Thus, along with Helicobacter pylori–positive gastric mucosa–associated lymphoid tissue (MALT) lymphomas, SS is a paradigm of antigen-driven lymphomatous evolution [4].

Clinical studies on SS-related lymphoma have been hampered by their relatively low incidence, the consequent challenges in performing large prospective studies, the lack of a universal approach to treatment, and by the absence of consensus in hematopathology with regard to nomenclature and classification. Despite these limitations, significant progress in the field has been recognized in recent years.

The life-time prevalence of NHL development in SS patients ranges between 5% and 10%, with the median age at lymphoma diagnosis being 58 years (range 33–82 years) and the median time from SS diagnosis to lymphoma evolution 7.5 years [1, 5, 6]. More than 98% of SS-associated lymphomas are of B-cell origin, of which 80% are low-grade lymphomas. These low-grade lymphomas include extranodal marginal zone (MZ) tumors of the MALT type (52.5%) and nodal MZ lymphomas (NMZL) (12.5%). Follicular and lymphoplasmacytic lymphomas occur much less commonly. High-grade, diffuse large B-cell lymphomas (DLBCL) account for 17.5% of lymphoma cases in SS [6].

In this review, we present current treatment approaches in patients with SS-associated B-cell NHLs and emphasize the need for tailored therapy according to the lymphoma subtype and patients’ individual clinical characteristics. We highlight recent advances in the natural history of SS-related lymphomas that influence therapeutic strategies, explore existing controversies in the field, and indicate areas that require additional investigation.

37.2Marginal Zone (MZ) Lymphomas

The three major subtypes of MZ lymphomas are extranodal MZ B-cell lymphomas of the MALT type (MALT lymphoma), primary splenic lymphomas, and NMZL. Each of these MZ lymphoma types represents a clinically and prognostically unique subcategory within the present World Health Organization (WHO) classification [7]. MALT lymphomas represent the vast majority of MZ lymphomas, whereas the other two entities are relatively rare disorders. MALT lymphomas were named after the lymphoid micro-anatomic compartment that nourishes its presumed normal counterpart, the MZ. The MZ is situated around the follicular mantle at the periphery of the splenic white pulp, as well as at the periphery of lymphoid follicles (Fig. 37.1). The MZ fosters B-cell populations of varied maturation stages that, although functionally heterogeneous, share the capacities for plasma cell differentiation and homing to certain tissue compartments (Fig. 37.2).

MZ lymphomas are the most common type of tumors encountered in SS patients [5, 6, 8]. According to one study, patients with SS exhibited a 28-fold higher risk of developing a MZ lymphoma compared with the general population [9]. Two recent, population-based Scandinavian studies reported a somewhat lower risk [9, 10].

Fig. 37.1 Splenic lymphoid follicle: Structure and elements. The lymphoid follicle has a palestaining germinal centers (GC) in which B-cells are proliferating. Note the presence of a mantle zone (ManZ) that contains small lymphocytes and an outer marginal zone (MarZ) that contains larger lymphocytes that are less packed than cell in the ManZ. Outside the MarZ is the red pulp. MarZs are more evident in splenic follicles than lymph node follicles (H&E, × 200)

37.2.1Extranodal Marginal Zone Lymphomas of MALT Type

As a rule, MALT lymphomas are indolent. They are located at mucosal and nonmucosal extranodal sites that contain epithelium, usually columnar epithelium [11, 12]. The majority of these sites are normally devoid of any organized lymphoid element, but the neo-formation of an acquired MALT component, elicited by certain external antigenic challenges, precedes MALT lymphoma development. Although MALT lymphomas are pathogenetically associated with diverse stimuli such as infection (Helicobacter pylori) or autoimmune insults (Hashimoto thyroiditis), all appear to derive from neoplastic transformation of MZ B lymphocytes [13–15]. The histological features of MALT lymphoma closely simulate the original lymphoepithelial complexes of Peyer’s patches. Characteristic features include reactive lymphoid follicles, with or without colonization by neoplastic cells of MZ and/or monocytoid morphology (centrocytelike cells) that infiltrate the overlying epithelium (lymphoepithelial lesions). These neoplastic cells are admixed with small B lymphocytes and plasma cells that may or may not be neoplastic [16] (Fig. 37.3).

