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assessment by bronchoscopy. Any pulmonary mass or pleural effusion detected should be examined histopathologically. The difficulty in staging MALT lymphoma lies in the application of traditional staging systems for nodal-type lymphoma in extranodal MALT lymphoma. The Ann Arbor system is based on the extension from contiguous nodes and can be misleading in MALT lymphomas, because the involvement of multiple extranodal sites may not reflect truly disseminated disease.
Several studies demonstrate that non-gastric MALT lymphomas in the general population have a good outcome [21, 22]. Five-year survival rates have ranged from 86 to 100%. Despite the fact that 30% of these patients present with disseminated disease, their outcome remains unaffected by the multi-focal nature of the lymphoma (5-year survival of 90%) [23]. Furthermore, none of the conventional oncologic approaches appear to influence the outcome of these patients. It has been suggested that chemotherapeutic intervention may be ineffective in preventing recurrence in the early stage of the disease [23].
Some patients with persistent disease can be allowed to go untreated for prolonged periods of time yet have normal life spans. A retrospective analysis by Ambrosetti et al. reported no significant differences in outcomes among SS patients with salivary MALT lymphomas who underwent no treatment or received a variety of treatment modalities, including surgery, radiotherapy, and chemotherapy [24]. This is consistent with a study conducted by our department, in which SS patients with salivary MALT lymphomas had a quite uncomplicated clinical course with a median overall survival of 6.4 years. Notably, at a median follow-up of 6 years, treated and untreated patients with MALT lymphomas showed the same overall survival [5]. Conversely, patients with nodal involvement or advanced disease, defined by concomitant nodal and extranodal and/or bone marrow infiltration, exhibit worse prognoses [23, 25].
The international prognostic index defines various risk groups according to clinical and laboratory parameters including age, stage, involvement of more than one extranodal site, lactate dehydrogenase level, and performance status. Patients determined to be at high risk of death by this index also have a poor prognosis [26].
The natural history of MALT lymphomas suggests a two-stage dissemination process. During the initial phase, the tumors spread to other MALT sites. In the second phase, the lymph nodes and bone marrow become affected [23]. Consequently, treatment should be “patient and case tailored,” taking into account the site and stage of the lymphoma along with the international prognostic index and clinical characteristics of the individual patient. In addition, bulky tumor, serologic markers such as elevated beta 2-microglobulin or reduced albumin levels, and the presence of a large-cell component in tissue histology at diagnosis are also linked to poor outcomes [26, 27].
37.2.2Therapeutic Approaches of MALT Lymphomas
For SS patients with MALT lymphoma localized to the salivary glands or other regions (stage IE), a “wait and watch” policy is appropriate. Chemotherapy is reserved for patients with disseminated lymphoma that infiltrates multiple (not regional) lymph
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nodes and/or bone marrow, as well as for those who fall into the high-risk category according to the international prognosis index. This strategy may be especially appropriate for elderly patients who have asymptomatic disease, as well as for those with substantial comorbidities that preclude a vigorous therapeutic approach.
Alkylating agents (cyclophosphamide, chlorambucil), purine analogues (fludarabine, cladribine), and anti-CD20 monoclonal antibody therapy are all suitable options for disseminated disease, but these recommendations have not been substantiated by large patient series and randomized trials [28–30]. In patients with disseminated MALT lymphoma at presentation who do not have SS, single chemotherapeutic agents such as alkylating agents and nucleoside analogues achieve a 75% complete remission rate, with projected 5-year event-free and overall survival rates of 50% and 75%, respectively [28]. However, responses differ dramatically according to whether patients have gastric or non-gastric involvement of their MALT lymphomas; patients without gastric involvement fare substantially worse [30].
In a study conducted by our department, 75% of patients with SS-associated MALT lymphomas achieved complete responses following treatment with 2-chloro- 2-deoxyadenosine [31]. OSS features, namely xerostomia, parotid gland enlargement, salivary flows, and hyposthenuria, also showed improvement, and the disappearance of cryoglobulins and monoclonal bands within the urine was also observed. In addition to its direct cytotoxic potential, 2-chloro-2-deoxyadenosine has been associated with a profound T-cell depletion. The potential implication of anti- gen-specific T-cells in MALT lymphoma pathogenesis explains the favorable effect of this agent in these lymphomas [32]. When considering this type of treatment, it is important to weigh the indolent nature of these malignancies against the potentially severe adverse effects that may accompany purine analogue administration.
Anti-CD20 monoclonal antibody strategies may also have a place in the management of MALT lymphoma. High response rates are particularly observed in untreated patients [29]. Preliminary studies have documented benefits of B-cell depletion with an antiCD20 monoclonal antibody for the glandular and extraglandular manifestations of SS patients [33–35]. The overall response rate appears to be on the order of 75%. However, anti-CD20 treatments are not universally effective in SS patients with MALT lymphomas [36]. Responses may differ according to the particular tissues involved because this treatment may fail to eliminate distinct B-cell sub-populations, e.g., MZ cells. Anti-CD20 treatments may also be antagonized by microenvironmental factors that promote B-cell survival, as recently has been described in a murine model of SS [37, 38].
