Section 7 -

Lymphoid Lesions of Salivary Glands Roderick H.W. Simpson

Salivary gland lymphoid infiltrates include a variety of benign conditions, especially autoimmune disease, important because of its association with extranodal malignant lymphoma. Salivary disease is simulated clinically by inflammatory processes and neoplasms of lymph nodes within or adjacent to the major glands, particularly nodal type lymphomas [1]. Non-Autoimmune Lymphoid Infiltrates Chronic sclerosing sialadenitis (Küttner tumour) occurs in the submandibular gland. Its exact aetiology is unknown, but up to 80% are associated with sialoliths in the excretory ducts, although it is uncertain whether these are the cause of the disease or a secondary process. Some patients also have a similar sclerosing pancreatitis, an IgG4-related disease. The histopathologic picture of chronic sclerosing sialadenitis varies from just scattered lymphoplasmacytic aggregates to severe changes of acinar atrophy and heavy chronic inflammation with germinal center formation to an end stage of destruction of the lobular architecture and scarring. The inflammation is centered on the acini rather than ducts, although minor intraductal aggregates of neutrophils are often present. IgG4-positive plasma cells and sometimes eosinophils are numerous in the non-sialolith cases, both in the systemic and localized forms [2]. Only exceptionally are lymphoepithelial lesions (LELs) found. Infectious diseases (e.g. mumps, CMV) are rarely biopsied; an exception is AIDS-related cystic lymphoid hyperplasia probably due to direct HIV infection. The cysts are lined by squamous epithelium accompanied by lymphoid tissue showing follicular hyperplasia, but with lysis of germinal centers and loss of mantle zone lymphocytes. LELs may be present [3], and a few cases appear identical to autoimmune sialadenitis, but with negative serology. Other inflammatory infiltrates include granulomatous diseases such as sarcoidosis and tuberculosis. Kimura's disease, seen predominantly in Oriental patients, frequently affects the salivary glands. Microscopy shows acinar atrophy and fibrosis, often surrounding ducts, and a heavy lymphoid infiltrate with formation of irregularly shaped follicles, together with numerous eosinophils often forming abscesses, typically within germinal centers. There is also a proliferation of high endothelial venules with slit-like lumina lined by non-vacuolated cuboidal or atrophic endothelial cells containing pale oval nuclei. Recurrences sometimes occur after excision [4]. Chronic inflammation may accompany any tumor (e.g. acinic cell carcinoma), due to secondary obstruction, infection, or a host reaction. In particular, lymphoepithelial carcinoma (often EBV-related) closely resembles its better known counterpart in the nasopharynx, comprising syncytial aggregates of cytokeratin-positive large cells intimately associated with a dense infiltrate of lymphocytes and plasma cells. Benign Autoimmune Lymphoid Infiltrates The preferred term for this histopathological condition is lymphoepithelial sialadenitis (LESA) [5], which has replaced the older synonyms, myoepithelial sialadenitis, benign lympho-epithelial lesion and Mikulicz disease. Sjögren's syndrome (SS) is a clinical term describing the combination of dry eyes and mouth due to autoimmune infiltrates of the lacrimal and salivary glands. It is often associated with other autoimmune or connective tissue diseases, particularly rheumatoid arthritis but also others. Most patients with SS develop LESA, but not so the reverse, as up to 50% of patients with LESA do not display the clinical features of SS. The aetiology of LESA is probably autoimmune, but the pathogenetic process is not understood. Nevertheless, it is likely that an interaction of genetic, environmental, viral (HCV in some patients) and immunological factors determines its onset and progress. About 80% of patients with LESA are female, with a mean age at presentation of 55 years (range 1 to 86). The parotids are affected in over 80% of cases (20% bilaterally), the submandibular and minor glands alone in 11% and 6% respectively, although they are involved more often in conjunction with parotid disease. Tumor-like lesions of the lips, palate and floor of mouth are relatively rare, but sub-clinical foci of lymphocytes and plasma cells are frequently