Salivary Glands



Salivary Glands


Joshua I. Warrick

Elise L. Krejci

James S. Lewis Jr.





  • I. NORMAL ANATOMY



    • A. Macroscopic/gross. The salivary glands are exocrine organs that secrete components of saliva to both break down carbohydrates and lubricate the passage of food. There are three major paired salivary glands: the parotid, the submandibular, and the sublingual. There are also numerous minor salivary glands located in the submucosa of the entire upper aerodigestive tract (UADT), from the lips and nasal cavity to the major bronchi.

      The parotid glands are the largest major salivary glands and are located between the ramus of the mandible and the mastoid process. Each gland is composed of a superficial lobe and a smaller deep lobe, and the facial nerve is intimately associated with both lobes. Each gland normally contains approximately 20 intraglandular lymph nodes. The secretions of the parotid gland empty via Stensen’s duct into the buccal mucosa of the oral cavity near the second maxillary molar.

      The submandibular glands (also referred to as the submaxillary glands) are located just medial to the body of the mandible, and are smaller than the parotid glands. Their secretions drain through Wharton’s duct into the floor of the mouth.

      The sublingual glands are the smallest of the major salivary glands and are located in the floor of the mouth between the genioglossus muscle and the mandible. Their secretions drain into the floor of the mouth directly via small ducts or through the larger (Bartholin’s) duct which drains into Wharton’s duct.


    • B. Microscopic. The major salivary glands are enclosed by a connective tissue capsule and divided into lobules composed of ducts and acini, whereas the minor salivary glands are unencapsulated. The acini are composed of mucinous and/or serous epithelial cells surrounded by a layer of myoepithelial cells which contract to aid in the movement of glandular secretions. Myoepithelial cells are inconspicuous in normal salivary gland sections.

      A single acinus may be composed of a mixture of serous and mucous cells. Serous cells are pyramidal in shape and contain basophilic periodic acid-Schiff (PAS)-positive granules within their cytoplasm. Mucous cells are more rounded, have basally oriented nuclei, and contain abundant clear mucin. The parotid gland is almost exclusively serous, the sublingual gland almost exclusively mucinous, and the submandibular gland is mixed serous and mucinous (e-Figs. 6.1 to 6.3).* The acini secrete fluid into the intercalated ducts, which are lined by a low simple cuboidal epithelium. Intercalated ducts are also the source of reserve cells that can repopulate the acinar system. The intercalated ducts join to form striated ducts, which merge to form interlobular ducts, which ultimately empty into the large named ducts.


  • II. GROSS EXAMINATION, TISSUE SAMPLING, AND HISTOLOGIC SLIDE PREPARATION



    • A. Biopsies of many salivary gland lesions are taken prior to surgery to characterize the lesion and direct management.



      • 1. Fine needle aspiration (FNA) is the procedure of choice for initial characterization of salivary gland lesions for many reasons (see cytology section that follows).



      • 2. Core needle and incisional biopsies of the parotid gland can damage the facial nerve branches so are rarely performed.


    • B. Resections. Some salivary gland masses are removed in their entirety without a previous tissue diagnosis. Superficial parotidectomy remains the initial procedure of choice for benign parotid gland tumors. Submandibular gland resections are usually performed without taking any significant periglandular soft tissue, although more tissue may be included with the specimen for submandibular or parotid tumors that are known or suspected to be malignant. The rare sublingual gland tumors necessitate a resection of the floor of mouth that is qualitatively similar to those performed for mucosal-based squamous carcinomas of the same area.

      In general, salivary gland specimens are small enough to prosect the day of receipt. The gland should be described, and its dimensions recorded. The deep (covered by muscle and fascia) and superficial (covered by subcutaneous fat) surfaces of the parotid gland can sometimes be discerned, and should be differentially inked. The specimen should be serially sectioned, and any mass or focal lesion described including dimensions, color, texture, and distance to the margins. Four to five sections of the tumor, including representative areas of the closest inked margins, should be taken. At least one section of the normal surrounding gland should also be taken. For the parotid gland, the surrounding gland and any periglandular soft tissue should be thoroughly searched for lymph nodes, which should be separately submitted.


  • III. DIAGNOSTIC FEATURES OF COMMON DISEASES



    • A. Inflammation and infection. Sialadenitis, or inflammation of the salivary glands, can be divided into bacterial causes, viral causes, and autoimmune disease.



