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Fine Needle Aspiration Biopsy Cytology of Salivary Gland: A Diagnostic Approach Based on Pattern Recognition
Fine needle aspiration biopsies (FNAB) of salivary gland and head and neck lesions can represent a major component of the total volume of FNAB in a pathologist’s practice. These specimens can also be the most challenging due to the number and complexity of the lesions in the head and neck area. It is difficult to memorize all of the possible variations that many salivary gland and head and neck lesions possess. Fortunately, many of the lesions and their variants fall under a relatively small number of architectural patterns seen on FNAB smears, and each pattern produces a more manageable list of diagnostic possibilities. This chapter focuses primarily on the diagnosis of salivary gland lesions and selected head and neck lesions. Mesenchymal and lymphoproliferative lesions are discussed in the soft tissue and lymph node chapters of this book, respectively.
The general approach to FNAB smears of salivary gland lesions includes evaluation of various cellular and extracellular components within the slide background. This includes the presence or absence of stromal material. In this context, “stroma” is defined as extracellular matrix that is produced by myoepithelial cells. The presence or absence of cellular-derived material, such as mucinous material and granular or cystic debris, is also assessed.
Secondly, the types of cells within the biopsy are evaluated. This includes the presence or absence and type of inflammatory cells and possibly neoplastic hematopoietic cells, as well as the presence or absence of epithelial cells (ductal cells, acinar cells, squamous cells, melanocytes, etc.), and if present, whether these cells form a single or mixed population of cell types. The tendency of these epithelial cells to form cohesive tissue fragments, loosely cohesive tissue fragments, or discohesive arrays is noted. The association of epithelial cells with stromal material is also an important observation.
FNAB Smear Patterns
The six basic smear patterns when evaluating FNAB smears of salivary gland/head and neck lesions are as follows:
1
Mixed Inflammatory Pattern ( Plate 2-1 )
A mixed population of inflammatory cells seen at scanning magnification (×5 or ×10) characterizes mixed inflammatory processes. These lesions often yield cellular smears and may include a combination of inflammatory cells including neutrophils, lymphocytes, histiocytes including multinucleated forms, plasma cells, and granulomatous tissue fragments. The inflammatory cells may be admixed with fragments of granulation tissue. Salivary gland acini and ducts may be present but are often rare or entirely absent in these processes. Entities that are associated with the mixed inflammatory pattern are often associated with an infectious process. Aseptic inflamed cystic processes, such as inflamed branchial cleft cysts, may also be associated with this pattern. Although this pattern is not associated directly with neoplastic processes, a neoplasm may be adjacent to a mixed inflammatory lesion and keratinous material can elicit a granulomatous response.
Plate 2-1
Pattern 1 Mixed Inflammatory
Plate 2-2
Pattern 2 Lymphocyte Only
Plate 2-3
Pattern 3 Epithelial Proliferations and Neoplasms Without Myoepithelial Stromal Component
Plate 2-3 Table
Pattern 3: Epithelial Proliferations and Neoplasms Without Myoepithelial Stromal Component
Entities in the Differential Diagnosis
|
Plate 2-4
Pattern 4 Epithelial Neoplasms With Abundant Myoepithelial Stromal Component
Plate 2-4 Table
Pattern 4: Epithelial Neoplasms With Abundant Myoepithelial Stromal Component
Entities in the Differential Diagnosis
|
Plate 2-5
Pattern 5 Epithelial Neoplasms With Scant Myoepithelial Stromal Component
Plate 2-5 Table
Pattern 5: Epithelial Neoplasms With Scant Myoepithelial Stromal Component
Entities in the Differential Diagnosis
|
Plate 2-6
Patter 6 Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Plate 2-6 Table
Pattern 6: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Entities in the Differential Diagnosis
|
2
Lymphocyte-Only Pattern ( Plate 2-2 )
Entities that are composed exclusively of lymphoid cells include benign intrasalivary or perisalivary gland lymph nodes, lymphomas, and lesions with other mixed components, including epithelial cells where the epithelial component has been undersampled. Discussions of benign reactive lymphoid proliferations and lymphomas are covered in Chapter 3 on lymph nodes. FLOAT NOT FOUND
The remaining FNAB smear patterns are associated with epithelial cells or epithelioid groups, with or without the presence of a lymphoid background, or with or without the presence of myoepithelial-derived stromal material. If myoepithelial stromal material is present, the relative amount of stromal material, whether abundant or scant, is associated with a different list of diagnostic possibilities. It should be noted that one specific entity may be associated with more than one architectural pattern (e.g., mucoepidermoid carcinoma), and that is uncommon for lesions associated with lymphoid cells to be associated with myoepithelial-derived stromal material and vice versa. All of the remaining patterns can be associated with benign and malignant entities.
