Extranodal Marginal Zone Lymphoma of the Central Nervous System

Extranodal marginal zone lymphoma of the central nervous system (CNS EMZBL) is a rare disease. We present a review of the literature and describe its presentation, differential diagnosis, treatment options, and outcomes. Systematic search of PubMed, Medline, and Embase databases via the Ovid engine for primary articles and case reports yielded 37 unduplicated peer-reviewed articles of CNS EMZBL. We identified 69 cases in these articles and 1 unreported case at our institution, which were included for this review's analysis. Median age at diagnosis was 55 years (range, 18-78 years), with a female preponderance of 77% (n = 54). Most common presenting symptoms were headache in 43% (n = 30), seizures in 31% (n = 22), and visual defects in 27% (n = 19). The most common treatment modalities were localized therapies, which were provided to 67% (n = 47) of cases. These included radiotherapy in 27% (n = 19), radiotherapy with surgery in 24% (n = 17), and surgery alone in 16% (n = 11). Ninety percent (n = 63) of patients had a median follow-up of 23 months. Complete remission was experienced by 77% (n = 49) patients, and 22% (n = 14) were alive with disease. Three patients had evidence of relapse, and one patient died. CNS EMZBL is an indolent, low-grade, radiosensitive lymphoma with good treatment outcomes and prognosis. It is an important differential to consider in extra-axial dural-based masses. Individualized management plans, with preference given to localized treatment options, should be considered after factoring in the site and extent of disease, its resectability, and the expected adverse effects of systemic therapy.     

Results of Upfront Therapy for Marginal Zone Lymphoma

BackgroundMarginal zone lymphomas (MZLs) are indolent disorders composed of 3 subtypes: extranodal marginal zone lymphoma (MALT), splenic marginal zone lymphoma (SMZL), and nodal marginal zone lymphoma (NMZL). Early-stage MALT is treated with radiotherapy or antibiotics, and advanced MALT and NMZL are managed with either watch and wait or chemotherapy. SMZLs are treated with splenectomy or rituximab. However, because these approaches have failed to cure patients with SMZL and NMZL, we have systematically used upfront chemotherapy for them, as well as for advanced MALT. We report the outcomes of this approach.Patients and MethodsA total of 44 patients with MZL were identified from our database and divided into 2 groups. Group 1 (22 with early-stage MALT) patients received either radiotherapy (n = 17) or antibiotics with or without surgery (n = 5). Group 2 included 9 patients with advanced MALT, 9 with SMZL, and 4 with NMZL. Group 2 was treated with FND-R (fludarabine 25 mg/m² on days 1 to 3, mitoxantrone 10 mg/m² on day 1, dexamethasone 20 mg on days 1 to 5, and rituximab 375 mg/m² on day 1; n = 14) or CHOP-R (cyclophosphamide 750 mg/m² on day 1, doxorubicin 50 mg/m² on day 1, vincristine 2 mg intravenous push on day 1, prednisone 100 mg/m² orally on days 1 to 5, rituximab 375 mg/m² on day 1; n = 8), followed by maintenance rituximab for 70%.ResultsAll patients achieved complete remission, and only 2 patients in group 1 had developed a relapse at 70 and 75 months. Both relapses were stage I MALT that had initially been treated with radiotherapy. Both were salvaged with FND-R and remained free of disease at 27 and 39 months after the relapse. At 10 years, the failure-free survival for the 44 patients was 80% and the overall survival was 100%. None of the patients in group 2 developed a relapse. The long-term toxicities have been acceptable.ConclusionsThe excellent responses using upfront chemotherapy for MZL suggests that this disorder is curable. Our results should be confirmed in a prospective trial.     

Treatment of Splenic Marginal Zone Lymphoma With Rituximab Monotherapy: Progress Report and Comparison With Splenectomy

Background.

Treatment of splenic marginal zone lymphoma (SMZL) patients is not standardized. Recent data suggest that rituximab is highly effective and could be considered as initial therapy.

Aim.

To assess the efficacy of rituximab monotherapy in a large series of patients with SMZL and compare these results with splenectomy results.

Methods.

