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Nodal marginal zone lymphoma

Nodal marginal zone lymphoma
Literature review current through: Jan 2024.
This topic last updated: Dec 04, 2023.

INTRODUCTION — Nodal marginal zone lymphoma (NMZL) is an uncommon subtype of non-Hodgkin lymphoma. NMZL is a primary nodal lymphoma with histologic features identical to lymph nodes involved by extranodal marginal zone lymphoma or splenic marginal zone lymphoma, but without prominent extranodal or splenic disease.

The epidemiology, pathogenesis, clinical features, pathology, and diagnosis of NMZL will be discussed here. Extranodal marginal zone lymphoma, splenic marginal zone lymphoma, and primary cutaneous marginal zone lymphoma are discussed separately.

(See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

(See "Splenic marginal zone lymphoma".)

(See "Primary cutaneous marginal zone lymphoma".)

(See "Treatment of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT lymphoma)".)

PATHOGENESIS — NMZL is postulated to originate from nodal marginal zone B cells [1]. The pathogenesis is incompletely understood but acquired mutations in oncogenes and tumor suppressor genes are involved. Gene sequencing has revealed recurrent mutations in KMT2D (previously known as MLL2), PTPRD, NOTCH2, and KLF2 [2].

While some studies have suggested an association between NMZL and infectious and autoimmune disorders, this association is not as well established as it is for extranodal marginal zone lymphoma and splenic marginal zone lymphoma. Epidemiologic studies have identified an association between hepatitis C virus infection and NMZL [3,4].

EPIDEMIOLOGY — NMZL is the least common of the marginal zone lymphomas and accounts for approximately 1 percent of non-Hodgkin lymphomas [5]. The incidence is approximately six cases per million person-years overall and increases from <1 per million for persons <40 years of age to >10 per million for persons >60 years of age [5]. Median age at diagnosis is approximately 70 years. There is a slight male predominance in most series. The incidence is highest among non-Hispanic White individuals and lowest among Black individuals [5].

Pediatric NMZL is a distinct entity with an excellent prognosis that typically presents with asymptomatic localized disease involving the lymph nodes of the head and neck [6].

CLINICAL PRESENTATION — The clinical presentation of NMZL is nonspecific and highly variable. Most patients with NMZL present with painless peripheral adenopathy in the cervical, axillary, inguinal, and/or femoral regions [7]. Staging studies often demonstrate widely disseminated (stage III or IV) nodal involvement. Up to one-third have tumors >5 cm (ie, bulky disease). Bone marrow is involved in 30 to 60 percent; rarely, circulating tumor cells are seen in the peripheral blood [8-10]. The spleen and other extranodal tissues are not usually involved at presentation; however, spread to these sites may be seen in individuals with widespread nodal disease.

Despite widespread involvement, most patients with NMZL are asymptomatic at diagnosis. The following are present in a minority of patients [7]:

B symptoms (ie, fevers, night sweats, or unintentional weight loss) – 10 to 20 percent

Anemia – 25 percent

Thrombocytopenia – 10 percent

Elevated lactate dehydrogenase – 12 to 48 percent

Increased beta-2 microglobulin – 29 to 45 percent

Monoclonal immunoglobulin – 6 to 33 percent

Systemic B symptoms and elevations in lactate dehydrogenase should lead to a more detailed investigation for large cell transformation. (See 'Histologic transformation' below.)

While variable, the majority of NMZL appear to be fluorodeoxyglucose (FDG)-avid on positron emission tomography (PET) [11,12].

PATHOLOGIC FEATURES — NMZL is a primary nodal lymphoma that is recognized as a distinct entity in both the World Health Organization Classification of Lymphoid Neoplasms, 5th Edition [13] and the International Consensus Classification of Lymphoid Neoplasms [14]. The spleen and other extranodal tissues are not usually involved at presentation; however, spread to these sites may be seen in individuals with widespread nodal disease. The cellular morphology and growth pattern vary, and the pathologic features must be interpreted within the context of clinical features.

Two morphologic types have been described [15,16]:

Cases resembling extranodal marginal zone lymphoma that are characterized by the presence of aggregates of "monocytoid" B cells with abundant pale cytoplasm in a parafollicular, perivascular, and perisinusoidal distribution. These cases do not express immunoglobulin D (IgD) and have an immunophenotype identical to those of extranodal marginal zone lymphoma [17]. (See "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

Cases resembling splenic marginal zone lymphoma that have infiltrates of tumor cells surrounding reactive-appearing germinal centers with attenuated mantle zones [17]. These cases typically express IgD and lack CD5, CD23, CD43, and cyclin D1. (See "Splenic marginal zone lymphoma", section on 'Pathologic features'.)

