salivary glands, 6 patients (17%) showed local regional nodal dissemination, and bone marrow involvement was observed in only 1 patient (3%). Of the remaining three patients, there was lacrimal gland involvement in two and involvement of the stomach in one. No transformation into diffuse large B-cell lymphoma was observed.

Overall survival does not seem to be inßuenced by its spreading to other MALT organs, although involvement of lymph nodes might be an adverse prognostic factor for transformation into high-grade lymphoma [13, 17].

The relative infrequency and heterogeneity of MALT lymphomas in general, with their clinical presentation varying according to the site of involvement, make it difÞcult to deÞne optimal treatment of these lymphomas. There is increasing evidence that antibiotics can be used as initial treatment of MALT lymphoma associated with microbial pathogens, such as gastric MALT lymphoma associated with H. pylori [18Ð21]. In other MALT lymphomas, local treatment (surgery or radiotherapy) results in excellent disease control in symptomatic local disease [5]. In the head and neck region, however, conventional radiotherapy (25Ð39 Gy) may lead to signiÞcant residual xerostomia, especially when the salivary glands are irradiated [22, 23]. An alternative might be low-dose 2 × 2 Gy involved Þeld radiotherapy, which is very effective in follicular lymphoma [24], and experience with this therapy in the treatment of MALT seems promising [15, 25]. For symptomatic disseminated disease chemotherapy is commonly used, with 75% complete remission rate and 5-year event-free survival and overall survival rates at 50 and 75%, respectively [12, 13, 26Ð28]. Rituximab, a chimeric murine/human anti-CD20 monoclonal antibody, has proven to be highly efÞcacious in patients with indolent and aggressive B-cell lymphoma, alone or in combination with chemotherapy [15, 29Ð32].

At present, no clear guidelines exist for the management of patients with MALTÐSS. These patients usually show an uncomplicated clinical course with a median overall survival of 6.4 years, both treated and untreated patients showed

the same overall survival [3]. A retrospective analysis reported no signiÞcant differences in outcomes among MALTÐSS patients undergoing surgery, radiotherapy, and chemotherapy [17]. Rituximab has also been used effectively in patients with MALT lymphoma, with or without associated SS [33Ð37].

In our view, morbidity in patients with MALTÐSS is not only determined by lymphoma, but also, maybe even more, by extraglandular activity of SS. Therefore, in patients with MALTÐ SS, both lymphoma and SS disease activity need to be addressedÑnot only clinical characteristics of the lymphoma, but also the severity of SS manifestations might determine the choice of treatment.

20.2Diagnosis

MALT lymphoma in patients with SS is part of a spectrum from indolent asymptomatic lymphoma without disease activity of SS, up to locally disseminated lymphoma with severe extraglandular SS manifestations. Patients suspected of SS should undergo complete SS diagnostics according to the latest consensus criteria [38]. In the EuropeanÐAmerican consensus criteria for diagnosing SS, pre-existent lymphoma is considered to be an exclusion criterion, because lymphoma of the parotid gland can cause mouth dryness and parotid gland swelling [38]. This criterion should be reconsidered with respect to the exclusion of MALT lymphoma, as this type of lymphoma could be considered as a continuum of SS. The majority of these lymphomas are associated with SS or other autoimmune diseases [17, 39]. Therefore, patients with MALT lymphoma of the salivary glands should also be further evaluated for SS, especially since patients with MALT lymphoma and associated SS usually have a more severe form of SS. Vasculitis, peripheral nerve involvement, nephritis, fever, anemia, and lymphopenia are observed signiÞcantly more often in MALTÐSS patients than in the general SS population [3].