The studied population included 85 patients. Fifty-eight received rituximab at a dose of 375 mg/m² per week for 6 weeks as induction followed by maintenance at the same dose every 2 months for 1–2 years, whereas 27 patients were treated using splenectomy only.

Results.

The overall response rate to rituximab 2 months after the end of induction was 95% (complete response [CR], 45%; unconfirmed CR, 26%; partial response, 24%). The median times to hematologic and clinical response were 2 weeks and 3 weeks, respectively. Forty-three of 55 patients already completed the maintenance phase: 28 sustained their initial response, 14 improved their response, and one progressed. Eighty-five percent of splenectomized patients responded, and two were treated with rituximab as consolidation after splenectomy and achieved a CR. The 5-year overall and progression-free survival (PFS) rates for rituximab-treated and splenectomized patients were 92% and 77% (p = .09) and 73% and 58% (p = .06), respectively. Furthermore, maintenance therapy with rituximab resulted in a longer duration of response (at 5 years, PFS was 84% for patients receiving maintenance and 36% for patients without maintenance, p <.0001).

Conclusions.

Rituximab is a very effective and well-tolerated therapy and may be substituted for splenectomy as the first-line treatment of choice for patients with SMZL.     

Molecular Genetics of Extranodal Marginal Zone (MALT-Type) B-Cell Lymphoma

Mucosa-associated lymphoid tissue lymphoma is now classified as extranodal marginal zone B-cell lymphoma. We reviewed the current literature on the biological and genetic mechanisms that lead to the development and progression of this unusual lymphoma. Particular attention was given to the clinical and biological significance of the immunoglobulin genes rearrangement, that has been proposed and widely used both diagnostically and as a tool to monitor the response to antibiotic treatment.     

A retrospective international study on primary extranodal marginal zone lymphoma of the lung (BALT lymphoma) on behalf of International Extranodal Lymphoma Study Group (IELSG)

Primary lymphoma of the lung is a rare entity. Clinical features, optimal treatment, role of surgery and outcomes are not well defined, and the follow‐up is variable in published data. Clinical data of 205 patients who were confirmed to have bronchus mucosa‐associated lymphoid tissue lymphoma from December 1986 to December 2011 in 17 different centres worldwide were evaluated. Fifty‐five per cent of the patients were female. The median age at diagnosis was 62 (range 28–88) years. Only 9% had a history of exposure to toxic substances, while about 45% of the patients had a history of smoking. Ten per cent of the patients had autoimmune disease at presentation, and 19% patients had a reported preexisting lung disease. Treatment modalities included surgery alone in 63 patients (30%), radiotherapy in 3 (2%), antibiotics in 1 (1%) and systemic treatment in 128 (62%). Patients receiving a local approach, mainly surgical resection, experienced significantly improved progression‐free survival (p = 0.003) versus those receiving a systemic treatment. There were no other significant differences among treatment modalities. The survival data confirm the indolent nature of the disease. Local therapy (surgery or radiotherapy) results in long‐term disease‐free survival for patients with localized disease. Systemic treatment, including alkylating‐containing regimens, can be reserved to patients in relapse after incomplete surgical excision or for patients with advanced disease. Copyright © 2015 John Wiley & Sons, Ltd.     

Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Splenic Marginal Zone Lymphoma

IntroductionSplenic marginal zone lymphoma (SMZL) is an indolent non-Hodgkin lymphoma usually with a good prognosis, but no clear metabolic behavior at fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT). The aim of our analysis was to investigate the prognostic role of baseline 18F-FDG PET/CT parameters in SMZL.Materials and MethodsWe retrospectively included 42 patients who received 18F-FDG-PET/CT before any treatments, and PET images were evaluated visually and semi-quantitatively by measuring lesion to liver (L-L) maximum standardized uptake volume (SUVmax) ratio (L-L SUV R), lesion to blood-pool SUVmax ratio (L-BP SUV R), metabolic tumor volume, and total lesion glycolysis. Progression-free (PFS) and overall survival (OS) curves were plotted according to the Kaplan-Meier method.ResultsIn all patients, an increased splenic FDG uptake (higher than the background) was identified, showing the presence of diffuse spleen uptake in 35 patients and focal uptake in the remaining 7 patients. At a median follow-up of 51 months, relapse or progression of disease occurred in 23 patients with an average time of 38.1 months from the baseline 18F-FDG PET/CT, and death occurred in 4 patients with an average time of 26.8 months. The estimated 2-year PFS and OS rates were 78% and 90%, respectively, whereas 5-year PFS and OS rates were 63% and 82%, respectively. At multivariate analysis, only L-L SUV R and L-BP SUV R were independent prognostic factors for PFS. In addition, no significant association was discovered for OS, considering all features.ConclusionsL-L SUV R and L-BP SUV R were independently correlated with PFS.     

