Chapter 101: Marginal Zone B-Cell Lymphomas

Marginal zone lymphomas (MZLs) represent a heterogeneous group of indolent lymphoproliferative disorders originating from memory B-lymphocytes, which are normally present in the marginal zone—that is, the outer part of the mantle zone—of the secondary lymphoid follicles. The spleen and the mucosa-associated lymphoid tissues (MALT) are the most frequently involved anatomic compartments; lymph nodes may also been involved, albeit rarely. The 2008 World Health Organization (WHO) Classification of Tumours of Haematopoietic and Lymphoid Tissue identifies three distinct subtypes of MZL based on the involved site, the clinical presentation and course of the disease, as well as the molecular profiles, namely, extranodal MZL of MALT type (also termed extranodal marginal zone lymphoma [EMZL]); splenic marginal zone lymphoma (SMZL); and nodal marginal zone lymphoma (NMZL).¹ In addition, two provisional entities are recognized by the 2008 WHO classification: splenic diffuse red pulp lymphoma and hairy-cell leukemia variant, which represent two subtypes of splenic lymphomas with features overlapping with those of MZL.

In adults, MZLs account for 5 to 17 percent of all non-Hodgkin lymphomas (NHLs); MALT lymphoma is the most frequent overall, being the third most frequent NHL and representing 7 to 8 percent of all B-cell neoplasms. It mostly affects middle-aged adults, at a median age of 60 years, with a slight female preponderance and often in association with chronic antigenic stimulation, either as a consequence of a chronic infection or an autoimmune disease. Gastric MALT lymphoma is by far the most common clinical entity, displaying considerable geographic variability with a higher incidence in areas associated with a high incidence of Helicobacter pylori infection. SMZL and NMZL represent 20 percent and 10 percent of MZLs, respectively, accounting for less than 2 percent of all NHLs. The median age at disease onset is 65 years for SMZL, and between 50 and 60 years for NMZL.^2,3

Each lymphoma subtype is presented and discussed separately in terms of epidemiology, etiology and pathogenesis, clinical presentation and treatment strategies.

DEFINITION

EMZL or MALT lymphoma is an extranodal lymphoma that arises both in organs with an anatomically well-defined MALT, such as the gut, the nasopharynx and the lung (in which MALT represents an acquired and specialized immunologic barrier associated with highly permeable mucosal sites in close contact with the external environment), and in sites which normally lack lymphoid tissue, but have accumulated B cells in response to a chronic infection or an autoimmune process, such as the salivary glands, the ocular adnexa (orbits, conjunctiva and lacrimal glands), the skin, the thyroid, the genitourinary tract (bladder, prostate, kidney, uterus), and the breasts.

EPIDEMIOLOGY

MALT lymphoma accounts for at least 50 percent of primary gastric lymphomas, typically presenting in middle-aged adults, with a female predominance. Gastric MALT lymphoma is particularly common in the north-eastern part of Italy, which is an area of high prevalence of H. pylori infection. In contrast, a specific subtype of small intestinal MALT lymphoma (termed immunoproliferative small intestinal disease [IPSID]) tends to be more frequent in the Middle East, on the Indian subcontinent, and in the Cape Region of South Africa.

ETIOLOGY AND PATHOGENESIS

Sustained antigenic stimulation, triggered either by a chronic infection or by an autoimmune process, induces an initially polyclonal B-cell proliferation, as well as the development of an inflammatory response, with the attraction of neutrophils, which release reactive oxygen species (ROS). ROS are genotoxic, and may induce a wide range of genetic abnormalities. Moreover, the prolonged proliferation of B-lymphocytes induced by a chronic lymphoproliferative stimulus may increase the risk of DNA damage (double-strand breaks and translocations), as a consequence of the genetic instability of B cells during somatic hypermutation and class-switch recombination. Genetic abnormalities tend to involve those genes related to the activation of nuclear factor-kappa B (NF-κB), a key transcription factor regulating the expression of several survival- and proliferation-related genes in B cells during immune responses. The constitutive activation of this signalling pathway results in uncontrolled B-cell proliferation and subsequent neoplastic transformation of the involved tissue.

The longstanding antigenic stimulation explains how lymphoid infiltrates—or an acquired MALT—may appear in extranodal sites normally lacking MALT. The MALT that organizes in proximity to an epithelium receives stimuli from the epithelium itself (as occurs in autoimmune disorders) or from antigens entering the lymphoid tissue through the epithelium or via the afferent lymphatics (as during exogenous infections).

