Lymphadenopathies of Salivary Glands
Definition
Lymphadenitides and lymphadenopathies of salivary glands, lymphoid characterized by lymphoepithelial lesions (LEL).
Pathogenesis
Normally, lymphoid tissues are intimately associated with salivary glands in various forms from simple lymphoid aggregates to fully structured lymph nodes (1,2,3,4,5,6). The observation of lymphoid tissues associated with salivary glands was made as early as 1898 by Neisse, who consistently found glandular inclusions in the periparotid lymph nodes of 14 autopsied infants (7). More recently, the histogenesis of the parotid glands was investigated in a study comprising human embryos and l4 human fetuses (3). Through the examination of sequential sections, the authors showed that the rudimentary lymph nodes arise in the primitive mesenchyme that penetrates the salivary glands and proliferates around their ductal and acinar structures. By the 13th week of gestation, these formations are already in place and their association with the salivary glands is a constant feature of normal development.
The parotid gland is the only salivary gland to contain lymphoid tissues within its capsule (Figs. 43.1 and 43.2). The lymphoid tissues are in fact well-developed nodes that anatomists divide into three superficial groups and one deeply located group (3). The proportion of lymphoid and salivary tissues vary, with the former sometimes being reduced to a thin shell around the parotid lobules (2). In the submaxillary gland, the lymph nodes are not within the capsule, but three to six lymph nodes normally lie adjacent to the gland (8). The conjoint anatomic location of salivary glands and lymph nodes is not dissimilar to the interlacing of epithelial and lymphoid tissues in the Waldeyer ring, tonsils, and adenoids, as well as in other areas around portals of entry.
Because of their close association, pathologic changes within the two tissues are often combined, thus raising questions about their pathogenesis and presenting problems of differential diagnosis. Thus, lymph nodes of the parotid or submaxillary glands may be the primary site of viral infections, or be secondarily involved in bacterial sialadenitides. Occasionally, these lymph nodes become the site of human immunodeficiency virus (HIV)/AIDS-associated lymphadenopathies and present with clinical and morphologic features that may resemble salivary gland disorders (9,10,11). They may also participate in autoimmune diseases of salivary glands, such as Sjögren or Mikulicz syndromes (12,13). Finally, salivary gland lymph nodes may be the primary site of a variety of lymphomas (14,15,16,17,18,19,20,21,22) or of metastases of regional carcinomas.
Clinical Syndrome
The involved salivary glands, usually the parotids, present as unilateral or bilateral masses. They are nodular and generally large, reaching 4 to 7 cm in diameter (5). The masses are composed of multiple enlarged lymph nodes and portions of salivary gland that are not easily distinguishable on gross examination. Consequently, not infrequently, they are surgically removed with the erroneous diagnosis of salivary gland tumor.
Sjögren Syndrome
Synonym
Gougerot-Sjögren Syndrome; Sicca syndrome.
Definition
Triad of keratoconjunctivitis sicca, xerostomia of salivary glands and autoimmune antibodies (Sjögren syndrome); the association of dacryocystitis (Mikulicz syndrome).
Pathogenesis
Sjögren syndrome (SS), the second most common autoimmune rheumatic disease, results from immune lymphocytes—predominantly CD8+ T cells (23)—that infiltrate the salivary glands (lacrimal glands in Mikulicz syndrome) (24). A link between SS and hepatitis C virus was suggested based on the increased incidence of SS in chronic liver disease; however, the presence of the virus was not demonstrated in the salivary epithelial cells and the association remains controversial (23,25).
Clinical Syndrome
Sjögren syndrome is more common in middle-aged, postmenopausal women and involves the parotid gland in 85% of cases. The swellings are painful and recurrent. Dryness of the mouth (or eyes), fatigue, and myalgias (24) are present.
Histopathology
The lesions consist of progressive atrophy and replacement of salivary acini and ducts by abundant lymphoid tissue (Figs. 43.3 and 43.4). The lymphoid proliferation is polyclonal, in the early phase presenting as a mild infiltration of B cells and plasma cells with the formation of periductal follicles with reactive germinal centers. Later, T cells become predominant, leading to near-total lymphatic transformation of the salivary tissue with atrophic glands, proliferation of lymphoepithelial lesions, and fibrosis (26,27,28). The altered salivary ducts form the characteristic structures, called epimyoepithelial islands or lymphoepithelial lesions (LEL), to acknowledge their formation by the hyperplasia and metaplasia by both epithelial and myoepithelial duct cells (29,30). The epimyoepithelial islands
are infiltrated by lymphocytes, predominantly T cells, which penetrate and often induce the apoptosis of the epithelial cells (Fig. 43.5). These characteristic formations may occur in the benign lesions referred to as myoepithelial sialadenitis (MESA) or LELs, or in their malignant counterparts, the mucosa-associated lymphoid tissue (MALT)-type (marginal zone) B-cell lymphomas, in which the infiltrating cells within the LELs are lymphoma B cells (18,31,32). The presence of LEL in both benign and malignant lymphoproliferative lesions of salivary glands suggests that they constitute a continuum from polyclonal benign to monoclonal malignant lymphoid neoplasms (33,34,35).
are infiltrated by lymphocytes, predominantly T cells, which penetrate and often induce the apoptosis of the epithelial cells (Fig. 43.5). These characteristic formations may occur in the benign lesions referred to as myoepithelial sialadenitis (MESA) or LELs, or in their malignant counterparts, the mucosa-associated lymphoid tissue (MALT)-type (marginal zone) B-cell lymphomas, in which the infiltrating cells within the LELs are lymphoma B cells (18,31,32). The presence of LEL in both benign and malignant lymphoproliferative lesions of salivary glands suggests that they constitute a continuum from polyclonal benign to monoclonal malignant lymphoid neoplasms (33,34,35).
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