Histology of Sjögren’s Syndrome

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Introduction

The formation of periductal lymphocytic infiltrates within the inflamed salivary glands represents the histological hallmark of primary Sjögren’s syndrome (pSS). Lymphomonocytic aggregates can spread within the tissue, affecting salivary gland morphology and function. On a discrete percentage of patients (∼25%), it is possible to observe the formation of organized germinal center (GC)-like structure, detection of which has been correlated to lymphoma development. Salivary gland histopathology is considered the gold standard for pSS diagnosis and is highly recommended in early phase clinical trials as a disease biomarker. This chapter reviews the histological features of normal and diseased salivary glands in the context of pSS and provides the reader with a tool to understand pSS histopathology and differential diagnosis, and to identify in the tissue key elements that characterize pSS pathogenesis.

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Salivary Gland Anatomy

Major salivary glands include the paired parotid, submandibular, and sublingual glands. The parotid glands are wedge-shaped, located in front of the ear and the posterior surface of the mandible. These are the largest salivary glands and are covered by fascia and parotid capsule. Each parotid gland weighs between 15 and 30 g and is divided by the facial nerve into a superficial and a deep lobe; the latter lies within the parapharyngeal space. The parotid glands are in close association with some branches of the facial nerve (cranial nerve [CN] VII).

The submandibular glands are about half the size of the parotid glands and weigh between 7 and 16 g. They are located in the submandibular triangle, which has a superior margin formed by the inferior edge of the mandible and inferior margins designed by the anterior and posterior bellies of the digastric muscle. Most of the submandibular gland lies posterolateral to the mylohyoid muscle.

The sublingual glands are the smallest of the major salivary glands, about one-fifth the size of the submandibular gland and weighing between 2 and 4 g. They lie as a flat structure in a submucosal plane within the anterior floor of the mouth, superior to the mylohyoid muscle and deep to the sublingual folds opposite the lingual frenulum. There is no true fascial capsule surrounding the glands, which are instead covered by oral mucosa. Several ducts from the superior portion of the sublingual gland either secrete directly into the floor of the mouth, or empty into the Bartholin duct that then continues into the Wharton duct.

About 600 to 1000 minor salivary glands line the oral cavity and oropharynx in the submucosa between muscle fibers. The greatest number of these glands, ranging in size from 1 to 5 mm, is in the lips, tongue, buccal mucosa, and palate, although they can also be found along the tonsils, supraglottis, and paranasal sinuses. Each gland has a single duct which secretes, directly into the oral cavity, saliva which can be either serous, mucous, or mixed.

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Histology of Normal Salivary Glands

Salivary glands are classified as exocrine glands, which secrete saliva through a duct system from a secretory structure called the salivary acinus . There are three main types of acini: serous, mucous, and mixed. Serous acini are roughly spherical and release via exocytosis a watery protein secretion. The acinar cells are pyramidal, with basally located nuclei surrounded by dense cytoplasm and secretory granules that are most abundant in the apex. Mucinous acini store a viscous glycoprotein (mucin) within secretory granules that become hydrated when released to form mucus. Mucinous acinar cells are commonly simple columnar cells with flattened, basally situated nuclei and water-soluble granules that make the intracellular cytoplasm appear clear. Mixed or seromucous acini contain components of both types, but one type of secretory unit may dominate. Between the epithelial cells and basal lamina of the acinus, flat myoepithelial cells form a lattice work and possess cytoplasmic filaments on their basal side to aid in contraction, and thus forced secretion, of the acini. Spindle-shaped myoepithelial cells are also observed around the intercalated ducts.

Salivary glands exhibit three types of ducts. The acini first secrete through small canaliculi into intercalated ducts, which are comprised of an irregular myoepithelial cell layer with narrow lumen. These in turn empty into striated ducts within the glandular lobe. Striated ducts are lined by columnar cells with basal striations caused by membrane invagination and mitochondria. Lastly, excretory ducts, lined by cuboidal epithelium, which turns into stratified squamous epithelium toward the terminal end of the duct, deliver the secrete into the mouth for the large salivary glands, namely the Bartholin duct, the Wharton duct, and the Steins duct.

The minor salivary glands are found throughout the oral cavity, with the greatest density in the buccal and labial mucosa, the posterior hard palate, and the tongue base. The majority of these glands are either mucinous or seromucinous, which secrete highly glycosylated mucins, antimicrobial proteins, and immunoglobulins. The minor salivary gland duct system is simpler than that of the major salivary glands, where the intercalated ducts are longer and the intralobular ducts lack basal striations.