Gene sequencing has revealed mutations in several genes that are also recurrently mutated in splenic marginal zone lymphoma including KMT2D (previously known as MLL2), NOTCH2, and KLF2 [2]. PTPRD is mutated in up to 20 percent of NMZL and is not mutated in splenic marginal zone lymphoma. One series also identified BRAF V600E mutations in 4 of 25 nodal marginal zone lymphomas [18], a finding of potential therapeutic importance because of the availability of BRAF inhibitors.

DIAGNOSIS AND DIFFERENTIAL DIAGNOSIS — The diagnosis of NMZL is usually suspected in a patient with painless lymphadenopathy. The diagnosis is best made by excisional lymph node biopsy followed by further evaluation to exclude extranodal marginal zone lymphoma, splenic marginal zone lymphoma, and other entities that resemble NMZL. A directed evaluation of extranodal sites should be performed to exclude primary extranodal disease. This is described in more detail as part of the pretreatment evaluation. (See 'Pretreatment evaluation' below.)

NMZL is a primary nodal lymphoma; the clinical presentation is a key part of making the diagnosis and excluding extranodal marginal zone lymphoma and splenic marginal zone lymphoma. The spleen and other extranodal tissues are not usually involved in NMZL at presentation; however, spread to these sites may be seen in individuals with widespread nodal disease. In some instances, it may be unclear exactly where the disease originated. A diagnosis of NMZL is favored if there is widespread nodal involvement, even in the setting of splenic enlargement and/or minimal extranodal involvement. In contrast, extranodal marginal zone lymphoma is favored when the extranodal involvement is prominent and nodal involvement is localized.

It is unclear whether marginal zone lymphoma of Waldeyer's ring should be classified as NMZL or extranodal marginal zone lymphoma. The diagnoses of splenic marginal zone lymphoma and extranodal marginal zone lymphoma are presented separately. (See "Splenic marginal zone lymphoma" and "Clinical manifestations, pathologic features, and diagnosis of extranodal marginal zone lymphoma of mucosa associated lymphoid tissue (MALT)".)

The diagnosis of NMZL should not be made when areas consistent with another low-grade B cell lymphoma (follicular lymphoma, mantle cell lymphoma) are present in the same node. Most cases with histologic features of both NMZL and another low-grade lymphoma appear to stem from the focal differentiation of another lymphoma (usually follicular lymphoma) to marginal zone B cells or monocytoid B cells. Thus, such cases do not represent true biclonal "composite" lymphomas and should be diagnosed as a single lymphoma (most commonly follicular lymphoma) other than NMZL [19].

Other B cell neoplasms that may be confused with NMZL include those that are also composed mainly of small B cells (table 1):

Follicular lymphoma (FL) – NMZL can demonstrate a partially nodular pattern of growth that may resemble FL. NMZL can usually be differentiated from FL by immunophenotype since, unlike FL, marginal zone lymphoma does not usually express CD10 or BCL6. Also, FL is strongly associated with a (14;18) translocation involving the BCL2 gene that is not a feature of NMZL. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma".)

Mantle cell lymphoma (MCL) – MCL with a mantle zone pattern of growth may superficially resemble NMZL, but can be differentiated in most cases by immunophenotype, as MCL usually expresses CD5, SOX11, and cyclin D1, the latter due to the presence of a (11;14) translocation that is not seen in NMZL. (See "Mantle cell lymphoma: Epidemiology, pathobiology, clinical manifestations, diagnosis, and prognosis".)

Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL) – CLL/SLL is distinguished by expression of CD5 and by a diffuse growth pattern associated with proliferation centers, a feature that is not seen in NMZL. (See "Clinical features and diagnosis of chronic lymphocytic leukemia/small lymphocytic lymphoma".)