Repertoire of Rearranged Immunoglobulin Heavy Chain Genes in Russian Patients With B-Cell Lymphoproliferative Diseases

IntroductionImmunoglobulin heavy chain variable region (IGHV) repertoire narrowing could be an evidence for the involvement of a limited set of antigens in the development of lymphomas. For chronic lymphocytic leukemia (CLL) the existence of more than 200 subgroups of tumor IGHV antigen-binding sites, so called “stereotypical” antigen receptors (SAR) has been shown. For others lymphomas the possibility of SARs is also suggested. The aim of this study is to compare the tumor IGHVs and possible SARs in various B-cell malignancies in Russia and other countries.Materials and MethodsThe study included samples of 1800 CLL patients, 52 patients with mantle cell lymphoma, 48 patients with hairy cell lymphoma and 37 patients with splenic marginal cell lymphoma. The nucleotide sequences of the IGHV genes were determined according to ERIC protocol.ResultsIn CLL most common IGHV genes were IGHV1-69, IGHV1-2, IGHV3-30 and IGHV4-34. The most common SARs were CLL#1, CLL#6, CLL#2, CLL#3. In MCL the most common genes were IGHV4-34, IGHV3-21, IGHV3-23. In 5 MCL patients CDR3 sequences were identified matching definitions of a stereotyped. In the half of SMZL patients was identified gene IGHV1-2. Other IGHV genes were much less common. Two pairs of SMZL patients have motives similar to each other. In HCL IGHV repertoire was the most variable, no trends for antigen receptor stereotypy were observed. It was found that SARs are highly disease-specific both at the level of nucleotide and amino acid sequences.ConclusionOur results suggest that antigens crucial for the pathogenesis of B-cell malignancies could be disease-specific. Further studies on extended samples of non-CLL patients concerning the role of SARs in pathogenesis of these diseases may also contribute to the development of new diagnostic and prognostic markers.     

Clinical Characteristics of 95 Patients With Ocular Adnexal and Uveal Lymphoma: Treatment Outcomes in Extranodal Marginal Zone Subtype

BackgroundLymphoma rarely presents in the ocular adnexa but is usually extranodal marginal zone (ENMZ) lymphoma when it does. Involved-field radiotherapy (IFRT) is the standard of care for unilateral disease, but the optimal management of more extensive disease is unclear.Patients and MethodsWe retrospectively evaluated the clinical characteristics and outcomes of 95 patients with ocular adnexal lymphoma (OAL) or uveal lymphoma treated or diagnosed at our institution. All patients identified were included in the risk factor analysis for progression-free survival (PFS). The initial treatment-related outcomes were assessed for ENMZ OAL only (n = 62).ResultsWith a median follow-up of 32 months, significant risk factors for PFS after initial treatment were age (hazard ratio, 1.33; 95% confidence interval, 1.02-1.74), female gender (hazard ratio, 2.04; 95% confidence interval, 1.04-4.00), and a history of lymphoma (hazard ratio, 2.31; 95% confidence interval, 1.12-4.78). In ENMZ, IFRT was associated with improved PFS (median, 5.4 years; P < .001). Progression occurred in 7 of 39 (23%), with 6 of the 7 (86%) at systemic sites. Single-agent rituximab was typically used for bilateral ocular or systemic presentations of ENMZ OAL. Progression occurred in 7 of 11 (64%), with no progression at systemic sites. All progression events in those initially treated with rituximab occurred in the ocular adnexa.ConclusionThe results of the present study have confirmed IFRT as the standard for unilateral ENMZ OAL. Single-agent rituximab was an effective agent for bilateral ocular or systemic ENMZ OAL, particularly for systemic control, but ocular progression should be closely monitored. Combined modality therapy should be studied further in bilateral and systemic ENMZ OAL.     