      • 1. Bacterial sialadenitis is rare and is generally a result of obstruction by stones (sialolithiasis). The causative organism is usually Staphylococcus aureus, followed by Streptococcus viridans and gram-negative rods. Surgical specimens from bacterial sialadenitis are almost never seen. However, sialadenitis may lead to an abscess that requires surgical drainage. Gross specimens may show a purulent exudate or a relatively intact gland. Microscopic sections can show abscesses, cystic degeneration, and/or bacterial colonies.


      • 2. Viral sialadenitis is most commonly caused by mumps (paramyxovirus), but can also be associated with Epstein-Barr, coxsackie, influenza A, and parainfluenza viruses. Surgical specimens are rarely encountered. Grossly infected glands are boggy and edematous, and chronic inflammation may be seen microscopically.


      • 3. Autoimmune sialadenitis is relatively common, and usually presents as Sjögren’s syndrome, characterized by facial swelling, dry mouth, and dry eyes (termed Sicca syndrome) with inflammatory arthritis and elevated autoantibodies. On physical examination, bilateral, symmetric enlargement of the salivary and lacrimal glands is seen. Diagnosis may be facilitated by a minor salivary gland biopsy, typically taken from the inner lip.

        Grossly, the major glands usually have a discrete, tan nodularity. Microscopically, in early disease, there is a lymphoplasmacytic septal inflammatory infiltrate with little to no abnormality of the parenchyma. The so-called “focus score,” a nodular collection of >50 lymphocytes, is considered diagnostic of autoimmune sialadenitis in the appropriate clinical context. In larger glands or in more severe disease, there is typically an extensive lymphoid infiltrate with germinal centers (e-Fig. 6.4). The acini are often atrophic, and interstitial fibrosis may be present. In late disease, acini may be completely absent leaving only isolated residual ducts, termed “epimyoepithelial islands,” with an associated dense intraepithelial lymphocytosis. In Sjögren’s syndrome, the lymphocytic infiltrate is polyclonal, in contrast to the monoclonal lymphoid proliferation seen in mucosa-associated lymphoid tissue (MALT) lymphoma.



      • 4. Chronic sialadenitis (or chronic sclerosing sialadenitis) is usually unilateral and clinically can mimic a true salivary gland neoplasm. When it occurs in the submandibular gland, it is known as a Kuttner tumor. Chronic sialadenitis most commonly results from sialolithiasis with obstruction, although some cases may be due to radiation therapy or duct strictures. It can have no structural or obvious etiology and recently most of these cases have been shown to be an autoimmune-related IgG4-related sclerosing disease similar to that occurring in the pancreas. Grossly, it is characterized by a very hard, fibrotic gland with lobulation and septation (e-Fig. 6.5). Histologic examination of the gland early in the disease process shows dilated ducts filled with secretions with an associated lymphocyte and plasma cell-rich infiltrate, occasionally with germinal center formation. As the disease progresses, fibrosis surrounds the ducts and results in lobulation of the gland (e-Fig. 6.6) with acinar atrophy and broad fibrous bands. Surgical excision may be required, either to definitively rule out a neoplasm or just for symptom relief.


      • 5. Necrotizing sialometaplasia is a rare inflammatory/destructive lesion that simulates malignancy and is thought to occur because of ischemic injury. Although it can occur anywhere along the UADT, the vast majority of cases occur in the hard palate. Men are slightly more commonly affected, and the average patient age is 46 years. Clinically, the lesion consists of a sharply defined and deep ulcer that develops rapidly (over a few days) and can persist for months. Grossly, the lesion consists of loose tissue with a surface ulcer and no distinguishing mass lesion. Microscopically, the most typical feature is coagulative necrosis of the minor salivary gland lobules with a prominent associated inflammatory response. There is extensive squamous metaplasia of the ducts (an alarming feature), but the lesion retains its overall lobular architecture (e-Fig. 6.7). The surface squamous mucosa may show pseudoepitheliomatous hyperplasia. The lack of peripheral infiltration and the retained lobular architecture are keys to recognizing the lesion as benign. No specific therapy is indicated because the lesion is self-healing.


    • B. Cystic lesions



      • 1. Acquired immune deficiency syndrome (AIDS)-related parotid cysts (ARPCs) are benign lymphoepithelial cysts. Patients present with unilateral or bilateral, painless, slowly enlarging parotid masses. They sometimes have associated cervical lymphadenopathy and/or nasopharyngeal swelling. Grossly, these lesions have multiple cystic spaces usually containing serous fluid. Microscopically, ARPCs consist of cysts that most often have a thin, mature squamous epithelial lining, although the lining is sometimes cuboidal or columnar with goblet cells. Below the epithelium, the cyst wall has dense lymphoid tissue with germinal centers. Occasionally, lesions within the gland can lack cystic change and appear similar to epimyoepithelial islands.