Patients must be evaluated by a multidisciplinary team, consisting of a rheumatologist/

Fig. 20.2 Biopsy technique of parotid gland according to the technique described by Kraaijenhagen [47]. In short, a 1-cm skin incision is performed around the lower

earlobe under local anesthesia. After blunt dissection to the parotid gland, an incisional biopsy is taken. The wound is closed in layers, no post-operative drape is applied

internist, ophthalmologist, oral and maxillofacial surgeon or ENT specialist, and a pathologist. Serological analysis should not only focus on anti-SSA/SSB autoantibodies, but also on IgMRf, immunoglobulins, complements C3 and C4, cryoglobulins, and monoclonal protein. Detection of early MALT lymphoma in the major salivary glands of patients with SS is often difÞcult because histopathological features are subtle, and monoclonal expansion does not necessarily indicate presence of malignant lymphoma. Whether monoclonal B-cell populations in lymphoepithelial lesions represent lymphoma or more benign types of expansion remains controversial [40].

We recently showed that for the diagnosis of SS, an incision of the parotid gland has the same diagnostic potential comparable with that of the labial salivary gland (for the technique, see Fig. 20.2) [41]. An incision biopsy of the parotid gland for the diagnosis of SS might lead to early detection of MALT lymphoma, but the clinical relevance of asymptomatic early MALT detection is not known. We studied 11 patients who underwent a parotid biopsy for the diagnostic work-up of SS, in whom MALT lymphoma was detected by chance [42]. There was no clinical suspicion of lymphoma (e.g., no parotid gland swelling). These patients generally had localized disease and showed no progression during follow-up when left untreated. Although localization of lymphoma in the labial glands has been

described incidentally [43], the parotid gland is the location of preference, and this must be kept in mind when performing an incision biopsy of the parotid gland in the routine diagnosis of SS. In patients with a persistent swelling of the parotid gland with or without SS, Þne-needle aspiration (FNA) is the evaluation of choice to differ between benign or malignant disease. FNA and immunophenotyping by ßow cytometry are complementary and might be useful in the differential diagnosis of non-Hodgkin lymphoma [44, 45], however, Þnal diagnosis and subtyping of non-Hodgkin lymphoma requires an incision biopsy or a superÞcial parotidectomy [46]. Imaging of MALT lymphoma is described in Fig. 20.1.

20.3Staging and Evaluation of Treatment Response

It is debatable whether it is necessary to perform full staging in patients with MALTÐSS, including CT scans of thorax and abdomen and bone marrow biopsy. Bone marrow involvement is rare in the patients described and probably does neither inßuence prognosis nor treatment [12]. Although in MALTÐSS the lymphoma usually arises in the main target of the autoimmune disease, i.e., the parotid gland, localization in other mucosal sites can occur [16]. Furthermore,

these extranodal localizations are often difÞcult to detect by CT scan. It might be advisable to evaluate salivary glands by imaging or biopsy in patients with SS and MALT lymphoma localized at other extranodal sites. Imaging of MALT lymphoma of the parotid gland by MRI often reveals a localized or a diffuse lesion in the gland accompanied by multiple cysts, which probably represent focal dilatations of salivary ducts resulting from compression of terminal ducts by the lymphoma (Fig. 20.1b) [48].

Criteria for response to treatment in patients with MALTÐSS are not standardized. The International Working Group response criteria for non-Hodgkin lymphoma [49] are not sufÞcient, as both MALT and SS activity must be evaluated in order to monitor clinically relevant response to treatment. Response criteria for lymphoma of the salivary gland should be based on clinical, radiological, and pathological criteria. Physical examination of head and neck, in combination with CT scan or MRI, is recommended to determine salivary gland involvement and locoregional lymphadenopathy. Post-treatment parotid biopsies may offer an additional method for evaluating treatment and have low morbidity [50]. However, criteria for the diagnosis of residual disease and complete remission of MALT in biopsies are not clearly deÞned. As in gastric MALT lymphoma after H. pylori eradication, residual lymphoid inÞltrate may still be present in parotid gland tissue in patients with SS, making evaluation of histological response difÞcult [51]. Moreover, these inÞltrates will most likely never completely disappear in SS as they are an integral part of the ongoing autoimmune disease. Moreover, the clinical signiÞcance of these inÞltrates, as in case of Þnding MALT lymphoma by chance in parotid biopsies during work-up for SS, is not well deÞned.