3
Epithelial Proliferations and Neoplasms Without Myoepithelial Stromal Component ( Plate 2-3 )
These entities are not associated with an inflammatory or stromal component and include non-neoplastic, benign neoplastic, and malignant entities. Although not a true “epithelial proliferation,” the most common benign entity associated with this pattern is normal salivary gland (see Fig. 2-2 ), while the most common malignant entity is mucoepidermoid carcinoma. FLOAT NOT FOUND
4
Epithelial Neoplasms With Abundant Myoepithelial Stromal Component ( Plate 2-4 )
This smear pattern requires the presence of an abundant amount of myoepithelial-derived stromal material that is easily recognizable at low-scanning magnification. The stromal component may be intimately associated with epithelial or myoepithelial cells, as in a mixed tumor, or may be acellular, as in the stromal balls of an adenoid cystic carcinoma. Pleomorphic adenoma or mixed tumor of salivary gland is by far the most common benign entity associated with this architectural pattern, whereas adenoid cystic carcinoma is the most common malignant neoplasm in this category. There are only a few entities associated with this pattern. FLOAT NOT FOUND
5
Epithelial Neoplasms With Scant Myoepithelial Stromal Component ( Plate 2-5 )
This smear pattern is similar to “epithelial neoplasms with abundant stromal component” except that the proportion of stromal material to epithelial cells is low and occasionally difficult to recognize on scanning magnification. Pleomorphic adenoma is also the most common benign entity associated with this pattern, while adenoid cystic carcinoma is the most common malignant entity. FLOAT NOT FOUND
6
Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background ( Plate 2-6 )
This smear pattern is a common pattern associated with salivary gland lesions, and the commonest entity is Warthin tumor, but the pattern includes several non-neoplastic, other benign neoplastic and malignant entities. The lesions with this pattern are generally not associated with myoepithelial-derived stroma. FLOAT NOT FOUND
I
Non-Neoplastic Entities
Normal Salivary Gland
Smear Pattern: Epithelial Proliferations and Neoplasms Without Myoepithelial Stromal Component
The parotid gland is composed of serous acini, the submandibular gland of mixed serous and mucinous glands, and the minor and sublingual glands of mucinous acini. Benign salivary gland material is commonly seen in FNAB smears as the only material present, but it can be found amid a pathologic process.
Cytologic diagnostic criteria ( Figs. 2-1, 2-2A and B )
-
Pattern: epithelial proliferations and neoplasms without myoepithelial stromal component .
-
“Bunch of grapes” pattern: mixture of acini consisting of acinar cells (serous cells in the parotid, serous, and mucinous cells in the submandibular gland and mucinous cells in minor salivary glands) and lesser numbers of ductal tissue fragments. Adipose tissue is commonly present.
The acinar cells have small, eccentrically placed dark nuclei, similar to the diameter of red blood cells, surrounded by an abundant amount of granular to foamy cytoplasm. Acinar cytoplasm is fragile; therefore it is not unusual for acinar bare nuclei to be present in the background, which may mimic a population of small lymphocytes. The tissue fragments of acini are sometimes intimately associated with benign salivary gland ducts, which are composed of bland cuboidal cells in rows and columns arrangement. The cytoplasm of ductal cells is dense and homogenous. The ducts can also be scattered separately in the background. The salivary gland acini and ducts are often closely associated with fragments of benign adipose tissue.