        Unlike autoimmune sialadenitis, the vast majority of human immunodeficiency virus (HIV) patients with ARPC have no autoimmune symptoms, no Sicca syndrome from glandular dysfunction, and no serum autoantibodies. The etiology of ARPC is thus unclear. Patients usually have bilateral disease by radiologic examination, even if there are no symptoms and no clinical mass in the contralateral gland. If the diagnosis is established by radiologic imaging and cytology, surgery is not necessary for other than cosmetic reasons.


      • 2. Benign lymphoepithelial cysts are unifocal lesions that occur in patients in their fifth and sixth decades. They most commonly involve the parotid gland, but are occasionally seen in the oral cavity. There is no association with systemic disease. Grossly, they consist of well-circumscribed unilocular cysts with contents ranging from serous to mucoid to caseous; keratinous debris may be present. Microscopically, they consist of a cyst lined by thin, mature squamous epithelium without papillary projections. In rare cases, the lining is cuboidal or columnar with goblet cells. Below the epithelium, the cyst
        wall has dense lymphoid tissue with germinal centers (e-Fig. 6.8). Excision is curative, and the lesion does not recur.


      • 3. Mucoceles are the most common non-neoplastic lesion of salivary gland tissue and are defined as pooling of mucin in a cystic cavity. Two types are recognized. In the retention type, the mucin is within a dilated duct. In the extravasation type, the mucin accumulates in the soft tissue. The lower lip is the most common site for mucoceles, followed by the tongue, the floor of the mouth (where the lesion is termed a “ranula”), and the buccal mucosa. The peak incidence of mucoceles is in the third decade. Grossly, a mucocele presents as a cystic cavity in the connective tissue that is filled with glistening fluid. Microscopically, the cyst wall may or may not have an epithelial lining, depending on the type. Those of the retention type have a lining and usually no surrounding inflammation, whereas those of the extravasation type consist of mucin with surrounding inflammatory cells and no lining. Some late lesions consist only of a collection of foamy histiocytes containing mucin (e-Fig. 6.9), which can be confirmed by PAS or mucicarmine stains. Surgical excision is usually curative.


  • IV. NEOPLASMS. Neoplasms of the salivary gland can be roughly classified based on the cell type(s) of the normal salivary gland toward which they differentiate: acinar, myoepithelial, or ductal. However, most neoplasms have dual differentiation because almost all show of those with ductal differentiation also have some myoepithelial differentiation. Most benign neoplasms have a malignant counterpart. The World Health Organization (WHO) classification of tumors of the salivary gland is listed in Table 6.1.



    • A. Benign neoplasms



      • 1. Pleomorphic adenoma (PA) is the most common neoplasm of the salivary glands. Ninety percent of PAs occur in the parotid gland and PAs represent 60% of parotid gland neoplasms; the majority of the remaining cases occur in the hard palate or submandibular gland. The tumor occurs over a wide age range, but the peak incidence is in the fourth and fifth decades. The tumor presents as a slow-growing, painless mass that usually is between 2 and 5 cm in diameter. On gross examination, these tumors appear well-circumscribed but are not usually encapsulated. They are never encapsulated when occurring in minor salivary glands. Sectioning reveals a rubbery, myxoid, tanwhite mass (e-Fig. 6.10). The microscopic appearance, as the name suggests, is highly variable, but always shows an intimate admixture of epithelial and mesenchymal elements. The epithelial component consists of ductal structures with an associated myoepithelial layer but also may contain collections of myoepithelial cells that can range from spindled to clear, plasmacytoid, or basaloid. The mesenchymal, or stromal, component is typically myxoid, hyaline, or chondroid (e-Fig. 6.11). Although defined subcategories have no clinical significance, pleomorphic adenomas have been divided into a myxoid type (>80% mesenchymal-type tissue), cellular type (>80% epithelial-type tissue), and mixed or classic type (generally an equal mix of components).

        Treatment requires complete excision because PAs are likely to recur if tumor is left behind or transected. Multinodular growth is uncommon in primary tumors but is frequent in recurrent disease, yielding a so-called “buckshot” pattern (e-Fig. 6.12). Therapy for recurrence is consequently more difficult.


