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Pathology Patterns Reviews

Review of Fine-Needle Aspiration Cytology of Salivary Gland Neoplasms, With Emphasis on Differential Diagnosis
Perkins Mukunyadzi, MD
Key Words: Salivary gland; Neoplasm; Fine-needle aspiration; Differential diagnosis
DOI: 10.1309/5FECYJ9639CMQM0L

The widespread use of fine-needle aspiration (FNA) biopsy of salivary gland lesions in many centers is testimony to its usefulness and acceptance as a diagnostic technique. Many pertinent questions concerning a mass arising in the salivary gland can be answered by evaluation of FNA cytologic material, and these include whether the mass is truly of salivary gland origin, whether the lesion is inflammatory or neoplastic, and if neoplastic, whether benign or malignant. On diagnosis of a neoplastic salivary gland lesion, the next important issue is to correctly classify the tumor, particularly if malignant. Specific cytologic diagnoses can be achieved in the majority of cases, thus enabling the clinician and patient to make appropriate informed decisions. The cytologic evaluation of salivary gland tumors, however, is limited by the wide range and heterogeneous nature of benign and malignant tumors arising in this area, many of which share similar or show overlapping cytologic features, making the diagnosis of rare tumors problematic. In this review, the cytologic features of the major salivary gland neoplasms, the differential diagnoses, and the salient points that, if examined carefully, help achieve a specific diagnosis are discussed.

Fine-needle aspiration (FNA) biopsy as a diagnostic procedure is well established and widely used to evaluate palpable lesions and, with the aid of imaging studies, is equally applicable to deep-seated lesions.1,2 In the head and neck area, lesions of the salivary glands frequently are evaluated by this technique; in fact in many centers, this is the first tissue-based procedure applied to establish a diagnosis before any surgical intervention. While use of needles to aspirate palpable lesions of the salivary glands is not new, this technique (coupled with the availability of improved fast stains on air-dried smears) has been refined over the years with the use of very thin needles.3,4 Nowadays, in many centers trained cytopathologists rather than surgeons perform FNA of salivary gland lesions using 23- or 25-gauge needles.5,6 The usefulness of salivary gland FNA relates to the fact that it is easy to perform, is minimally invasive, smear evaluation is immediate, and the procedure can be repeated several times to obtain more tissue for diagnosis or special studies.7,8 When a malignant diagnosis is given, the surgeon and the patient are in a better position to discuss and plan for the next course of action, while the diagnosis of a benign lesion provides immediate relief to the patient, sparing the anxiety of waiting several days for a surgical biopsy diagnosis.2,9 A review of the FNA cytologic findings of salivary gland lesions is presented, starting with a brief discussion of normal salivary gland cytology, comments on diagnostic accuracy, and post-FNArelated tissue changes. The review focuses on the detailed cytologic findings of each of the major neoplasms of the salivary glands and the differential possibilities that need consideration in particular situations. In addition, a synoptic discussion of nonneoplastic inflammatory lesions that clinically and cytologically can mimic malignancy is given.
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Pathology Patterns Reviews

Accuracy of Salivary Gland FNA

It is generally agreed by many cytopathologists that FNA of salivary glands is a good diagnostic test with reasonable sensitivity and specificity, ranging from 60% to 100% and 90% to 100%, respectively.5 However, as pointed out by Stanley10 and Schwarz et al,11 it is difficult to compare the accuracy of statistical data because many of the published series are small and, in others, unsatisfactory or nondiagnostic cases were excluded in the overall figures. False-negative and false-positive results occur in salivary gland FNA. False-negative results are due mainly to errors of underdiagnosing low-grade tumors because of their bland cytologic features and the difficult evaluation of hypocellular cystic lesions so common in this area, while false-positive diagnoses emanate from overcalls of reactive changes, such as occur in the setting of associated inflammatory reactions.12,13 But perhaps more problematic and challenging is the heterogeneity of benign and malignant tumors, whose underlying cytologic features are similar, with differences in some cases being quantitative rather than qualitative. The shared cytomorphologic features account for the indeterminate or suspicious diagnoses and long lists of differential possibilities given at times. However, in the hands of experienced cytopathologists ensuring proper sampling and specimen handling, the diagnosis of many salivary gland lesions is possible.14-16

Image 1 Normal salivary gland tissue showing acinar structures and the ductal system. Note the presence of adipose tissue (H&E, 200).

