinical and radiographic evidence of disease and the disappearance of all disease-related symptoms if present before therapy. A partial remission (PR) was defined as a 50% reduction in tumor bulk. Stable disease was defined as less than a PR but was not progressive disease (PD). PD required a 50% increase in the sum product of the greatest dimensions of any previously identified abnormal lymph node or lymph node masses or the appearance of any new lesion during or at the end of therapy. Overall survival (OS) was measured from time of diagnosis until death from any cause. Recurrence-free survival (RFS) was measured from time of diagnosis to the time of primary treatment failure, disease recurrence/progression, or death from lymphoma. Statistical Analysis The patients who achieved CR or PR were classified as responders. Summary statistics were completed for the study population as a whole to gain a better understanding of the study population. Additional summary statistics were calculated for cases with extranodal, splenic, or nodal involvement. The Fisher exact test was used to determine whether the distribution of categorical variables differed by site of involvement; a Kruskal-Wallis test was used to determine whether distribution of continuous variables differed by involvement. Kaplan-Meier survival curves were created to examine RFS and OS. For comparison of survival curves, the log-rank test was used. Univariate proportional hazards models were also created to examine the effect of these variables upon OS and RFS. Finally, a multivariate proportional hazards model was created to predict OS and RFS while adjusting for variables of interest.
RESULTS Patient Characteristics Table 1 summarizes the 275 patients in this study. There were 211 (77%) patients with extranodal MZL, 37 (13%) with splenic MZL, and 27 (10%) with nodal MZL. The
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Factors Affecting the Outcome of MZLs/Mazloom et al
Table 1. Patient Clinical and Laboratory Summary
MZL Subtype No. Median age, y Gender Autoimmune disorders Stage of disease
Symptoms Zubrod performance score
Male Female I II III IV Unknown stage Absent B symptoms B symptoms 0 1 2 3
LDH 618 IU/L Serum ß2-microglobulin 2.5 mg/L Serum albumin
