Clinical features and possible prognostic factors in patients with Marginal Zone Lymphoma: Retrospective analysis from two centers

Marginal zone lymphoma accounts 5%-17% of all non-Hodgkin lymphomas and has an indolent clinical course. The parameters that predict prognosis and the need for treatment are still unclear. The aim of the current study was to examine the impact of parameters on the course of disease and the need for treatment in marginal zone lymphoma. Methods A retrospective study was conducted with marginal zone lymphoma patients in the two centres between 2010 and 2018. The demographic and disease characteristics, and also hematological and biochemical parameters at the time of diagnosis were examined. The effect of the parameters on overall survival and need for treatment were analyzed. treatment was 58.4 months and there was no signicant difference among the groups. The platelet count of untreated patients at the time of diagnosis were signicantly higher than patients who received treatment. No signicant relationship was found between any parameter and overall survival.


Introduction
Marginal zone lymphoma (MZL) is characterized by the proliferation of B cells in postgerminal centers found in mucosa-associated lymphoid tissue (MALT), lymph nodes, and the spleen [1]. MZL has indolent clinical course commonly and present with limited stage of disease [2]. Median age of MZL is about 60 years and there is slight female predominance. MZL accounts 5-17% of all non-Hodgkin lymphomas (NHL) [3].
MZL includes three subtypes: extranodal (EMZL), splenic(SMZL) and nodal MZL (NMZL) depending on site of involvement [4]. Although many morphologic and immunophenotypic features of these subtypes are similar with their indolent course, there are also differences in frequency, pathogenesis, clinical presentation and treatment [5]. According to the 2016 Revised WHO Classi cation, extranodal MZL is the most frequent subtype while nodal MZL is the least common form [6].
EMZL involves the organs with low lymphoid tissue like stomach, lungs, salivary glands that have accumulated B cells in response to chronic infections or autoimmunity. The most common site is stomach. Bone marrow (BM) and peripheral lymph node involvement is rare. Patients with SMZL, present with splenomegaly, abdominal lymphadenopathy (LAP) and cytopenia due to BM involvement. Patients with NMZL have lymphnode-based disease and spleen or extranodal sites have not been affected [7].
NMZL has worse prognosis than EMZL and SMZL [8]. Treatment options depends on disease subtypes, localization of involvement and symptoms [9]. Some patients can be followed with watch-and-wait principle where as some require treatment during follow-up period. Recurrence usually occurs within 5 years after treatment [10].
As it is a rare disease group, the prognostic factors of MZL have been studied in small cohorts [11].
Although studies have determined factors such as age, serum lactate dehydrogenase (LDH), B symptoms, and beta 2 microglobulin to be associated with prognosis or OS of the disease, the results are heterogeneous [9]. Parameters predicting the need for treatment are still unclear. Therefore, in the current study, the impact of parameters on the course of disease and need for treatment was analysed in patients with MZL. Statistical analysis SPSS Statistics 20 software (IBM, Armonk, NY, USA) was used for statistical analysis. Descriptive data were given as a percentage. The Independent Samplest-test (t-table value) was used to compare two independent groups with normal distribution and the Mann-Whitney U-test (Z-table value) was used for data not showing normal distribution. χ 2 -cross tables were used to detect the relationship between qualitative variables. Only signi cant statistical variables in univariate analysis were included in the multivariate Cox regression model. Two-sidedp-values < 0.05 were considered statistically signi cant. Receiver operating characteristic curve (ROC) and area under the curve (AUC) analysis were used to determine the cut-off value of ferritin to assess its relationship with survival. Survival was estimated from Kaplan-Meier curves. OS was calculated from the time of diagnosis to death or until the nal visit.

Material And Methods
Comparisons between patient groups were made using the log-rank test.

Ethical approval and informed consent
All procedures performed in this study were conducted in accordance with the ethical standards of the institutional and / or national research committee and the 1964 Declaration of Helsinki and its subsequentamendments or comparable ethical standards. Patient records from Ankara Diskapi Yildirim Beyazit and Gulhane Training and Research Hospitals con rmed that all patients gave informed consent before hospitalization and prior to chemotherapy and for other relevant diagnostic / therapeutic procedures.