Microbial species thought to be associated with MALT lymphoma include: H. pylori and Helicobacter heilmannii, hepatitis C virus (HCV), Campylobacter jejuni, Borrelia burgdorferi, and Chlamydia psittaci. These entities have been found to be related with the development of MALT lymphoma of the stomach, IPSID, cutaneous MALT lymphoma and orbital MALT lymphoma, respectively.^4,5,6,7 H. pylori has been documented as the etiologic agent in more than 90 percent of gastric MALT lymphoma, which arises from H. pylori–stimulated autoreactive B cells.⁸ H. pylori can be demonstrated by histology, polymerase chain reaction, or urea breath test, and can be isolated and cultured. H. pylori appears to be a fundamental factor for the development of the disease, and its elimination often induces a remission of the lymphoma by itself without any other intervention, thus fulfilling all four of Koch’s postulates and establishing the microorganism as the main etiologic factor. However, because only a minority of patients with an overt H. pylori infection develop the disease, it is obvious that the pathogenesis of gastric EMZL also depends on other, largely unknown factors, perhaps related to the host, the environment, or the virulence of the infecting H. pylori strain.

It has also been demonstrated that viable C. psittaci can be found not only in monocytes and macrophages infiltrating orbital MALT lymphoma, but also in patients’ blood and conjunctiva, raising the possibility of microbial eradication and disease remission by antibiotic therapy with drugs such as doxycycline.⁹

Autoreactive B cells found in autoimmune diseases, such as those infiltrating the thyroid in Hashimoto thyroiditis, or the salivary glands in Sjögren syndrome, organize progressively into a well-developed MALT, mimicking lymphoproliferation and eventually evolving into an overt lymphoma. Patients with Sjögren syndrome have a 44-fold increased risk of developing lymphoma, and patients with Hashimoto thyroiditis have a 70-fold increased risk of thyroid lymphoma.^10,11

GENETIC ABERRATIONS

Recurrent genomic lesions, including chromosomal translocations and unbalanced aberrations, can be detected in MALT lymphomas in up to 40 percent of the cases, depending on the specific aberration. The t(11;18)(q21;q21) translocation is the most common structural chromosomal abnormality in MALT lymphoma, being demonstrated in 15 to 40 percent of the cases, especially in gastric and lung MALT lymphoma.¹² Other chromosomal translocations include t(14;18)(q32;q21), t(1;14)(p22;q32) and t(3;14)(p13;q32), all involving the immunoglobulin heavy chain variable region (IGHV) gene on chromosome 14, and displaying a specific anatomic distribution (Table 101–1).¹³ The presence of any of these chromosomal alterations correlates with a lack of any further genetic instability or chromosomal imbalances.

Current knowledge of the genetic lesions seen in MALT lymphoma suggest a model of multistage development and progression from a preneoplastic lesion to overt lymphoma. The accumulation of genetic abnormalities is associated with a loss of dependency from antigenic stimulation (with subsequent antibiotic resistance) and with possible histologic transformation.

CLINICAL FEATURES

EMZL mostly presents as Ann Arbor stage IE disease, which implies the sole involvement of the extranodal site of origin, with possible extension of the disease to tributary lymph nodes in close proximity to the affected organ. Marrow and peripheral lymph node infiltration is uncommon, observed in less than 20 percent of the cases at presentation. The stomach is the most commonly involved organ, accounting for approximately one-third of cases. Other typical presentations include the salivary glands, the orbits and the ocular adnexa, the thyroid, the lungs, the skin, the breasts, the liver, and other gastrointestinal sites, apart from the stomach. Disseminated disease can be documented in up to 25 percent of patients with gastric MALT lymphoma, although those with nongastrointestinal extranodal disease exhibit disseminated lymphoma in nearly half of the cases.¹⁴ Gastric MALT lymphoma is often multifocal, which may explain the high rate of relapse in the gastric stump after surgical excision. Synchronous involvement of gastrointestinal and extraintestinal sites is detected in approximately 10 percent of cases.

Systemic lymphoma-related symptoms are generally uncommon, and the clinical aspects and presenting symptoms generally correlate with the primary location of the disease.

Gastric MALT lymphoma presents with nonspecific dyspepsia, epigastric pain, and nausea. Chronic bleeding may become evident with progressively worsening iron-deficiency anemia. The antrum is the most frequently involved portion of the organ, although any part of the stomach can be affected: intragastric nodularities, enlarged rugal folds, thickened gastric walls, irregularly shaped superficial erosions or shallow ulcers all represent macroscopic features of this lymphoma.