Lymphoplasmacytic lymphoma (LPL, also known as Waldenström macroglobulinemia [WM]) – The differentiation between nodal LPL and IgM-secreting NMZL is sometimes difficult as the immunohistochemical features of NMZL and LPL are similar. Although MYD88 mutations are seen in the vast majority of WM, they are not specific; MYD88 mutations can be seen in 5 to 10 percent of patients with NMZL. Clinically, NMZL is more likely to present with prominent lymphadenopathy, while LPL can exclusively affect the marrow without extramedullary involvement. IgM levels in NMZL tend to be lower than in LPL, typically lower than 1000 mg/dL. (See "Epidemiology, pathogenesis, clinical manifestations, and diagnosis of Waldenström macroglobulinemia".)

MANAGEMENT

Pretreatment evaluation — The pretreatment evaluation of a patient with NMZL is focused on determining the extent of disease and comorbidities that may impact on choice of therapy. In general, we perform the following examinations:

Physical examination with determination of the patient's performance status by the Eastern Cooperative Oncology Group (ECOG) or Karnofsky performance scales (table 2 and table 3).

Laboratory testing includes a complete blood count with differential and platelet count, chemistries with liver and renal function and electrolytes, lactate dehydrogenase, HIV, and hepatitis C virus serology. Patients should also be tested for hepatitis B virus prior to the use of rituximab therapy. Women of childbearing age should undergo a pregnancy test if chemotherapy or radiation therapy is planned.

Imaging should include a contrast-enhanced computed tomography (CT) scan of the chest, abdomen, and pelvis. The decision to include positron emission tomography (PET) is individualized. Studies evaluating the use of PET in marginal zone lymphoma have demonstrated variable fluorodeoxyglucose (FDG) avidity, although the sensitivity for detecting nodal involvement is high [11,12,20-24]. Combined PET/CT is more sensitive than CT alone, but false positive exams may be seen. Unlike in some other lymphoma subtypes, FDG PET/CT has a low sensitivity for identifying bone marrow involvement in NMZL. In a series of 61 patients with NMZL of whom 51 percent had pathologically confirmed bone marrow involvement, FDG PET/CT had the following test characteristics for identifying bone marrow involvement: sensitivity 39 percent, specificity 100 percent, positive predictive value 100 percent, negative predictive value 61 percent [25].

Stage is determined with the Lugano modifications to the Ann Arbor staging system (table 4). If clinical stage I or II disease is suspected, a bone marrow aspiration and biopsy should be performed to confirm limited disease.

In addition, for patients with localized nodal involvement, clinicians should have a high degree of suspicion for marginal zone lymphoma of an extranodal primary site that has spread to the lymph nodes:

Neck node involvement – Evaluate for ocular, parotid, thyroid, and salivary gland marginal zone lymphoma. A more detailed examination may be necessary in patients with Sjögren’s disease or Hashimoto thyroiditis because of the strong association between these disorders and extranodal marginal zone lymphoma [26,27].

Axillary node involvement – Evaluate for lung, breast, and skin marginal zone lymphoma.

Mediastinal or hilar node involvement – Evaluate for lung marginal zone lymphoma.

Abdominal node involvement – Evaluate for splenic and gastrointestinal marginal zone lymphoma.

Inguinal or iliac node involvement – Evaluate for gastrointestinal and skin marginal zone lymphoma.

Treatment

Goals of therapy — Patients with advanced (stage III or IV) NMZL are usually not cured with conventional treatment. While remissions can be attained, repeated relapses are common. Treatment focuses on the alleviation of symptoms, reversal of cytopenias, and improvement of quality of life. As such, asymptomatic patients often do not require immediate treatment but should be followed for the development of symptoms and progression of disease. This approach is similar to that used for other clinically indolent non-Hodgkin lymphomas such as follicular lymphoma. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Indications for treatment'.)

An important exception is the minority of patients who present with NMZL confined to a single lymph node or group of adjacent nodes (stage I); such patients may be candidates for radiation therapy administered with curative intent. (See "Initial treatment of stage I follicular lymphoma", section on 'Radiation therapy (RT)'.)

The prognosis of patients with NMZL is discussed separately. (See 'Prognosis' below.)

Choice of therapy — There is no single preferred therapy for NMZL, and we encourage patients to participate in trials, whenever possible. Most data come from retrospective studies and extrapolation of data from other common indolent lymphomas, such as follicular lymphoma. While patients with marginal zone lymphoma tend to respond to therapies used for other indolent lymphomas, some studies that have provided data for this subpopulation have noted differences in response rates and other clinically important outcomes, as described below. Until more data are available from trials limited to patients with marginal zone lymphoma, patients with marginal zone lymphoma not on a clinical trial are often treated in a similar fashion to those with the more common indolent lymphoma follicular lymphoma. The treatment of follicular lymphomas is discussed in more detail separately. (See "Initial treatment of stage I follicular lymphoma" and "Initial treatment of stage II to IV follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma".)