FNA-Related Tissue Changes

The issue of post-FNArelated tissue changes is important, as these changes may affect the histologic interpretation of resected specimens. However, Mukunyadzi et al6 found that the use of very thin (25-gauge) needles leads to insignificant bleeding and minor tissue damage. Potential tissue changes include tumor infarction, hemorrhage, granulation tissue, and metaplastic changes.20,21 Granulation tissue and metaplastic cellular changes potentially can be confused with sarcoma, carcinosarcoma, or both.22 Post-FNA tumor infarction and other changes have been reported in the literature, although most tissue changes often were focal and insignificant.23 Seeding of the needle tract by tumor cells, a potential serious complication of FNA, has been reported in the literature but remains extremely rare.24 In a study of 94 salivary gland masses, when 25-gauge needles were exclusively used in the aspiration of salivary gland lesions, the resultant tissue changes were, in many cases, minor and did not preclude histologic interpretation of the resected specimen.6 However, despite the rarity of significant post-FNA tissue changes, surgical pathologists need to be aware of such changes to avoid potential diagnostic errors in the histologic interpretation of the resected specimens.

Normal Salivary Gland FNA Cytology

Normal salivary glands are rarely aspirated. However, normal salivary gland tissue is observed in the inadvertently aspirated normal tissue obtained together with abnormal tissue or in cases in which the target lesion is missed.17,18 Normal salivary gland FNA cytology recapitulates the normal histologic features Image 1 and shows a mixture of acinar cells, duct cells, adipose tissue Image 2, and scattered inflammatory cells. The acinar cells are disposed of in grape-like arrangements, composed of round or pyramidal cells, usually with uniform eccentric nuclei and abundant granular or vacuolated cytoplasm. Duct cells often form small groups or linear arrangements and appear crowded compared with acinar cells because of the lesser amount of cytoplasm that they possess. Duct cells are smaller than acinar cells, and if they lose their cytoplasm, they can easily be confused with lymphocytes. It is not uncommon to observe adipocytes, normal constituents of salivary gland tissue, associated with tissue fragments, particularly in FNA samples of the parotid gland.17,19
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Classification of Salivary Gland Lesions

Any tumefacient lesion of the salivary glands is amenable to evaluation by FNA cytology. The salivary gland
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mass lesions can be broadly classified into inflammatory, nonneoplastic, and neoplastic tumors. A listing of the salivary gland tumors includes the more common pleomorphic adenoma, Warthin tumor, adenoid cystic carcinoma, mucoepidermoid carcinoma, acinic cell carcinoma, various cystic entities, and many rare tumors that are infrequently encountered in FNA cytology. This review focuses on the discussion of neoplastic salivary gland tumors. Benign Salivary Gland Neoplasms This group of salivary gland tumors constitutes the majority of salivary gland tumors, accounting for about 85%, 63% and 14% in the parotid, submandibular, and sublingual glands, respectively. More than 50% of the tumors of the minor salivary glands are adenomas. They include the common pleomorphic adenoma and Warthin tumor and other relatively rare tumors such as myoepithelioma, oncocytoma, sebaceous adenoma, cystadenoma, and papillomas.10,25,26 Pleomorphic Adenoma A great number of salivary gland FNA aspirates, particularly of the parotid gland, will turn out to be pleomorphic adenomas, synonymously and more appropriately known as benign mixed tumor. In the parotid gland, pleomorphic adenoma accounts for more than 70% of all the tumors, but it is rare in the sublingual gland.1,19 More cases of pleomorphic adenoma are seen in females than males and usually manifest during the fourth decade as slow-growing masses. On palpation, the tumor feels firm, round, or bosselated and may be movable. In rare situations or cases of long duration, pleomorphic adenoma may be fixed to the underlying tissues, show ulceration, or manifest with pain, clinical findings that are highly suggestive of malignancy.27-29 The appearance of the aspirated material of pleomorphic adenoma (if the specimen is not too bloody) is characteristic, showing droplets of thick or pasty mucoid material, and the material should be grossly inspected. Smear cellularity is variable, but many cases are usually quite cellular. Cytologically, the smears show 3 main components: extracellular matrix, myoepithelial and ductal cells present in various proportions, and stroma. In many cases, myoepithelial cells dominate the smear, forming irregular tissue fragments and scattered background single cells. The myoepithelial cells have tremendous potential for differentiating into various cytomorphologic forms, a finding that is more striking in cytologic smears than in histologic sections and includes plasmacytoid Image 3, spindled, and stellate cells and clear cell changes. Ductal cells are less conspicuous and usually show flat sheets composed of small cuboidal cells with round nuclei. The third component of pleomorphic adenoma, the stroma, is seen often as the metachromatic magenta chondromyxoid matrix (Image 3).27,28 This matrix
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Image 2 Smear of normal salivary gland aspirate demonstrating acinar cells arranged as a bunch of grapes cluster. Smaller ductal cells can be identified in the center of the cluster, while fragments of adipose tissue also are present (Papanicolaou, 200).