Lymphoepithelial sialadenitis, the histologic hallmark of SS, is characterized by a lymphoid population that surrounds and infiltrates the salivary ducts. Lymphoepithelial lesions result from the disorganization and proliferation of ductal epithelial cells [17]. These lesions, which appear first as small clusters, progressively organize into lymphoid follicle-like structures that contain germinal centers. The phenotype of these immunocompetent cells, mainly primed CD4+ T lymphocytes, suggests the formation of activated follicular structures in which activated B-cells produce autoantibodies [18–20]. This MALT component, acquired

Fig. 37.2 B-cell maturation in the peripheral lymph nodes. After leaving the bone marrow, the naive mature B-cells initially migrate to the outer region of the lymph node in the “primary” follicles to later transfer to the follicle mantles. Subsequently, these IgM+/IgD + cells come into contact with antigen and transform into proliferating extrafollicular B blasts, from which short-lived plasma cells and “primed” B-cells are derived. These “primed” B-cells stimulate and sustain the germinal center reaction, during which they transform into rapidly proliferating centroblasts. During the mitotic proliferation and differentiation of the centroblasts into centrocytes, somatic mutations in the variable region of the immunoglobulin genes emerge in a randomized manner. The centrocytes with mutations that lead to an increase in the affinity of the immunoglobulin receptor differentiate further, enabling them to pass out of the germinal center into the marginal zone to become longlived plasma cells or “memory” B-cells. The long-lived plasma cells predominantly populate the bone marrow and organs that are directly exposed to foreign antigens (gastrointestinal tract). Memory IgM+CD27+ B-cells are the counterpart of MZ cells and possess preferential homing to mucosa-associated lymphoid tissue sites (Peyer’s patches, bronchus, larynx)

Fig. 37.3 Lymphoepithelial lesions in MALT lymphoma of salivary gland. Centrocytelike cells surround the salivary ducts and infiltrate the epithelium to form lymphoepithelial lesions (arrow). Within the lesions, the majority of the intraepithelial lymphocytes have a similar morphology to the neoplastic cells of the surrounding lymphomatous infiltrate. (H&E, × 200). MALT mucosa-associated lymphoid tissue

secondarily to the autoimmune process, represents the substrate from which B-cell lymphomatous proliferation develops.

The distinction between lymphoepithelial sialadenitis with features of acquired MALT and MALT lymphoma remains both obscure and controversial, because clonally expanded populations of B-cells have been detected in both conditions. The distinction still relies upon the identification of particular morphological features. The presence of centrocyte-like, monocytoid and plasmacytoid cells that form broad halos around epithelial nests or broad strands and interconnect lymphoepithelial lesions are features consistent with a neoplastic process (Fig. 37.4). Other features indicating MALT lymphoma include the secondary infiltration of the reactive germinal centers by malignant lymphocytes, the presence of atypical plasma cells that contain Dutcher bodies (nuclear inclusions), clusters of histiocytes, and overt fibrosis. All the above, along with monoclonality confirmed by immunophenotyping, establish the MALT lymphoma diagnosis [17].

In SS patients, MZ lymphomas of the MALT type are primarily low-grade and localized (stage I and II) to extranodal areas [5] (Table 37.1). The salivary glands are the most commonly affected site, but other common extranodal sites are the stomach, nasopharynx, ocular adnexa, skin, liver, kidney, and lung. Twenty percent of patients display involvement of more than one extranodal site at diagnosis, illustrating the preferential migration of these cells to multiple mucosal sites. This fact emphasizes the importance of extensive staging procedures in SS patients with MALT lymphomas.

Loco-regional lymph node involvement is common with MALT lymphomas, but generalized peripheral lymphadenopathy is extremely rare. Major salivary gland enlargement, particularly of both parotid glands, is the typical presenting symptom. Most patients display indolent disease with good performance status and the absence of B symptoms, splenomegaly, and bone marrow infiltration. Elevated levels of lactate dehydrogenase (LDH) or beta 2-microglobulin levels are unusual. SS patients with MALT lymphomas frequently also have concurrent vasculitis affecting the peripheral nerves, skin, and kidneys. Anemia, lymphopenia, paraproteinemia, and mixed monoclonal cryoglobulinemia (type II) contribute further to a distinctive clinical syndrome that is not encountered in MALT lymphomas that are unrelated to SS.

Regardless of the affected site at presentation, diagnostic studies should include the standard lymphoma staging procedures and the examination of Waldeyer’s ring with complete blood count; basic biochemical studies; serum protein electrophoresis; and assays for lactate dehydrogenase, beta 2-microglobulin, and cryoglobulins. Computed tomographic scans of the chest, abdomen, and pelvis are also appropriate, as is bone marrow biopsy (Table 37.2). The initial staging should include a gastroduodenal endoscopy with multiple biopsies from gastro-esophageal junction, each region of the stomach, and the duodenum. H. pylori infection also needs to be either confirmed or excluded. Fresh biopsy and washings material should be available for cytogenetic studies in addition to routine histology and immunohistochemistry.

Sites commonly involved by MALT lymphomas may require special diagnostic procedures. Ultrasonography and magnetic resonance imaging are useful for investigations of the thyroid, soft tissues (hard palate), salivary glands, and orbits. Primary bronchial mucosa–associated lymphoid tissue lymphoma requires histological