seen in the labial glands in SS, and a semi-quantitative assessment of a lip biopsy may have a place in the investigation of a patient with a dry mouth. Microscopic examination of the earlier stages of LESA shows that the salivary ducts are dilated and surrounded by an increasing lymphoid infiltrate with germinal centers. Unlike in non-autoimmune chronic inflammatory conditions, B-cells focally infiltrate the duct epithelium itself. In many examples of LESA, some of the B-cells are characteristic, and are known as marginal zone or monocytoid B-cells, or centrocyte-like (CCL) cells. These cells tend to be cytologically uniform in any given lesion, and may take one of three forms: 1. small mature cells similar to, but slightly larger than mantle zone lymphocytes; 2. cells containing irregularly shaped nuclei often with clefts; 3. cells with more abundant pale cytoplasm [6]. These cells are seen immediately beneath the epithelium where they merge into the mantle zones of the germinal centers. Plasma cells are also concentrated around the ducts; they and the B-cells are usually polytypic for light chains. T-cells, often numerous, are seen throughout the infiltrate, particularly around germinal centers. In time, the ducts condense, with partial or complete loss of their lumina, to form lymphoepithelial lesions (LELs), previously known as epimyoepithelial islands. These consist of cohesive aggregates of epithelium with hyalinized basal lamina material containing variable numbers of B-cells, but myoepithelial cells are relatively inconspicuous. As the disease progresses the acini become atrophied and then totally replaced by lymphoid tissue leading to clinical enlargement of the salivary glands. Monoclonality by PCR can be demonstrated in over 40% of patients with LESA [7], but this alone is probably insufficient for a diagnosis of lymphoma, and stronger evidence is required from the demonstration of monoclonality by immunohistochemistry or flow cytometry [8]. Malignant Lymphoma Lymphomas represented 16.3% of all malignant tumors of the major salivary glands at the AFIP from 1985-95 [9]. Most occur in women, usually over the age of 50 [5, 10]. They are either nodal or extranodal: the former involve intraparotid lymph nodes and are the same as those found in other nodes. Most arising in the salivary parenchyma are extranodal marginal zone lymphomas (EMZLs), also known as mucosa-associated lymphoid tissue (MALT) lymphomas. Extranodal Marginal Zone Lymphoma (MALT Lymphoma) EMZLs usually present clinically as parotid enlargement, sometimes bilateral. There is often a history of SS, but not always. In one series, 46% of patients had this association, and a further 29% had positive HCV serology [11]. Cases have been reported in other autoimmune diseases and in post-transplant patients. In contrast to nodal lymphoma, in a series of 33 salivary EMZLs, only 12% had bone marrow infiltration at presentation, 21% regional node involvement and 6% widespread lymphadenopathy; one case had lymphoma in the stomach [11]. Grossly, the gland in EMZL is firm, with a homogenous white or beige cut surface. The lobular structure may be retained, or there may be a multiple nodules separated by normal tissue. In 3% of cases, the ducts are dilated giving a multicystic appearance. The microscopic picture evolves with time [6, 10]; the earliest morphologically recognizable feature of at least borderline malignancy is proliferation of CCL cells to form a distinct halo around the LELs of LESA; monoclonality can be demonstrated at this stage [12]. Admixed with the CCL cells are plasma cells (sometimes very numerous) and transformed blast cells, and surrounding these zones in turn is a heavy lymphoid infiltrate with prominent reactive follicles. As the lymphoma evolves in a background of LESA, a decreasing proportion of the total mass is reactive. The CCL cell halos expand and coalesce to form extensive sheets, destroying the LELs. They displace then replace the follicles, or they may colonize the germinal centers replacing the normal cells with a uniform infiltrate of CCL cells, so that areas may assume a follicular-like architecture [13]. In addition, there may be foci of sclerosis, and infiltration by epithelioid histiocytes, which can form granulomas. Small numbers of large transformed blast cells may be seen in low grade EMZL, but when