Acute Sialadenitis
Smear Pattern: Mixed Inflammatory
Clinical Features
Acute sialadenitis is often caused by a viral or bacterial infection. Affected patients often present with a generalized tender swelling of the gland. This lesion is often diagnosed on the basis of clinical findings and is usually not aspirated. A common cause of acute sialadenitis of the submandibular gland is an Actinomyces infection. The gland is usually tender to palpation and painful on FNAB, often producing watery material.
Cytologic diagnostic criteria ( Figs. 2-3A-C, 2-4 )
-
-
Combination of proteinaceous debris, acute inflammatory cells, histiocytes, and reactive salivary gland ducts and acini.
-
Often no normal salivary gland elements.
-
Stellate fragments of granulation tissue are common, composed of branching blood vessels, fibroblasts, and myofibroblasts admixed with inflammatory cells including histiocytes.
-
“Sulfur granules,” or aggregates of filamentous bacteria, are common in cases of Actinomyces infection.
Cytopathology
Differential Diagnosis
One should keep in mind that the presence of granulation tissue can be confused with a nonkeratinizing squamous cell carcinoma (SCC). The plump endothelial cells, which line the vascular spaces, can show a considerable degree of nuclear enlargement and prominent nucleoli. Although these cells can appear particularly alarming, the chromatin pattern of these nuclei is open and vesicular, and the nuclei themselves are relatively uniform in size. Strict adherence to nuclear characteristics of malignancy should lead the observer to recognize benign granulation tissue in these inflammatory cases. In addition, in cell blocks the vessels within granulation tissue should demonstrate positivity to vascular immunohistochemistry (IHC) stains such as CD34, CD31, and factor VIII and negativity to cytokeratins.
Chronic Sialadenitis
Smear Pattern: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Clinical Features
Chronic sialadenitis can occur in any salivary gland, although most cases involve the submandibular gland. Patients often present with swelling and firmness of the gland, with or without pain, often after eating. Chronic sialadenitis is often a result of complete or partial obstruction of the salivary gland ducts by sialoliths or other entities, including an adjacent neoplasm. Previous radiation therapy or infection including bacterial or viral infection can also lead to chronic sialadenitis.
FNAB may be painful and yield a small amount of fluid. FNAB smears may show small fragments of material dispersed throughout the slides.
Cytopathology
Salivary gland obstruction often results in chronic inflammation, atrophy of the salivary gland acini, fibrosis, and occasionally dilatation of the salivary gland duct, which may lead to subsequent cyst formation. Some areas of the gland may be uninvolved.
Cytological diagnostic criteria ( Figs. 2-5A and B )
-
Pattern: epithelial proliferations and neoplasms associated with a lymphoid background.
-
Mixed population of chronic inflammatory cells admixed with a variable number of salivary gland ducts and acini.
-
Depending on the duration of the inflammatory process, the number of acini may be reduced, exhibit atrophic features, or be absent all together.
-
Tightly cohesive salivary gland duct tissue fragments loosely scattered throughout the background, often show blunted edges.
Ductal epithelium can undergo squamous, mucinous, sebaceous, ciliated, and oncocytic metaplasia. Occasionally, lymphoid cells may be closely associated with the salivary gland ducts and are prone to lymphoid streaking artifact when present on FNAB smears. A background of extravasated serous or mucinous debris may be present. Occasionally, cases show the presence of small microcalcifications or crystalline fragments.
Differential Diagnosis
The presence of oncocytic metaplasia in a case of chronic sialadenitis may raise the possibility of a Warthin tumor, particularly if the lesion presents as a cystic lesion. However, the number of oncocytic clusters is few in comparison with most cases of Warthin tumor.