Results
Evaluation was made of 40 MZL patients, comprising 25 (62.5%) females and 15 (37.5%) males with a mean age of 64.13 ± 10.39 years. The demographic and clinical characteristics of the patients are shown in Table 1. The total follow-up period was mean 19.6 months (range, 0.1-92.9 months). During the follow-up period, 25 patients required treatment and 15 patients were followed up without treatment. The median TTD was 29.9 months (range,13.7-30.9 months). In the comparison of treated and untreated patients, there was a signi cant difference in respect of platelet count. The initial platelet count of patients who received treatment was signi cantly lower than untreated patients (p = 0.040). Table 2 shows the comparisons of these two groups. Logistic regression analysis was performed and platelet count was found to be an independent risk factor for treatment need (OR: 0.93, 95% CI: 0.87-0.99, p = 0.029) ( Table 3). According to receiver operating characteristics (ROC), the platelet cut-off value was determined as 148500x10 6 /L with 80.0% sensitivity and 52% speci city (AUC = 0.703; p < 0.05).  According to the survival analysis, the median OS of all MZL patients was 58.4 months (range, 53.5-95.9 months). A statistically signi cant difference was found in terms of OS according to diagnostic subtypes (p = 0.009). OS was signi cantly higher in patients with nodal MZL than in extranodal and splenic MZL patients (Table 4). There was no signi cant effect on OS of age, gender, IPI score, hemogram parameters including hemoglobin, platelet count, WBC, neutrophil count, lymphocyte count, and monocyte count. The OS of patients who received treatment was mean 92.9 months and for untreated patients it was 58.4 months, with no signi cant difference determined between the groups (p < 0.05)

Discussion
Factors that may affect the need for treatment, prognosis and survival of MZL patients have been investigated for many years [1,9].
Since MZL has indolent low grade lymphoma like follicular lymphoma, the need for treatment can be determined according to the Groupe pourl'Etude de Lymphome Folliculaire (GELF) criteria. GELF recommends treatment for patients with involvement of ≥ 3 nodal sites, eachwith a diameter of ≥ 3 cm, any nodal or extranodal tumor mass with a diameter of ≥ 7 cm, B symptoms, splenomegaly, pleural effusions or peritoneal ascites, or cytopenia [12], [13]. Therefore, some MZL patients require treatment where as others are followed up without treatment. The parameters, especially at the time of diagnosis, which can predict the need for treatment during follow-up are still unclear. Mayer et al determined that age, serum LDH, a high IPI score and transformation into aggressive lymphoma are independent risk factors for reduced OS in MZL [14]. In the current study, it was demonstrated that an initial lower platelet count is a predictive parameter for the need for treatment. However, no signi cant relationship was found between platelet count and OS.
Previous studies have reported that platelet count was prognostic for some hematological malignancies, such as splenic marginal zone lymphoma and acute lymphoblastic leukemia [15,16]. Bone marrow in ltration, the side-effects of drugs, splenic sequestration, or infections may be the cause of thrombocytopenia in lymphoma [17]. A previous study showed that thrombocytopenia was an independently poor prognostic factor of OS and progression-free survival in patients with diffuse large Bcell lymphoma [18].
Another current study reported that SMZL patients with anemia, hypoalbuminemia, International Prognostic Index (IPI) scores of 2 to 3, higher LDH levels, age > 60 years and platelet counts < 100000/L, had required treatment [19]. In the current study, there was no correlation between Hb, IPI, LDH levels, and the age of receiving treatment.
From a scan of literature, it can be seen that the survival rate of extranodal MZL is higher. A previous study determined that prognosis was signi cantly better for patients with extranodal MZL [8]. Mazloom et al reported that splenic MZL patients had the best prognosis in a study of 275 MZL patients [20].
Unlike these ndings in literature, the results of the current study determined the OS of nodal MZL to be higher than that of extranodal and splenic MZL.
Limitations of this study were the retrospective design and low number of patients. In addition, the prognostic impact of molecular/genetic characteristics and pathological features was not evaluated due to unavailable data. Therefore, larger prospective studies are needed to con rm the prognostic factors.
In conclusion, platelet count was identi ed as a risk factor for the need for treatment. Platelet count at diagnosis is an objective and simple blood test that may be helpful to predict the course of the disease, although further studies are warranted.