MALT lymphomas of the ocular adnexa most often arise in the orbit (40 percent of cases), with masses that cause progressive proptosis, periorbital edema and abnormalities in ocular motility and vision. The conjunctiva is the site of origin in approximately 35 to 40 percent of the cases, with bilateral involvement observed in nearly 15 percent of patients. More rarely, the lymphoma originates from the lacrimal gland (10 percent of the cases) or the eyelid.

Cutaneous MALT lymphoma generally presents with papules, plaques or nodules mainly involving the trunk and the upper limbs; the occurrence of multiple lesions affecting noncontiguous regions is, however, not infrequent. Lesions may show spontaneous remissions, but cutaneous relapses are the rule.

Immunoproliferative small intestinal disease, which is considered a special variant of intestinal MALT lymphoma, usually manifests with a severe and unremitting malabsorption. The lymphoma usually remains confined to the upper intestine and the regional lymph nodes, spreading beyond the abdomen only in advanced stages of the disease and upon transformation into high-grade lymphoma.

MORPHOLOGY

The neoplastic lymphocytes tend to infiltrate the marginal zone around reactive B-cell follicles, external to an intact follicular mantle. Their cytoplasm is pale, and they display small to medium-sized and irregularly shaped nuclei, with dispersed chromatin and inconspicuous nucleoli, either resembling germinal center centrocytes or monocytoid elements. Scattered, centroblast-like large cells may be present, although never predominant, as well as mature plasma cells in up to a third of cases. Lymphoepithelial lesions are characterized by invasion or necrotic destruction of the glandular epithelium by infiltrating lymphoma cells: they are highly characteristic of MALT lymphoma, particularly gastric MALT lymphoma (Fig. 101–1), although they are not pathognomonic. Germinal centers may also be colonized by MZL cells, thus conferring a vaguely nodular or follicular pattern; lymphoma cells may also undergo a blastic or plasma cell differentiation. Upon immunohistochemistry, cells are CD20+, CD79a+, CD21+, and CD35+, lacking CD5, CD23, and CD10, typically expressing immunoglobulin (Ig) M (less often IgA or IgG), with an immunoglobulin light-chain restriction.

DIFFERENTIAL DIAGNOSIS

A distinction between reactive (i.e., acquired) and neoplastic MALT is sometimes difficult, especially for MALT lymphoma at early stages of evolution. The demonstration of clonality by virtue of light-chain restriction (on immunohistochemistry or flow cytometry) is of great diagnostic value. Other entities to be considered are other indolent B-cell lymphomas involving extranodal sites, such as mantle cell lymphoma, small lymphocytic lymphoma and follicular lymphoma. An extended immunohistochemical panel, including CD5, CD23, CD10, and cyclin D1, along with cytogenetic and molecular analysis is required to rule out other diagnoses.

STAGING PROCEDURES

A complete and detailed patient’s history and a full physical exam, along with blood studies evaluating renal and liver function, lactate dehydrogenase (LDH), serum protein electrophoresis and immunofixation, and complete serology for HIV, HCV, and hepatitis B virus are considered mandatory.¹⁵ Cryoglobulins should be measured in HCV-positive individuals. Computed tomography of the neck, chest, abdomen, and pelvis, as well as marrow aspiration and biopsy, are required. H. pylori status should always be evaluated on the gastric biopsy or through a urea breath test, and repeated after therapy if positive at baseline. Endoscopic ultrasound to evaluate the regional lymph nodes and gastric wall infiltration is also recommended in gastric MALT lymphoma. Fluorescence in situ hybridization for t(11;18) is optional, but useful to guide therapy. Involvement with C. jejuni, C. psittaci, or B. burgdorferi may be detected in tumor biopsies from intestine, ocular adnexa or skin, respectively, by polymerase chain reaction, immunohistochemistry or of in situ hybridization.

THERAPY

H. pylori eradication therapy should be administered to all patients with H. pylori–positive MALT lymphomas, independent of stage at presentation or histologic grade. The outcome of H. pylori eradication must be confirmed by urea breath test at least 6 weeks after eradication therapy, and at least 2 weeks after proton pump inhibitors withdrawal.