they comprise diffuse areas, the tumor is considered to be high grade [7]. This occurred as a late event in 12% in one series [11]. The CCL cells may involve local lymph nodes, first by expanding the area between follicles and in due course by replacing large parts of the affected node by sheets of lymphoma cells, giving an appearance identical to monocytoid B-cell lymphoma. The CCL cells express B-cell markers, e.g. CD20, CD79a, and there is surface immunoglobulin with light chain restriction; bcl-2 staining is usual. They do not react with CD5, CD10 (with very rare exceptions), CD23 or bcl-1 (cyclin D1). Cytokeratin highlights the LELs; reactive histiocytes and T-cells express their appropriate markers [14]. Several cytogenetic abnormalities are found in EMZLs, with differences between primary sites. In the salivary gland, 74% of cases show one or more genetic aberrations, most frequently trisomy 3 (in 55%), trisomy 18 (in 19%) and the t(14;18) (q32;q21) translocation in 12% [15]. The last of these juxtaposes the MALT1 gene next to the promoter region of the immunoglobulin heavy chain genes with subsequent MALT1 overexpression. The risk of EMZL evolving in LESA is estimated at 4-7% [5], and the two conditions are intimately linked. It would appear that a sustained B-cell inflammatory response directed against a relatively narrow range of antigens facilitates the selection of a single clone of neoplastic B-lymphocytes [1] and then, with the acquisition of secondary genetic changes, to EMZL. Histologic criteria alone cannot identify exactly when a clonal B-cell population emerges in LESA, and in practice the process is not so much a sharp change from one (benign) entity to another (malignant) one, but rather as a spectrum of lymphoma gradually evolving from a purely inflammatory process [7, 10]. [Table 1]. Cytogenetic investigation shows an increased frequency of abnormalities in high grade EMZLs compared to low grade neoplasms and in LESA, but there are no clear cut distinctions to be of diagnostic use. Low grade EMZLs restricted to the salivary glands are relatively indolent, usually remain localized, and are often curable with local treatment [9]. In one series, 10% of patients died of disease, but only after histologic transformation to high grade B-cell lymphoma [11]. Lymphomas Other Than Extranodal Marginal Zone Lymphoma Primary non-MALT extranodal salivary lymphomas are very rare. Most are T-cell neoplasms, including CD30+ large cell tumors, CD56+ NK/T-cell lymphomas and a lesion resembling enteropathy-associated lymphoma. Histologically, neoplastic T-cells can infiltrate epithelium mimicking LELs [16]. Primary and disseminated nodal Hodgkin's and non-Hodgkin's lymphomas can involve the intra-salivary and adjacent lymph nodes, and should be classified using the appropriate scheme, e.g. WHO [17]. Few diagnostic difficulties arise with a nodal lymphoma confined to the nodes, but if a follicular lymphoma invades into the gland itself, it must be distinguished from apparently similar structures in EMZL, i.e. reactive follicles (an integral component of the disease process), or pseudofollicles (germinal centers colonized by tumour cells) [13, 18]. This distinction is important as EMZL and nodal lymphomas behave differently. The differential diagnosis is usually obvious from the morphology. The presence of residual LELs containing aggregates of CCL cells points strongly to EMZL. Immunohistochemistry may help: cytokeratins highlight LELs. CD10 stains some mainly low grade follicle center cell lymphomas, whereas EMZLs are almost always negative [18]. Table 1. Overview of autoimmune and neoplastic salivary lymphoid proliferations. Benign LESA, non-clonal. Borderline (histological or clonal evidence of neoplasia, but unlikely to disseminate). LESA, clonal. LESA with halos of CCL/monocytoid B-cells. Low grade lymphoma (potential for spread to nodes and less often, systemically). Low grade EMZL (confluent proliferation of CCL/monocytoid B-cells). Low grade EMZL with plasmacytic differentiation. Intermediate/high grade lymphoma (arises de novo or in low grade lymphoma) High grade EMZL, with diffuse areas of large B-cells. Adapted from Quintana et al [7]. References Simpson RHW, Sarsfield PTL. Benign and malignant lymphoid lesions of the salivary glands. 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