Our approach differs according to disease and patient factors:

For patients with NMZL limited to a single lymph node region, we suggest radiation therapy administered with curative intent (eg, 24 Gy to the involved site/node). (See "Initial treatment of stage I follicular lymphoma", section on 'Radiation therapy (RT)'.)

Management of more advanced stage disease usually includes immunotherapy with monoclonal antibodies directed at CD20 (eg, rituximab) with or without chemotherapy. The decision to use combination therapy (ie, chemotherapy plus rituximab) depends on the goals of therapy and patient values [28,29]; the addition of chemotherapy results in deeper responses and prolonged progression-free survival (PFS), but does not improve overall survival (OS) and is associated with increased toxicity.

Combination therapy may be preferred by patients who have more severely symptomatic bulky disease and those who place a high value on a longer treatment-free period. Others reserve chemotherapy for relapsed or refractory disease following single-agent rituximab. (See 'Incorporation of chemotherapy' below.)

Single-agent rituximab may be preferred by patients who are more mildly symptomatic and by those who place a high value on the avoidance of the short-term toxicities associated with chemotherapy. (See 'Single-agent rituximab' below.)

An initial trial of treatment directed at the hepatitis C virus (HCV) infection may be indicated for patients with HCV who are asymptomatic from their lymphoma and would otherwise not require the initiation of lymphoma-direct treatment. A number of reports, primarily from Europe, have described remissions following HCV treatment in some patients with indolent lymphoma, including marginal zone lymphoma [30]. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Patients with hepatitis C'.)

Relapsed disease is usually managed with the serial administration of systemic treatments (eg, rituximab, chemotherapy, targeted therapy [eg, BTK inhibitor, lenalidomide]). Prolonged disease-free survival (DFS) has been achieved after autologous hematopoietic cell transplantation in select patients. (See 'Targeted therapies (BTK inhibitors, lenalidomide)' below and 'Hematopoietic cell transplantation' below.)

Single-agent rituximab — Single-agent rituximab may be preferred by patients who are more mildly symptomatic and by those who place a high value on the avoidance of the short-term toxicities associated with chemotherapy. It is also an acceptable initial treatment for patients with comorbid conditions that make them poor candidates for combination therapy. Rituximab has a low toxicity profile and has been shown to delay disease progression in these populations.

Different schedules have been used. The following administration schedules were used in the randomized trials and are equally acceptable approaches:

Rituximab 375 mg/m2 intravenously per week for a total of four doses [31,32].

Rituximab 375 mg/m2 intravenously per week for four weeks, followed by four additional doses administered every two months [28,29].

Major toxicities with rituximab include infusion reactions (ie, fevers, rigors, and hypotension) and infections related to immunosuppression. Rare cases of progressive multifocal leukoencephalopathy have been reported. Rituximab imposes a risk of hepatitis B reactivation among patients positive for hepatitis B surface antigen (HBsAg) or antibodies against hepatitis B core antigen (anti-HBc). (See "Infusion-related reactions to therapeutic monoclonal antibodies used for cancer therapy", section on 'Rituximab' and "Secondary immunodeficiency induced by biologic therapies", section on 'Rituximab' and "Hepatitis B virus reactivation associated with immunosuppressive therapy".)

Support for the use of immunotherapy in marginal zone lymphoma is based on the extrapolation of a benefit among patients with other lymphomas that express CD20. In addition, an international trial of patients with extranodal marginal zone lymphoma not responding to or not suitable for local therapy randomly assigned treatment to chlorambucil with or without rituximab [28,29]. After completion of the planned accrual, a third arm was incorporated to investigate the use of single-agent rituximab. The entire cohort of 454 patients were followed for a median of 7.4 years with the following results:

When compared with chlorambucil alone, the combination of rituximab plus chlorambucil resulted in improved rates of complete remission (CR; 79 versus 63 percent), event-free survival (EFS) at five years (68 versus 51 percent), and PFS (72 versus 59 percent). Rituximab infusion was associated with infusion-related symptoms in approximately 20 percent, the majority of which were mild (grade 1).