Antibiotic therapy is based on the epidemiology of the infection in the patient’s country of residence, and should take into account locally expected antibiotic resistance patterns. The most common approach is based on three drugs: a proton pump inhibitor, in association with either amoxicillin or metronidazole, and clarithromycin, for 10 to 14 days.¹⁶

The role of surgery has been questioned, as gastric MALT lymphoma is generally multifocal, thus requiring an extensive (total or subtotal) gastrectomy, usually severely impairing the quality of life. Nevertheless, gastrectomy can be considered in cases with major hemorrhage, massive infiltration of the gastric walls (with an enhanced risk of perforation during chemotherapy), or pyloric stenosis.¹⁷

Patients with nongastric MALT lymphoma and gastric MALT lymphoma patients who fail to respond to H. pylori eradication or who have no evidence of H. pylori infection should be considered for alternative treatments. However, there is no evidence-based consensus delineating optimal alternative treatment strategies. Involved field radiation therapy (25 to 35 Gy) is a reasonable option for localized disease.^18,19 Chemotherapy or rituximab immunotherapy, or a combination of both, are effective in the treatment of all stages of disease (Table 101–2).^{20,21,22,23,24,25,26} It is important to note that patients with the t(11;18) translocation are usually unresponsive to alkylating drugs if administered as single agents. Fludarabine has important antitumor activity,²⁷ especially when combined with rituximab,²⁸ as has the combination of chlorambucil plus rituximab.²⁹ Radioimmunotherapy with ⁹⁰Y-ibritumomab tiuxetan is also effective for patients with MALT lymphoma.³⁰

COURSE AND PROGNOSIS

MALT lymphoma usually has a favorable outcome, with a 5-year overall survival greater than 85 percent in most series. The reported median time-to-progression seems to be more favorable for gastrointestinal MALT lymphomas than nongastrointestinal lymphomas; however, no significant differences in overall survival have been demonstrated between the two disease subgroups. Approximately 30 to 50 percent of patients with a H. pylori–positive gastric MALT lymphoma show persistent or progressive disease after H. pylori eradication with antibiotic therapy. Among complete responders, almost 15 percent relapse within 3 years, suggesting that additional therapies are required in a significant percentage of patients. Histologic transformation to diffuse large B-cell lymphoma has been reported in approximately 10 percent of the cases, usually as a late event that occurs independently from dissemination.

DEFINITION AND EPIDEMIOLOGY

SMZL is a mature B-cell neoplasm arising from postgerminal center lymphocytes and involving the white pulp follicles of the spleen, the splenic hilar lymph nodes, the marrow and often the blood, showing characteristic neoplastic lymphoid elements referred to as “villous lymphocytes.” It accounts for 1 to 2 percent of all lymphomas, with a median age at diagnosis of nearly 65 years (range: 30 to 90 years) and a slight male predominance.

ETIOLOGY AND PATHOGENESIS

The precise pathogenesis of SMZL is unknown: the cell of origin is a marginal zone B cell, which is believed to be of postgerminal center origin, as demonstrated by the presence of somatic hypermutations in IGHV genes^31,32; however, up to one-third of cases are nonmutated. Conversely, SMZL exhibits a low frequency of somatic mutations involving oncogenes such as BCL-6, PAX5, and PIM1, which suggests a pathway of differentiation that may not involve a transit through the germinal center.³³

In cases of SMZL associated with chronic HCV infection, longstanding antigenic stimulation of B-lymphocytes as a result of the interaction of the viral E2 glycoprotein with CD81 on B cells is responsible for lymphocytes activation through the B-cell receptor (BCR), which ultimately leads to an increased rate of proliferation of B cells. Antiviral treatments can induce remissions of SMZL, thus proving the causative role of the infection in the pathogenetic process of HCV-related SMZL.³⁴ SMZL associated with chronic HCV infection is often associated with mixed cryoglobulinemia and the development of cryoglobulinemic vasculitis.

GENETIC ABERRATIONS AND MOLECULAR PATHOGENESIS

Cytogenetic abnormalities can be found in up to 80 percent of SMZL patients, most frequently consisting of complete or partial 3q trisomy (30 to 80 percent of cases) and gains of 12q (15 to 20 percent of patients). However, the most significant karyotype aberrations, considered typical of SMZL, are deletions or translocations involving 7q32, which are reported in nearly 40 percent of the cases. Other alterations involving chromosomes 8, 9p34, 12q23–24, 17p, and 18q, although not typical, are helpful for the diagnosis of SMZL.³⁵

SMZL displays a characteristic transcriptional profile with a molecular signature consisting of over-expression of genes involved in the AKT1, BCR, and NF-κB signalling pathways. Mutations in signalling pathways involved in marginal zone B-cell development are also observed in nearly 60 percent of SMZL, with mutations of NOTCH2 being the most frequent, accounting for 20 percent of the cases.³⁶ As these mutations are restricted to SMZL, they represent a potential diagnostic marker (and presumably a therapeutic target) for this lymphoma subtype.