      • 2. Warthin tumor (papillary cystadenoma lymphomatosum) is the second most common benign salivary gland tumor and is found exclusively in the parotid gland. It is the most common bilateral or multifocal salivary gland tumor, usually presents in the sixth or seventh decade, and is associated with smoking. Grossly, it presents as a soft, brown or yellow mass that is composed of cysts that are classically filled with viscous brown fluid. Microscopically, the lesion has a characteristic and highly reproducible morphology with papillary projections into cystic spaces which have an epithelial lining composed of two layers of cells with oncocytic features (e-Fig. 6.13). The epithelium overlies a dense, polyclonal, lymphoid component with germinal centers. Warthin tumors may show a giant cell reaction, fibrosis, or squamous metaplasia from trauma and/or cyst rupture. Surgical excision is almost always curative as recurrence is rare. Associated malignancy is also very rare and is usually either squamous cell carcinoma or lymphoma.









        TABLE 6.1 WHO Histologic Classification of Tumors of the Salivary Glands










































































































        Malignant epithelial tumors


        Acinic cell carcinoma


        Mucoepidermoid carcinoma


        Adenoid cystic carcinoma


        Polymorphous low-grade adenocarcinoma


        Epithelial-myoepithelial carcinoma


        Clear cell carcinoma, not otherwise specified


        Basal cell adenocarcinoma


        Sebaceous carcinoma


        Sebaceous lymphadenocarcinoma


        Cystadenocarcinoma


        Low-grade cribriform cystadenocarcinoma


        Mucinous adenocarcinoma


        Oncocytic carcinoma


        Salivary duct carcinoma


        Adenocarcinoma, not otherwise specified


        Myoepithelial carcinoma


        Carcinoma ex pleomorphic adenoma


        Carcinosarcoma


        Metastasizing pleomorphic adenoma


        Squamous cell carcinoma


        Small cell carcinoma


        Large cell carcinoma


        Lymphoepithelial carcinoma


        Sialoblastoma


        Benign epithelial tumors


        Pleomorphic adenoma


        Myoepithelioma


        Basal cell adenoma


        Warthin’s tumor


        Oncocytoma


        Canalicular adenoma


        Sebaceous adenoma


        Lymphadenoma



        Sebaceous



        Non-sebaceous


        Ductal papillomas



        Inverted ductal papilloma



        Intraductal papilloma



        Sialadenoma papilliferum


        Cystadenoma


        Soft tissue tumors


        Hemangioma


        Hematolymphoid tumors


        Hodgkin’s lymphoma


        Diffuse large B-cell lymphoma


        Extranodal marginal zone B-cell lymphoma


        Secondary tumors


        From: Barnes L, Eveson J, Reichart P, Sidransky D, eds. World Health Organization Classification of Tumours. Pathology and Genetics. Head and Neck Tumours. Lyon: IARC Press: 2005. Used with permission.










        TABLE 6.2 Major Architectural Patterns of Basal Cell Adenoma











        Tubular


        Solid


        Trabecular


        Membranous (“dermal anlage tumor”)



      • 3. Basal cell adenomas are benign tumors that are composed of small basaloid cells. They generally occur in adults, and 75% occur in the parotid gland. They usually present as an asymptomatic, slowly growing mass. The membranous subtype (“dermal anlage tumor”) may be multicentric. The occurrence of numerous basal cell adenomas, dermal cylindromas, and trichoepitheliomas is called Brooke-Spiegler Syndrome.

        On gross examination, these tumors are usually solid, well-circumscribed, and pink to brown. Some may be cystic. Microscopically, four patterns are recognized: tubular, solid, trabecular, and membranous (Table 6.2). In all patterns, the tumor is composed of two cell types. Small cells with little cytoplasm typically lie at the neoplasm’s edge, frequently show peripheral palisading, and give the tumor its basaloid appearance. Polygonal basaloid cells with slightly more cytoplasm and round to oval nuclei with more open chromatin usually lie in the center of the nests. The trabecular and membranous patterns have a “jigsaw puzzle” appearance with rounded nests of tumor cells shaped like puzzle pieces (e-Fig. 6.14). The membranous pattern additionally shows hyalinized, eosinophilic, linear, or nodular basement membrane-like material around the nests (e-Fig. 6.15). The tubular pattern consists of tubular, gland-like structures (eFig. 6.16). The solid pattern consists of solid nests of cells. The tumor cells express ductal and myoepithelial markers including pan-cytokeratin, S-100, smooth muscle actin, and p63.

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Oct 20, 2016 | Posted by in PATHOLOGY & LABORATORY MEDICINE | Comments Off on Salivary Glands
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