When compared with rituximab alone, the combination of rituximab plus chlorambucil resulted in improved rates of CR (79 versus 56 percent), EFS at five years (68 versus 50 percent), and PFS (72 versus 57 percent). Patients treated with chlorambucil had higher rates of hematologic toxicity, although the absolute numbers were small.

All three arms had a five-year OS of approximately 90 percent.

Response rates to single-agent rituximab are lower than those seen in follicular lymphoma. In the multicenter RESORT trial, 71 patients with low tumor burden previously untreated marginal zone lymphoma received four weekly doses of rituximab [31,32]. Of these, 37 patients (52 percent) achieved a complete or partial response and were randomly assigned to rituximab maintenance or to observation and retreatment with rituximab at the time of progression. Overall response rates differed by subtype: splenic marginal zone lymphoma (5 of 5 patients), NMZL (17 of 28 patients), and extranodal marginal zone lymphoma (15 of 38 patients). This compares to a 73 percent overall response rate among patients with follicular lymphoma in the same trial. While observation was associated with a shorter time to treatment failure and shorter time to first cytotoxic chemotherapy, estimated OS at five years was similar in both groups (90 percent).

Incorporation of chemotherapy — The combination of rituximab plus chemotherapy may be preferred as initial therapy over rituximab alone by patients who have more severely symptomatic bulky disease due to its ability to achieve deeper responses. Others reserve chemotherapy for relapsed or refractory disease following single-agent rituximab.

The preferred chemotherapy regimen to combine with rituximab is not clearly defined and depends on patient comorbidities and expected toxicities. For most patients, we offer bendamustine plus rituximab as used for follicular lymphoma. As described above, rituximab can also be combined with chlorambucil. (See 'Single-agent rituximab' above.)

Patients with marginal zone lymphoma have been included in studies of alkylating agent-based regimens such as R-CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone plus rituximab), R-CVP (cyclophosphamide, vincristine, and prednisolone plus rituximab), and the combination of bendamustine plus rituximab (BR). As examples:

Two randomized trials compared BR versus R-CHOP or R-CVP in patients with indolent lymphoma, including marginal zone lymphoma [33,34]. BR resulted in at least equivalent efficacy and less toxicity. The vast majority of patients receiving BR demonstrated a response, most of which were sustained at five years.

A randomized, phase 3 noninferiority trial comparing BR versus R-CHOP included 67 patients with marginal zone lymphoma [33]. In the patients with other histologic subtypes, BR improved PFS and was less toxic than R-CHOP. Among the patients with marginal zone lymphoma, median PFS with BR was not significantly different from that with R-CHOP (57 versus 47 months; HR 0.70, 95% CI 0.34-1.43).

A second randomized, phase 3 study comparing BR versus R-CHOP or R-CVP included 46 patients with marginal zone lymphoma [34,35]. Among the patients with marginal zone lymphoma, BR resulted in similar CR (20 versus 24 percent) and overall (92 versus 71 percent) response rates. BR was associated with higher rates of vomiting and drug hypersensitivity and lower rates of peripheral neuropathy/paresthesia and alopecia. BR improved PFS (66 versus 56 percent at five years; HR 0.61, 95% CI 0.45-0.85) for the group as a whole, a finding which lost statistical significance when the patients with mantle cell lymphoma were removed from the analysis. OS was similar in the two treatment arms (HR 1.15; 95% CI 0.72-1.84).

As these trials included a small number of patients with MZL, further support for BR comes from nonrandomized trials and observational studies. In an international retrospective study of BR as initial therapy for 237 patients with extranodal MZL, the estimated five-year PFS and OS were 81 and 90 percent, respectively [36]. Rituximab maintenance was associated with longer PFS, but not OS. Additional details regarding BR for follicular lymphoma are discussed separately. (See "Initial treatment of stage II to IV follicular lymphoma", section on 'Bendamustine plus rituximab'.)

While uncommonly used, the combinations of pentostatin, cyclophosphamide, and rituximab (PCR) and fludarabine plus rituximab (FR) have also shown activity in nonrandomized phase 2 trials [37-39].

Targeted therapies (BTK inhibitors, lenalidomide) — Novel targeted therapies may be of particular importance for patients with progression within 24 months of initial systemic chemotherapy since such patients have worse survival than those with longer initial remissions [40,41]. They also provide a treatment option for multiply relapsed marginal zone lymphoma (MZL).