CLINICAL FEATURES

Isolated and generally asymptomatic splenomegaly and cytopenias are the most significant clinical characteristics of this lymphoma. The majority of patients seek medical attention because of the presence of anemia and/or thrombocytopenia, mostly related to hypersplenism rather than marrow insufficiency as a consequence of disease infiltration. Lymphocytosis is always present, and basophilic villous cells in blood may also be found. Splenomegaly is detectable upon physical examination; dyspepsia and abdominal discomfort, due to the enlarged (or sometimes markedly enlarged) spleen, are often reported. Massive splenomegaly, frequently associated with small splenic hilar lymph nodes, is the typical feature of advanced cases.

Autoimmune phenomena can be associated with this lymphoma, a result of the production of autoantibodies sustained by the neoplastic clone. Hemolytic autoimmune anemia or immune thrombocytopenia are present in 10 to 15 percent of patients. In up to 40 percent, a serum monoclonal paraprotein can be detected.

MORPHOLOGY

A micronodular lymphoid infiltrate of small lymphocytes typically surrounds and replaces the splenic white pulp germinal centers in SMZL, with involvement of the red pulp also consistently observed. The malignant cells resemble those of marginal zone MALT lymphoma; although some are larger and resemble centroblasts or immunoblasts. Plasmacytic differentiation is usually appreciated within germinal centers. Neoplastic lymphocytes are typically CD20+, CD23−, CD38−, CD5−, CD10−, cyclin D1−, IgD+. Intertrabecular lymphoid nodules in the marrow mimic the morphology of tumor nodules in the spleen, with occasional reactive germinal centers surrounded by neoplastic cells. Neoplastic lymphocytes can usually be recognized in the blood,³⁷ with the classic villous morphology, characterized by the presence of polar small cytoplasmic projections (seen in only a subset of cells).

DIFFERENTIAL DIAGNOSIS

SMZL can be distinguished from other indolent lymphomas associated with splenomegaly by the integration of clinical, morphologic, immunohistochemical and genetic data. Both follicular lymphoma and mantle cell lymphoma may show a micronodular pattern of splenic involvement: however, the expression of both CD5 and cyclin D1 by mantle cell lymphoma and of CD10 by follicular lymphoma represent clear diagnostic clues differentiating these subtypes. A more challenging distinction is with lymphoplasmacytic lymphoma because plasmacytic differentiation is seen in 28 percent of cases of SMZL. The presence of a very large IgM paraprotein spike (>10 g/L) favors the diagnosis of lymphoplasmacytic lymphoma (LPL) rather than SMZL, though small IgM paraprotein spikes may also been seen in SMZL (<10 g/L usually).

THERAPY

Treatment is required only in symptomatic SMZL patients with massive splenomegaly causing pain, early satiety or cytopenias, defined as hemoglobin less than 100 g/L, platelets less than 80,000/μL, or neutrophils less than 1000/μL. Asymptomatic patients may be followed clinically without intervention for many years, since treatment does not influence survival.¹⁵

When treatment is indicated because of the occurrence of clinical symptoms, the recommended frontline therapy is splenectomy, which allows a rapid correction of anemia, thrombocytopenia and neutropenia—if present—and the removal of the dominant focus of the disease, even though such management does not influence marrow infiltration or blood lymphocytosis. Postsplenectomy partial remissions are generally stably maintained for years, and patients can remain asymptomatic, with a median time to next treatment of 8 years.³⁸

Systemic therapy is required when major contraindications to surgery exist, in elderly patients, in those who relapse or progress after splenectomy and in case of advanced disseminated nodal disease or high-grade transformation. Rituximab, used both as a single agent or combined with chemotherapy, is highly effective in this subgroup of patients^41,42 and is preferred to splenectomy by some authorities. Chemotherapy regimens are based on alkylating agents (such as chlorambucil or cyclophosphamide), fludarabine or bendamustine.^39,40

COURSE AND PROGNOSIS

The median overall survival for patients with SMZL is 5 to 10 years, although a median survival time of less than 4 years has been documented in a subset of patients presenting with advanced or aggressive disease (25 to 30 percent of cases). In 10 to 20 percent of cases, histologic transformation into a diffuse large B-cell lymphoma occurs.