Image 3 Pleomorphic adenoma. This very cellular smear shows loose clusters of plasmacytoid myoepithelial cells and metachromatic chondromyxoid stroma (rapid Romanowsky, 400).

usually is mixed intimately with the cellular elements and may be so abundant as to obscure the latter. On Papanicolaou-stained slides, the matrix is cyanophilic and appears fibrillary Image 4.29 In rare cases, additional minor components such as metaplastic squamous cells, cystic fluid, sebaceous cells, inflammatory cells, and even tyrosine crystals may be identified.30,31
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DOI: 10.1092/5FECYJ9639CMQM0L

Pathology Patterns Reviews

Image 4 Smear of pleomorphic adenoma showing the characteristic fibrillary appearance of the matrix. Note the presence of myoepithelial cells intimately admixed with the stroma (Papanicolaou, 400).

The diagnosis of pleomorphic adenoma is usually obvious after the identification of the 3 components just described.15 However, the considerable variation in the proportions of the constituent elements is a challenge because of the resultant long list of differential diagnoses Table 1. Stroma-deficient or cellular cases may be difficult to recognize as pleomorphic adenoma and may be confused with other tumors of the salivary gland. The differential diagnoses include low-grade carcinomas, and the monomorphic adenoma, metastases, and the plasmacytoid appearance of the myoepithelial cells may be mistaken for malignant lymphoma or plasma cell proliferations.8,32,33

Monomorphic Adenoma (Basal Cell Adenoma) Monomorphic adenoma, also synonymously known as basal cell adenoma, represents a group of benign salivary gland neoplasms characterized by a monomorphic population of small blue or basaloid cells. The histologic subclassification of basal cell adenomas is based on the growth patterns, hence the recognition of several types: tubular, trabecular, solid, membranous or dermal analogue, and canalicular.19,33-35 The diagnostic dilemma in the evaluation of monomorphic adenomas relates to their resemblance to other primary or secondary small blue cell tumors that may be encountered in the salivary glands. The list of such tumors includes adenoid cystic carcinoma (particularly the solid variant), cellular variant of pleomorphic adenoma, basal adenocarcinoma, metastatic cutaneous basal cell carcinoma, metastatic small cell carcinoma, and pilomatrixoma.32,33,36,37 As a group, the basal cell adenomas are rather uncommon tumors (2% of all salivary gland neoplasms) and are encountered infrequently in FNA of the salivary glands.25,38 The smears of monomorphic adenomas often are cellular but variable, showing cohesive, irregular, jigsaw puzzle configurations or flat trabecular patterns and scattered (naked) single cells. A hint of peripheral palisading may be present in some clusters. Individual cells appear small and basaloid, exhibiting high nuclear/cytoplasmic (N/C) ratios and scant cytoplasm. The nuclei appear round to ovoid, show even distribution of fine chromatin, and are without obvious nucleoli. Basal cell adenomas may contain metachromatic collagenous matrix, analogous to the matrix of pleomorphic adenoma or adenoid cystic carcinoma, although it is usually nonfibrillary on Papanicolaou stain. When the matrix assumes the form of cylinders and spheres, it becomes difficult to distinguish monomorphic adenoma from adenoid cystic carcinoma Table 2. However, the matrix of basal cell adenoma tends to show interdigitation