Studies have evaluated Bruton tyrosine kinase (BTK) inhibitors (eg, ibrutinib, zanubrutinib) and lenalidomide in patients with marginal zone lymphoma, although most are significantly limited by the small number of patients with MZL and short follow-up.

Both zanubrutinib and the combination of lenalidomide plus rituximab are approved by the US Food and Drug Administration (FDA) for the treatment of relapsed MZL based on single-arm trial data. While ibrutinib had accelerated approval in this setting based on higher than expected response rates in a single-arm phase 2 trial [42,43], the manufacturer voluntarily withdrew approval for this indication after a confirmatory phase 3 trial evaluating the addition of ibrutinib to chemoimmunotherapy (SELENE, NCT01974440) did not meet its primary endpoint of improved progression-free survival [44].

Zanubrutinib – Two open-label, single-arm phase 2 trials evaluated zanubrutinib in a total of 86 patients with relapsed MZL (MAGNOLIA, NCT03846427 [45] and BGB-3111-AU-003, NCT02343120 [46]). A response was documented in 68 to 80 percent, with a CR in 17 to 20 percent and a median time to response of approximately 3 months. Estimated PFS rates were 83 to 84 percent at one year and 72 percent at three years. Common toxicities included gastrointestinal toxicity, infections, and bleeding/bruising. Based on these data, zanubrutinib is approved by the FDA for MZL relapsing after at least one anti-CD20-based regimen [47].

Lenalidomide plus rituximab – Open-label, phase 2 studies of lenalidomide plus rituximab have reported complete responses in 55 to 65 percent of patients with previously untreated MZL [48,49]. However, the efficacy of lenalidomide in this population was questioned when a subgroup analysis of the 63 patients with MZL included in the phase 3 randomized AUGMENT trial evaluating lenalidomide plus rituximab versus placebo plus rituximab in relapsed non-Hodgkin lymphoma did not reveal a PFS benefit (HR 1.00; 95% CI 0.47-2.13) [50]. Lenalidomide plus rituximab is approved by the FDA for previously treated MZL. Further information about administration and toxicity is discussed separately. (See "Treatment of relapsed or refractory follicular lymphoma", section on 'Lenalidomide plus rituximab or obinutuzumab'.)

Hematopoietic cell transplantation — There are limited data regarding the use of high dose chemotherapy followed by autologous hematopoietic cell transplantation (HCT) in NMZL. Small case series suggest that fit patients with chemotherapy-sensitive disease at the time of relapse may achieve long-term disease control. Eligibility for HCT is primarily determined based on the patient's age, their performance status, and/or the presence of comorbid conditions. (See "Determining eligibility for autologous hematopoietic cell transplantation".)

The largest series included 199 patients undergoing autologous HCT for relapsed, non-transformed marginal zone lymphoma (111 extranodal, 55 nodal, and 33 splenic) between 1994 and 2013, 95 percent of whom had chemotherapy-sensitive disease [51]. Estimated rates of relapse/progression, nonrelapse mortality, second malignancy, and OS at five years were 38, 9, 6, and 73 percent, respectively. The risk of relapse decreased with time from transplant, suggesting that some patients achieve long-term disease control. On multivariate analysis, older age and splenic marginal zone lymphoma subtype were associated with worse survival.

The high rates of death due to early transplant-related complications in most series are reflective of the study time period [52,53]. Advances in protocols for autologous HCT has resulted in lower nonrelapse mortality rates among patients with non-Hodgkin lymphoma (eg, 2 to 5 percent). Long-term toxicities of autologous HCT include treatment-related myelodysplasia/secondary leukemia, secondary solid tumors, cardiac disease, pulmonary toxicity, and infection. This is discussed in more detail separately. (See "Long-term care of the adult hematopoietic cell transplantation survivor", section on 'Autologous HCT'.)

Prognosis — Patients with NMZL are usually not cured with conventional treatment. While remissions can be attained, repeated relapses are common. Five-year OS in various series has ranged from 55 to 80 percent [10,54-58]. Prognostic factors are not well defined. A higher FLIPI (follicular lymphoma international prognostic index) score is associated with worse OS [10,58,59]. At the time of relapse, the duration of initial remission provides a measure of tumor aggressiveness. Patients with progression within 24 months of initial systemic chemotherapy have worse survival than those with longer initial remissions [40,41]. (See "Clinical manifestations, pathologic features, diagnosis, and prognosis of follicular lymphoma", section on 'Follicular lymphoma IPI (FLIPI)'.)