Malignant processes such as mucoepidermoid carcinomas and squamous carcinomas may be associated with chronic inflammation; therefore the presence of lymphoid cells alone does not distinguish chronic sialadenitis from these malignant entities. The presence of extravasated mucinous material and/or the presence of squamous or mucinous metaplasia within the ductal epithelium may also heighten the concern for a mucoepidermoid carcinoma, particularly a low-grade type. Reactive and metaplastic ductal cells in some cases of chronic sialadenitis can show a significant degree of nuclear enlargement and resemble intermediate cells of mucoepidermoid carcinoma or basaloid or keratinizing cells of SCC. However, atypical ductal cells in cases of chronic sialadenitis usually do not exhibit the degree of cellularity and discohesion as compared with these malignant alternatives. Profound nuclear anaplasia is not a feature of chronic sialadenitis. One should keep in mind that it is not uncommon for areas of chronic sialadenitis to occur adjacent to a neoplastic process.
Chronic Sclerosing Sialadenitis (Kuttner Tumor)
Smear Pattern: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Clinical Features
Chronic sclerosing sialadenitis is a subset of chronic sialadenitis involving the submandibular gland often bilaterally. It usually affects adults, most commonly older than 40 years of age. There is a slight male predominance. The lesion is now felt to be an IGg4-associated plasma cell lesion. Most patients experience a generalized firmness of the gland, which can mimic a neoplastic process. There is usually firm resistance to the needle on FNAB, and the smears often show a scant amount of tissue.
Cytopathology
This chronic inflammatory process leads to marked periductal fibrosis of the salivary gland ducts that results in severe atrophy of the salivary gland acini.
Cytologic diagnostic criteria ( Figs. 2-6A and B )
-
Pattern: epithelial proliferations and neoplasms associated with a lymphoid background .
-
Moderate to marked lymphoid background and plasma cells, admixed with a low number of epithelial tissue fragments, primarily composed of ductal cells.
-
Fragments of sclerotic debris, occasionally associated with attenuated ductal structures and chronic inflammatory cells.
The relatively small number of epithelial tissue fragments on FNAB are associated with the degree of acinar atrophy and sclerosis of the gland. The findings are similar to cases of chronic sialadenitis with an increased amount of dense collagenous stroma that surrounds the scattered salivary gland ducts.
Differential Diagnosis
Kuttner tumor can resemble lymphoepithelial sialadenitis. However, chronic sclerosing sialadenitis almost exclusively involves the submandibular gland, whereas lymphoepithelial sialadenitis primarily affects the parotid gland. Although a background of chronic inflammatory cells characterizes both lesions, the lymphoid population of lymphoepithelial sialadenitis is usually more intense and shows a greater degree of polymorphism as compared with a Kuttner tumor. Aspirates of Kuttner tumor show relatively small ductal structures surrounded by sclerotic material, whereas lymphoepithelial sialadenitis demonstrates the presence of moderate- to large-sized lymphoepithelial tissue fragments.
Granulomatous Sialadenitis
Smear Pattern: Mixed Inflammatory
Clinical Features
Granulomatous sialadenitis may be unilateral or bilateral in its presentation and can affect essentially all age groups on the basis of the etiology of the granulomatous response. Causes of granulomatous sialadenitis are numerous and include duct obstruction with extravasation of mucin from sialolithiasis, adjacent tumor, or infection such as tuberculosis; fungal infection; cat scratch disease, sarcoidosis; autoimmune diseases such as Crohn disease; and allergy.
Granulomatous sialadenitis may present in a similar fashion to chronic sialadenitis: generalized swelling of the gland that may or may not be associated with tenderness on FNAB.
Cytopathology
Granulomatous sialadenitis is characterized by the mixed inflammatory pattern . The inflammatory component varies depending on the cause of the inflammatory process.
Cytologic diagnostic criteria ( Fig. 2-7 )
-
Pattern: mixed inflammatory, including granulomas .