Mantle Cell Lymphoma: An Update

Mantle cell lymphoma is a distinctive pathologic entity that incorporates the previous histopathologic categories of centrocytic lymphoma and lymphocytic lymphoma of intermediate differentiation. These lymphomas are characterized by common histologic and immunologic characteristics that suggest derivation from the follicular mantle zone. Mantle cell lymphomas are characterized by the t(11;14) (q13;q32) translocation and its molecular counterpart bcl-1 rearrangement. This translocation activates a gene called BCL-1/PRAD-1. The identification of the BCL-1 gene product as a cyclin has added a new dimension to our understanding of the variety of mechanisms involved in lymphomagenesis.     

Chemoimmunotherapy for Mucosa‐Associated Lymphoid Tissue‐Type Lymphoma: A Review of the Literature

Background.

Biological treatments, chemoimmunotherapy, and radiotherapy are associated with excellent disease control in both gastric and extragastric mucosa-associated lymphoid tissue (MALT) lymphomas. Systemic treatment approaches with both oral and i.v. agents are being increasingly studied, not only for patients with disseminated MALT lymphoma, but also for those with localized disease. To date, however, recommendations for the use of available systemic modalities have not been clearly defined.

Materials and Methods.

The present report reviews the current data on systemic treatment options for patients with MALT lymphoma and provides recommendations for their use in everyday practice.

Results.

Different chemotherapeutic agents, including anthracyclines, alkylators, and purine analogs, have been successfully tested in patients with MALT lymphoma. Reducing side effects while maintaining efficacy should be the main goal in treating these indolent lymphomas. From the data from the largest trial performed to date, the combination of chlorambucil plus rituximab (R) appears to be active as first-line treatment. Similarly, R-bendamustine also seems to be highly effective, but a longer follow-up period is needed. R-monotherapy results in lower remission rates, but seems a suitable option for less fit patients. New immunotherapeutic agents such as lenalidomide (with or without rituximab) or clarithromycin show solid activity but have not yet been validated in larger collectives.

Conclusion.

Patients with MALT lymphoma should be treated within prospective trials to further define optimal therapeutic strategies. Systemic treatment is a reasonable option with potentially curative intent in everyday practice. Based on the efficacy and safety data from available studies, the present review provides recommendations for the use of systemic strategies.

Implications for Practice:

In view of the biology of MALT lymphoma with trafficking of cells within various mucosal structures, systemic treatment strategies are increasingly being used not only in advanced but also localized MALT lymphoma. In the past, different chemotherapeutic agents, including anthracyclines, alkylators, and purine analogs, have been tested successfully. However, modern regimens concentrate on reducing side effects because of the indolent nature of this distinct disease. As outlined in this review and based on recent data, chlorambucil plus rituximab (R) may be considered one standard treatment within this setting. In addition, R-bendamustine seems to be a very promising combination. According to recent trends, however, “chemo-free” approaches (i.e., antibiotics with immunomodulatory effects [clarithromycin]) or other immunotherapies (lenalidomide ±R) may be important therapeutic approaches in the near future.     

Extranodal marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue arising in the lateral ventricle

Extranodal marginal zone B-cell lymphomas of mucosa-associated lymphoid tissue (MALT) lymphomas are a well-described type of low-grade B-cell non-Hodgkin lymphoma. They typically arise adjacent to mucosal surfaces in the gastrointestinal tract, lung and conjunctiva, and, less frequently, in the skin, salivary gland and thyroid gland. Unusual locations, such as the genitourinary tract, thymus and meninges, have also been reported. We recently encountered a case of an intracranial MALT lymphoma in a 53-year-old man who presented with persistent headaches and a seizure. The lesion developed as a mass within the lateral ventricle, appeared to be arising from the choroid plexus, and was not associated with meninges. Histologically, there was a vaguely nodular, dense lymphoid infiltrate with occasional benign follicles colonized by marginal zone lymphoma, suggesting derivation from a focus of prior inflammation. Translocations involving the MALT1 gene were not identified but karyotypic evaluation highlighted a complex cytogenetic profile with many chromosomal abnormalities. This rare case provides insight into the pathophysiology of MALT lymphomas.     