A prognostic model has been recently developed and validated in a cohort of more than 300 patients⁴³ based on three variables: hemoglobin concentration (<120 g/L), LDH (if elevated at diagnosis), and albumin levels (<35 g/L). This model, although lacking therapeutic implications, allows stratification of patients into three risk-groups, including a low-risk group (no risk factors) with an 88 percent 5-year cause-specific survival rate, an intermediate-risk group (one risk factor) with a 73 percent 5-year cause-specific survival rate, and a high risk group (at least two risk factors) with a 50 percent cause-specific survival rate.

DEFINITION AND EPIDEMIOLOGY

Nodal MZL is a mature, postgerminal center B-cell lymphoma, sharing many morphologic and immunohistochemical characteristics with EMZL and SMZL, although it is considered a distinct clinicopathologic subtype by the current WHO classification. It is a rare disease, accounting for less than 2 percent of all lymphomas, with a median age at onset of between 50 and 60 years. The association with autoimmune phenomena is weak for this lymphoma, in contrast to other MZLs.

GENETIC ABERRATIONS AND MOLECULAR PATHOGENESIS

No typical cytogenetic aberrations have been demonstrated for NMZL: among the reported abnormalities are gains of chromosomes 3, 7, 12, and 18, and structural rearrangements of chromosome 1, with breakpoints in 1q21 or 1p34.⁴⁴ Gain of several regions of chromosome 3 constitute a common marker of NMZL, occurring in 20 to 25 percent of patients, and are shared with patients presenting with EMZL. More than three-quarters of patients harbor somatic IGHV gene mutations, and show a biased use of IGHV segments 3 and 4. These mutations are equally seen in both HCV-positive and HCV-negative patients; however, IGHV gene segment 1–69 seems to be preferentially used in HCV-related cases, suggesting differential antigenic stimulation driving lymphoma B-cell precursor selection, and the possible pathogenic role of HCV itself.⁴⁵

CLINICAL FEATURES

The majority of patients affected by NMZL present with disseminated peripheral and abdominal nodal involvement. Marrow infiltration is seen in less than half of the patients, and blood involvement is rare. Extranodal disease is absent, by definition and the presence of splenomegaly should suggest a diagnosis of SMZL. Performance status is generally good with lymphoma-related symptoms reported in 10 to 40 percent of the cases. A serum monoclonal component is detected in only 10 percent of patients.

MORPHOLOGY

Neoplastic elements within lymph nodes have a marginal zone pattern of infiltration, with residual follicles being well-preserved or expanded in some cases (“MALT-type” NMZL), diminished in other cases (“splenic-type” NMZL), or sometimes colonized by the lymphoma cells, in which case marked plasmacytoid differentiation and a nodular or follicular growth pattern mimicking follicular lymphoma is often seen (Fig. 101–2).

DIFFERENTIAL DIAGNOSIS

Pediatric NMZL is a different clinical entity that arises in adolescent patients, with a striking predominance in males. Atypical cells within lymph nodes show a marked pleomorphism and an interfollicular distribution with marginal zones considerably expanded.¹ Patients generally present with localized stage I disease, which can be managed conservatively (surgical excision and observation), with low rates of disease recurrence.

The pathologic distinction between NMZL, LPL and follicular lymphoma with marginal zone differentiation can be difficult. Immunohistochemistry may be a useful diagnostic tool by demonstrating BCL6 and CD10 expression in follicular lymphoma, whereas the demonstration of a large IgM paraprotein spike in the serum suggests LPL rather than NMZL.

THERAPY

No specific treatment consensus guidelines have been developed for NMZL, and patients are generally well managed according to treatment paradigms developed for follicular lymphoma and other indolent NHLs. In limited stage disease, surgery and radiotherapy are often appropriate, whereas immunochemotherapy is the most suitable option for patients presenting with symptomatic advanced stage disease.^15,46 Patients with concomitant HCV infection and no urgency for lymphoma treatment should receive antiviral treatment with interferon and ribavirin.⁴⁷ High-dose therapy and autologous stem cell transplantation can be considered for patients with aggressive presentations and short remission durations following standard immunochemotherapy regimens.⁴⁶

COURSE AND PROGNOSIS

The average 5-year survival of NMZL is approximately 60 to 70 percent, with an estimated 5-year event-free survival of nearly 30 percent, thus indicating a high tendency of disease to relapse over time, albeit with rare involvement of extranodal sites.