-
Infectious cases: Granulomas are composed of epithelioid or spindle histiocytes with oval to elongated nuclei. Aggregated histiocytes may be present situated in a background of chronic inflammatory cells, sometimes with giant cells and necrotic debris. When present, frank granular necrosis suggests mycobacterial, fungal, or cat scratch infection, while necrotic cellular debris with neutrophils may be more indicative of fungal or cat-scratch disease.
-
Granulomatous sialadenitis associated with a rupture of a duct or cyst may result in extravasation of serous or mucinous debris accompanied with collections of epithelioid granulomas and giant cells. Depending on the extent of granulomatous inflammation, normal salivary gland acini and ducts may not be present.
-
Sarcoidosis is characterized by tight, cohesive epithelioid granulomas; necrosis and acute inflammation are absent.
Differential Diagnosis
Granulomatous sialadenitis often mimics cases of acute or chronic sialadenitis, particularly when granulomas are rare or difficult to recognize. One should keep in mind that cases of granulomatous sialadenitis may be associated with benign or malignant obstructive lesions of the salivary glands.
Ancillary Diagnostic Studies
Acid-fast bacterium stains, Grocott methenamine silver or diastase periodic acid−Schiff (PAS) stains, and Warthin starry stains are useful in cases of acid-fast, fungal, or cat scratch disease, respectively, and can be performed on direct smears or on the cell block, while cultures for acid-fast bacterium and fungi are mandatory using needle washings or separate passes.
Necrotizing Sialometaplasia
Smear Pattern: Mixed Inflammatory
Clinical Features
Necrotizing sialometaplasia (NSM) is a rare condition that primarily affects the minor salivary glands, most commonly on the palate. Other oral and extraoral sites may be affected, especially after previous surgery or radiation. There is general consensus that the development of the lesion is preceded by an ischemic event. A rapidly growing and ulcerating lesion of the palate, which may resemble a malignant process, characterizes most cases. The lesion may be associated with pain. Many of these lesions will heal spontaneously over time, usually within 2 to 12 weeks.
Cytopathology
Cytologic diagnostic criteria ( Figs. 2-8A-C )
-
Pattern: mixed inflammatory usually with necrotic debris .
-
Acute and chronic inflammation, granulation tissue formation, and squamous metaplasia of the salivary gland ductal cells in tissue fragments and single dispersed cells, with possible cytologic atypia.
-
Ghostlike acini forming grapelike clusters; well-preserved acini may be absent.
Differential Diagnosis
The differential diagnosis (DD) includes a high-grade salivary gland neoplasm such as a mucoepidermoid carcinoma or a primary SCC of the oral mucosa, particularly in cases with significant reactive metaplastic ductal atypia. Strict adherence to cytologic criteria of malignant epithelial cells will usually avoid a misdiagnosis of necrotizing sialometaplasia as a malignant epithelial tumor.
Ancillary Diagnostic Studies
A recent study has reported the presence of residual myoepithelial cells highlighted with myoepithelial markers, such as calponin, P63, and smooth muscle actin (MSA), in cases of necrotizing metaplasia. These myoepithelial markers are absent in cases of malignant tumors, such as mucoepidermoid carcinoma and SCC.
Lymphoepithelial Sialadenitis
Smear Pattern: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Clinical Features
Lymphoepithelial sialadenitis is a feature of Mikulicz disease, a localized autoimmune process, and Sjögren syndrome, a systemic autoimmune disorder; both disorders are more common in women. However, lymphoepithelial sialadenitis can occur in patients without any known history of autoimmune disease. There is an increased risk of the development of lymphoma in those affected, particularly extranodal marginal zone B-cell lymphoma (lymphoma arising in mucosa associated lymphoid tissue [MALT]).
Lymphoepithelial sialadenitis presents with a diffuse enlargement of the salivary gland, usually the parotid gland. The lesion usually presents bilaterally, although it can manifest as a generalized unilateral enlargement. When this lesion presents in patients with Sjögren disease, there is often concomitant dry eyes and mouth, the compilation of symptoms comprising primary Sjögren syndrome.