Primary lymphoblastic B-cell lymphoma of the cranial dura mater: a case report and review of the literature

Primary lymphomas of the cranial dura mater are rare. Mucosa-associated lymphoid tissue extranodal marginal zone lymphomas are the most common subtype of non-Hodgkin's lymphomas that present as primary cranial dura tumors. A 33 year-old male presented with a 3-month history of a growing lump in the right frontal area. Neuroimaging studies demonstrated an extra-axial, broad-based mass with a dural tail in the right frontal bone convexity. Biopsy led to the diagnosis of localized dural precursor B-cell lymphoblastic lymphoma. The patient was treated with a combination of chemotherapy and radiotherapy, achieving durable disease-free survival. This is the first report of precursor B-cell lymphoblastic lymphoma of dura mater. A review of the literature on primary lymphomas of cranial dura mater is presented.     

Regression of pulmonary MALT lymphoma after treatment with rituximab

We describe a patient with extranodal (pulmonary) marginal zone B-cell lymphoma of mucosa-associated lymphoid tissue (MALT) who was refractory to treatment with cytotoxic chemotherapy. After a single four-week course of rituximab she had significant regression of pulmonary lesions and remains progression free 19 months after finishing her treatment. This case report demonstrates the potential efficacy of rituximab as a single therapeutic agent in patients with pulmonary MALT lymphoma.     

R-CHOP方案治疗脾边缘区B细胞淋巴瘤一例并文献复习

  目的　探讨老年脾边缘区淋巴瘤（SMZL）患者的最佳治疗途径。方法　对R-CHOP方案治疗的1例SMZL进行病例分析并复习相关文献。结果　患者经2个周期R-CHOP方案化疗达完全缓解,原方案巩固治疗4个周期,序贯利妥昔单抗维持治疗2年,病情仍呈缓解状态。几项回顾性研究显示利妥昔单抗治疗SMZL 3年无进展生存（PFS）明显优于单纯脾切除及单用化疗。结论　利妥昔单抗联合或不联合化疗,可能成为老年初治SMZL患者的最佳选择,脾切除联合利妥昔单抗适合单抗治疗无效的患者。     

Primary Cutaneous B‐Cell Lymphoma: Management and Patterns of Recurrence at the Multimodality Cutaneous Lymphoma Clinic of The Ohio State University

Background.

The increasing incidence of primary cutaneous B-cell lymphomas (PCBCLs) presents new challenges for clinicians. Despite advances in the clinical and pathologic characterization of PCBCL, the significance of the current staging approach as a risk profiling tool and the effect of various treatments on outcome remain unclear.

Materials and Methods.

We retrospectively reviewed patients who presented with a diagnosis of PCBCL seen at The Ohio State University between 1998 and 2012. We reviewed the initial presentation and treatment modality. We then assessed whether the treatment modality (conservative skin-directed vs. definitive radiation with or without systemic therapy), stage (T1 or ≥T2), or histologic subtype (primary cutaneous follicle center lymphoma [PCFCL] vs. primary cutaneous marginal zone B-cell lymphoma [PCMZL]) affected the risk of recurrence.

Results.

We identified 67 patients referred with an initial diagnosis of PCBCL. After imaging, 12 did not meet the criteria for PCBCL and were classified as having systemic B-cell lymphoma with cutaneous involvement. The remaining 55 patients included 25 with PCMZL, 24 with PCFCL, 2 with primary cutaneous large B-cell lymphoma leg type, and 4 with unclassifiable disease. According to the International Society of Cutaneous Lymphoma-European Organization for Research and Treatment of Cancer staging, 30 cases were T1 (55%), 14 T2 (25%), and 11 T3 (20%). Comparing the time to first recurrence (TFR) by indolent PCBCL subtypes, we found no difference in the recurrence risk for either stage (T1, p = .51 vs. T2/T3, p = .30). Comparing TFR by treatment modality, we found no difference in TFR within T1 patients (p = .34) or T2/T3 patients (p = .44).

Conclusion.

Our limited analysis highlights the importance of complete staging at diagnosis and suggests that the treatment modality does not affect the risk of recurrence in T1 indolent PCBCL.