Recurrences of MALT lymphoma at the same or different nodal or extranodal sites have been reported in 25–35% of patients, even years after the achievement complete responses. This highlights the need for life-long follow-up [29]. The roles of higher doses of rituximab (or other B-cell depletion strategies), maintenance treatment, and combination therapy with conventional chemotherapeutic agents require further exploration. All of these approaches have proven beneficial in other types of lymphoma [39]. The combination of anti-CD20 monoclonal antibody administration with fludarabine or 2-chloro-2-deoxyadenosine has been reported to achieve a high complete response rate in both gastric and non-gastric MALT lymphomas [40, 41]. The concomitant use of an anti-CD20 monoclonal antibody with
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MARGINAL ZONE LYMPHOMA (MZL)
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−Single Agent
Rituximab 375/m2/wkx4 Chlorambucil 6mg/m2/dx6−12 mo
Cyclophosphamide 10mg/m2/dx6−12 mo Fludarabine 30 mg/m2 x 5d/mo x 3−6 mo Cladribine 0.12 mg/kg/d x 5d/mo x 3−6 mo
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R-CHOP/3wk x 6−8 cycles
Fig. 37.5 Therapeutic guidelines for the management of SS-associated MZ lymphomas. No established guidelines have been developed for the treatment of extranodal salivary MALT lymphomas in SS patients. Our policy for the management of these lymphomas is presented in this figure. In localized disease, a wait and see policy is adopted with close follow-up. If lymphoma is disseminated with nodal and bone marrow involvement or the patients have several risk factors according to IPI, single agent chemotherapy such as chorambucil, 2cda, or rituximab is administered. Doxorubicin-based combined chemotherapy should be reserved for patients who have a high-grade transformation or high tumor burden as indicated by high LDH levels, a tumor mass greater than 7 cm, and bulky regional nodal involvement. In our experience, the use of R-CHOP regimen as a first-line treatment appears to be effective in SS patients with NMZLs
2-chloro-2-deoxyadenosine increases the response rate and quality of response, significantly prolonging the time to treatment failure. In addition, an increased number of patients treated with this combination proved negative for minimal residual disease, which correlates with a longer time to treatment failure [41]. Figure 37.5 illustrates our algorithm for the management of MZ lymphomas in SS patients.
Prospective, multicenter, large series, randomized, double-blinded studies of SS patients with MALT lymphoma are needed to compare different chemotherapy regimens and determine the optimal approach for patients with disseminated or relapsing disease. Potentially active drugs could also include those that target the inhibition of the NFkB pathway, the downstream molecular product of the translocations involving MALT1 gene, such as bortezomid. The frequency of translocations involving
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MALT1 appears to be low in SS patients with non-gastric MALT lymphomas. In contrast, t(11;18)(q21;q21) which involves the MALT1 gene frequently occurs in patients with gastric MALT lymphoma and SS, which may explain, in part, why these patients are largely resistant to H. pylori eradication therapy [42]. Interestingly, the t(11;18)(q21;q21), specific to MALT-type lymphoma, is found in 18–24% of patients with gastric MALT lymphoma. In addition to antimicrobial therapy failure, this specific translocation is accompanied by a resistance to alkylating agents but is a marker for sensitivity to an anti-CD20 monoclonal antibody [43–45].
37.2.3Nodal Marginal Zone B-Cell Lymphomas (NMZL): Histology, Differential Diagnosis, and Outcome
Patients with NMZL have worse outcomes compared to those with MALT lymphomas. The 5-year survival rates in NMZL range between 50% and 70% [46]. The survival curves for NMZL do not display any plateau, suggesting that disease is not with current treatments. The 5-year event-free survival is approximately 30%. The estimated median time to progression ranges between 1 and 2 years [47]. At diagnosis, 20% of patients have lymph node histology that reveals an increased percentage of large cells (>20%) and a high mitotic rate, indicating a transformation to diffuse large B-cell lymphoma [47].
More than two-thirds of SS patients with NMZL present with an advanced stage, displaying peripheral, abdominal nodal involvement and splenomegaly [6]. The nodal spread of MALT lymphoma in a patient with SS could resemble a NMZL, because the lymph node histologies in these conditions share several morphological features. However, isolated or disseminated lymphadenopathy in the absence of extranodal lesions should alert the clinician to the possibility of NMZL. NMZL may show different patterns of lymph node infiltration such as “marginal zone”-like/ perifollicular, nodular, diffuse, or a combination of patterns [48] (Fig. 37.6). As a consequence, it is impossible to distinguish NMZL from MALT lymphoma by morphology or immunohistochemistry. Only thorough clinical staging can confirm a NMZL in the absence of concurrent extranodal involvement (Table 37.3).
37.2.4Managing NMZL
NMZLs resemble other primary nodal B-cell lymphomas such as follicular with respect to B symptoms, elevated serum concentrations of lactate dehydrogenase, performance status, and international prognosis index. NMZL represents a therapeutic dilemma because precise therapeutic guidelines do not exist, owing largely to the absence of data from studies with substantial numbers of cases. The current therapies for NMZL are heterogeneous and determined by the age of the patient and the clinical stage aggressiveness of the tumor. NMZL typically has a short time to progression. Feasible treatment options include polychemotherapy with anthracycline-based chemotherapy combined with an anti-CD20 monoclonal antibody. In our experience,