HISTOLOGIC TRANSFORMATION — An integral part of the natural history of all indolent non-Hodgkin lymphomas, including NMZL, is progression to a higher-grade histologic subtype, such as diffuse large B cell lymphoma. Large cell transformation has been reported in up to 15 percent of patients with NMZL; the estimated median time from diagnosis to transformation is 4.5 years (range 1 to 22 years) [58,60,61].

Large cell transformation should be suspected in patients with systemic B symptoms (eg, fatigue, night sweats, weight loss), elevations in lactate dehydrogenase, and/or rapidly enlarging lymph nodes. If large cell transformation is suspected clinically, a PET scan can help guide biopsy site selection.

There are little data to guide the selection of therapy in the setting of large cell transformation. We manage large cell transformation in a similar fashion to histologic transformation of follicular lymphoma. This is discussed in more detail separately. (See "Histologic transformation of follicular lymphoma" and "Autologous hematopoietic cell transplantation in follicular lymphoma", section on 'Following histologic transformation'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Marginal zone lymphoma".)

SUMMARY AND RECOMMENDATIONS

Epidemiology and presentation – Nodal marginal zone lymphoma (NMZL) is a primary nodal lymphoma with histologic features similar to extranodal marginal zone lymphoma (MZL) or splenic MZL, but with prominent lymph node involvement and less prominent extranodal and splenic involvement. It is rare, comprising approximately 1 percent of non-Hodgkin lymphoma cases. (See 'Epidemiology' above.)

Most patients present with asymptomatic stage III or IV non-bulky nodal disease (table 4). (See 'Clinical presentation' above.)

Diagnosis – NMZL resembles extranodal MZL and splenic MZL morphologically and immunophenotypically. (See 'Pathologic features' above.)

The diagnosis of NMZL is made based on nodal biopsy evaluation in the context of the clinical presentation. This diagnosis should be made with caution in patients with a condition that places them at high risk of extranodal marginal zone lymphoma (eg, Sjögren’s disease) and should not be made when another low-grade B cell lymphoma (eg, follicular lymphoma) is present in the same node. (See 'Diagnosis and differential diagnosis' above.)

General treatment principles

Goals of therapy – Patients with NMZL are usually not cured with conventional treatment. While remissions can be attained, repeated relapses are common. Treatment focuses on the alleviation of symptoms, reversal of cytopenias, and improvement of quality of life. (See 'Goals of therapy' above.)

Encourage clinical trials – There is no single preferred therapy for NMZL, and we encourage patients to participate in trials whenever possible.

Extrapolation of data from other indolent lymphomas – For patients with NMZL not on a clinical trial, we offer treatment similar to that used for the more common indolent lymphoma, follicular lymphoma (FL) (algorithm 1). Patients with MZL were included in many of the studies that support these treatment recommendations for FL. (See 'Treatment' above and "Initial treatment of stage I follicular lymphoma" and "Treatment of relapsed or refractory follicular lymphoma".)

For patients with NMZL limited to a single lymph node region, we suggest radiation therapy administered with curative intent rather than observation (Grade 2C). (See "Initial treatment of stage I follicular lymphoma", section on 'Radiation therapy (RT)'.)

Patients with more advanced asymptomatic NMZL do not require immediate treatment but should be followed closely. For patients with more advanced, symptomatic NMZL, we offer an anti-CD20 monoclonal antibody (eg, rituximab or obinutuzumab) with or without chemotherapy. The decision to incorporate chemotherapy depends on the goals of therapy and patient values; the addition of chemotherapy results in deeper responses and prolonged progression-free survival but does not improve overall survival and is associated with increased toxicity. (See 'Choice of therapy' above.)

Relapsed disease is usually managed with the serial administration of systemic treatments (eg, rituximab, chemotherapy, targeted therapy [eg, BTK inhibitor, lenalidomide]). Prolonged disease-free survival has been achieved after autologous hematopoietic cell transplantation in select patients. (See 'Targeted therapies (BTK inhibitors, lenalidomide)' above and 'Hematopoietic cell transplantation' above.)

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Topic 113327 Version 26.0

References

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