Implications for Practice:

Primary cutaneous B-cell lymphoma (PCBCL) is a rare malignancy with an increasing incidence. Clinicians must recognize the importance of a complete workup to accurately diagnose PCBCL, given the effect on prognosis and treatment. It was observed that nearly 20% of the patients who presented initially with cutaneous B-cell lymphoma were classified as having systemic B-cell lymphoma after whole body imaging. The findings from the present retrospective analysis of a single-institution cohort suggest that for early-stage indolent PCBCL, no front-line treatment strategy that decreases the risk of recurrence is obvious. No difference in the risk of recurrence between conservative skin-directed and other therapies was observed. These data support a continued need to compare front-line treatment therapies.     

Rituximab monotherapy is highly effective in splenic marginal zone lymphoma

Splenectomy has traditionally been considered as a standard first line treatment for splenic marginal zone lymphoma (SMZL) conferring a survival advantage over chemotherapy. However it carries significant complications, especially in elderly patients. The purpose of this retrospective study was to report our experience on the efficacy of Rituximab as first line treatment in 16 consecutive SMZL patients, diagnosed in our department. The diagnosis was established using standard criteria. Patients' median age was 57 years (range, 48-78). Prior to treatment initiation all patients had splenomegaly, nine had anemia, five lymphocytosis, five neutropenia and six thrombocytopenia. Rituximab was administered at a dose of 375 mg/m2/week for 6 consecutive weeks. The overall response rate was 100%. After treatment, all patients had a complete resolution of splenomegaly along with restoration of their blood counts. Eleven patients (69%) achieved a CR, three (19%) unconfirmed CR and two (12%) a PR. Among the complete responders seven patients had also a molecular remission. The median time to clinical response was 3 weeks (range, 2-6). Rituximab maintenance was given to 12 patients. Eleven of them had no evidence of disease progression after a median follow-up time of 28.5 months (range, 14-36), while two out of four patients who did not receive maintenance, relapsed 7 and 24 months after the completion of induction treatment. Median follow-up time for the entire series was 29.5 months (range, 15-81). No deaths were recorded during the follow-up period. Therapy was well tolerated. The present study demonstrates that rituximab is an effective treatment for SMZL and could be considered as a substitute or alternative to splenectomy.     

Bendamustine-rituximab regimen in untreated indolent marginal zone lymphoma: experience on 65 patients

First line therapy of patients with marginal zone lymphomas (MZL) is not well established and various regimens with chemo-immunotherapy can be used. Rituximab plus bendamustine (BR) is an effective and manageable treatment option for patients affected by indolent non-Hodgkin lymphoma. The aim of this monocentric retrospective study was to analyze the effectiveness and safety of the use of BR regimen in MZL patients in first line in daily clinical practice. The treatment schedule was rituximab at the dose of 375 mg/m² on day 1 of each cycle and bendamustine at the dose of 90 mg/m² on day 2 and 3, every 28 days for a maximum of 6 cycles. We analyzed 65 MZL patients (28 extranodal [EMZL], 23 splenic [SMZL], and 14 nodal [NMZL]) who underwent BR regimen as first line treatment. The median time from diagnosis to therapy was 2.5 months. Final responses were: 38 complete response (CR, 58.5%), 20 partial response and 7 progressive disease, leading to an overall response rate (ORR) of 89.2%. With respect to the histology, the ORR was 89.3% for EMZL, 82.6% for SMZL and 100% for NMZL, respectively (difference not statistically significant). With a median follow-up time of 44.6 months (range, 3.3-175.0 months), 2 (one EMZL after 42 months and one SMZL after 10 months) of 38 (5.2%) CR patients had disease relapse, yielding an estimated disease free survival of 89.2% at 61.1 months. The estimated 6-year progression free survival was 71.8% with 15 relapsed/progressed patients showing lymphoma recurrence within 48 months from end of treatment. The most frequently reported adverse events (any grade) were neutropenia (N = 35, 53.8%), fatigue (N = 15, 23.0%), and nausea (N = 12, 18.4%). All toxicities quickly resolved and no treatment-related death occurred. The BR regimen is effective and feasible in MZL patients inducing prolonged disease control with manageable toxicities.