20.4Treatment

There is no evidence-based treatment for SS. Corticosteroids and disease-modifying antirheumatic drugs (DMARDs) have no major effect on disease course of SS [52], although in

selected patients prednisone seems to improve salivary ßow and clinical and histological features [53Ð55]. Cyclophosphamide, with or without prednisone, has been shown to be effective in patients with renal involvement and in different other severe extraglandular complications of SS, such as systemic vasculitis and polyneuropathy [6, 56, 57]. Currently, B-cell-directed therapies (B-cell depletion) seem very promising [58]. Rituximab, alone or in combination with cyclophosphamide and prednisone (RÐCP), has also been reported to be of beneÞt in patients with secondary SS [36, 59, 60]. A recent review showed rituximab to be efÞcient regarding its effects on systemic complications and fatigue in patients with SS [61]. Currently, rituximab is standard of care for treatment of symptomatic disseminated B-cell lymphoma. It is usually combined with chemotherapy, although it is effective as single agent as well in selected cases of indolent lymphoma including MALT lymphoma [62].

No clear guidelines are available for the treatment of patients with MALTÐSS. In our view the choice of treatment should be based on the philosophy that MALTÐSS and SS are manifestations of the same disease and therefore should be treated (if at all) keeping both SS activity and MALT symptomatology in mind. Current guidelines for management and treatment of patients with MALTÐSS in our center are depicted in Fig. 20.3 and are based on our own experience [42]. In patients with asymptomatic MALT lymphoma without high SS disease activity (e.g., only arthralgia, fatigue, and/or RaynaudÕs phenomenon), Òwatchful waitingÓ seems a suitable option. Especially in these patients, surgery or radiotherapy might even be more harmful than close monitoring without treatment. In patients with symptomatic MALT lymphoma, e.g., a persistent disabling parotid gland swelling, but with low SS disease activity, local treatment with low-dose involved Þeld radiotherapy (2×2 or 1×4 Gy) might be sufÞcient, but experience with this approach in MALT lymphoma is rare. We treated a patient with disabling MALT lymphoma of the parotid gland with 2×2 Gy radiotherapy of the head and neck, which led to decrease

Fig. 20.3 Diagnosis of MALTÐSS: clinical algorithm leading to MALTÐSS diagnosis. a Patients in whom MALTÐSS is diagnosed by chance at routine diagnostic biopsy for SS diagnosis. b Patients with known SS and strong clinical suspicion of lymphoma. c Patients with unknown parotid gland swelling; MALTÐSS: patient with MALT lymphoma and associated SjšgrenÕs syndrome (SS); FNA: Þne-needle aspiration; extraglandular disease: polyarthritis/myositis, glomerulonephritis, nervous

system involvement, cryoglobulinemic vasculitis, other severe organ involvement, and serological abnormalities: cryoglobulinemia, C4 < 0.10 g/L; RÐCP: six intravenous infusions of 375 mg/m2 of rituximab and 6Ð8 cycles of

CP, given every 3 weeks. For schedule see Czuczman et al. [60]. Patients receive a dose of 4 Gy, either as

2×2 Gy, after an interval of 48 h, or as an single fraction of 4 Gy [24]

of swelling and an improvement of salivary gland function (Fig. 20.4). It is hypothesized that low-dose radiotherapy diminishes the obstruction of salivary secretion created by the lymphoma,

but does not damage the salivary parenchyma. Further studies investigating this are necessary.

High initial SS disease activity seems to constitute an adverse prognostic factor for

Fig. 20.4 a Patient with MALT lymphoma of the left parotid gland. b Same patient 3 months after 2×2 Gy lowdose involved Þeld radiotherapy. c, d Axial MRI before and after radiotherapy showing regression of MALT

lymphoma. e Parotid salivary gland function (mL/min) of the left and right parotid gland at baseline, 3 and 6 months after radiotherapy