Cytopathology
Lymphoepithelial sialadenitis is characterized by a reactive lymphoid infiltration of the salivary gland, with disappearance of salivary gland acini and hyperplasia and metaplasia of the remaining salivary gland ducts. These epithelial tissue fragments are often infiltrated with lymphocytes, resulting in lymphoepithelial tissue fragments.
Cytologic diagnostic criteria ( Figs. 2-9A-C )
-
Pattern: epithelial proliferations and neoplasms associated with a lymphoid background .
-
Heterogeneous population of lymphoid cells including germinal centers and plasma cells.
-
Acinar groups usually absent. Tight, cohesive ductal tissue fragments and variably sized cohesive epithelial, monolayered sheets, often infiltrated with lymphocytes. Cells within monolayered sheets have a moderate amount of dense cytoplasm that surrounds round, oval, and spindle-shaped bland nuclei, with varying degrees of nuclear overlap and occasional nuclear grooves.
Differential Diagnosis
The presence of hyperplastic epithelial groups admixed with lymphocytes may mimic a Warthin tumor; however, Warthin tumors are composed of oncocytic cells unlike lymphoepithelial sialadenitis. Oncocytic sheets in Warthin tumors are generally not infiltrated by lymphoid cells, unlike the epithelial fragments in lymphoepithelial sialadenitis. In addition, the lymphoid component within Warthin tumors is composed of a rather monomorphic population of small lymphocytes, unlike the polymorphous population in lymphoepithelial sialadenitis. Warthin tumors are usually cystic, unlike the solid presentation of most cases of lymphoepithelial sialadenitis.
Chronic sialadenitis is another consideration in the setting of lymphoid cells with epithelial tissue fragments. Most cases of chronic sialadenitis have fewer lymphocytes, without germinal center formation, and have atrophic acini and small ductal structures. Lymphoepithelial tissue fragments may occur in chronic sialadenitis, but this is not the usual finding in this lesion.
Occasionally, lymphoepithelial sialadenitis may mimic an intraparotid lymph node, especially in cases where lymphoepithelial groups are few in number or in cases of suboptimal sampling of the mass.
Lymphoma can arise in the setting of lymphoepithelial sialadenitis, especially in long-standing cases. A monomorphic population of lymphocytes in the setting of a lymphoepithelial sialadenitis should raise the concern for a mucosal-associated lymphoid tissue (MALT) lymphoma, especially with a history of accelerated enlargement of the gland. One should consider obtaining material for IHC and flow cytometry to rule out lymphoma in such a case.
Benign Lymphoepithelial Cyst
Smear Pattern: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
Clinical Features
Benign lymphoepithelial cysts most commonly occur within the parotid gland. Most patients affected with benign lymphoepithelial cysts are older than 30 years; there is no sex predilection. Non−human immunodeficiency virus (HIV)-related lesions are most commonly unicystic and unilateral. HIV-related lesions may present with simultaneous or subsequent bilateral parotid lesions, in addition to significant lymphadenopathy.
Cytopathology
Cytologic diagnostic criteria ( Fig. 2-10 )
-
Pattern: epithelial proliferations and neoplasms associated with a lymphoid and cystic background .
-
Cystic debris, lymphocytes, and macrophages.
-
Epithelial components usually consist of tissue fragments of squamous cells, although columnar, cuboidal, or ciliated cells, similar to the epithelium in branchial cleft cysts, can occur.
Differential Diagnosis
The DD includes other cystic lesions such as branchial cleft cyst, Warthin tumor, and the cystic variant of mucoepidermoid carcinoma. The latter two lesions are easily distinguished from lymphoepithelial cysts, provided that they have been well sampled to reveal the diagnostic neoplastic epithelial cells. Any residual mass remaining after a cystic lesion has been aspirated should always be rebiopsied to rule out a related neoplastic process.
Postradiation Sialadenitis
Smear Pattern: Epithelial Proliferations and Neoplasms Associated With a Lymphoid Background
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