Table 1 Differential Diagnoses for Pleomorphic Adenoma*

Cytologic Finding (Pleomorphic Adenoma) Plasmacytoid myoepithelial cells Increased duct cells Matrix-poor tumor cells Differential Diagnosis Malignant lymphoma Plasmacytoma Low-grade carcinoma Monomorphic adenoma Low-grade carcinoma Myoepithelioma Metastases Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma Carcinoma ex pleomorphic adenoma Low-grade mucoepidermoid carcinoma Diagnostic Hints Identify myoepithelial cells Matrix and nuclear detail; no lymphoglandular bodies Careful characterization of matrix Matrix Nuclear detail Difficult to exclude Necrosis, mitosis, nuclear detail, history Identify myoepithelial cells Evaluate stroma-cell interface Identify typical myoepithelial cell features Different staining characteristics on rapid Romanowsky/ MGG stains; no mucous and intermediate cells

Increased stroma with or without hyaline globules Nuclear atypia (mild to moderate and focal) Mucoid background

MGG, May-Grnwald-Giemsa. * For proper matrix characterization, both air-dried, rapid Romanowskystained and fixed Papanicolaou-stained smears are needed.

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Table 2 Differential Diagnoses for Monomorphic Adenoma (Basaloid Cell Adenoma)

Cytologic Finding (Monomorphic Adenoma) Basaloid small cells Differential Diagnosis Diagnostic Hints Necrosis, mitosis, high-grade nuclear features, pleomorphism favors malignancy; may be impossible to distinguish Abnormal nuclear detail, necrosis favors malignancy May be impossible to distinguish; palisading favors adenoma; site of tumor origin Identify myoepithelial cells; naked nuclei favor monomorphic adenoma Clinical data, nuclear molding, necrosis, no stroma favor malignancy

Basal cell adenocarcinoma Adenoid cystic carcinoma Polymorphous low-grade adenocarcinoma (problem: hyaline globules of stroma) Cellular pleomorphic adenoma Metastatic small cell carcinoma

with tumor cells at the periphery, and, in addition, delicate vessels and spindle cells may be present, embedded in the stroma. In contrast, in adenoid cystic carcinoma, the stromatumor cell interface is sharply defined; the matrix is commonly acellular and devoid of blood vessels. The dermal analogue subtype of basal cell adenoma is virtually indistinguishable cytologically from adenoid cystic cell carcinoma.10,36,39 Clinical history and imaging studies are crucial in the diagnosis of metastatic small cell carcinoma and cutaneous basal cell carcinoma, entities that cytologically resemble basal cell adenomas. Presence of high-grade nuclear features, mitosis, nucleoli, and necrosis are more suggestive of carcinoma than of monomorphic adenoma.40,41 Warthin Tumor Warthin tumor is a benign tumor commonly encountered in salivary gland FNA specimens. Warthin tumor occurs

frequently in the parotid gland, is slightly more common in females, shows an association with cigarette smoking, and may be bilateral in about 10% of the cases. On palpation, most Warthin tumors feel soft or boggy but in situations of increased fluid accumulation they may feel quite tense and firm.1,10,42 Histologic examination of Warthin tumor reveals the characteristic cystic spaces lined by a bilayer of oncocytic cells and abundant lymphocytes in the subepithelial stroma Image 5. The aspirated material appears chocolate brown. The cellularity of the smears is variable and may be quite hypocellular owing to fluid dilution. The 3 main components that characterize the FNA cytology of Warthin tumor are oncocytes, lymphocytes, and the fluid background Image 6. Oncocytes usually are seen as flat, cohesive sheets 2 to 3 cells in thickness and often devoid of stroma. The oncocytes have abundant dense cytoplasm, relatively large but bland nuclei, and uniformly low N/C ratios.19 The cytoplasmic

Image 5 Warthin tumor. Histologic examination reveals a bilayer of oncocytes lining the cyst wall and abundant lymphocytes in the subepithelial stroma (H&E, 400).

Image 6 Smear of Warthin tumor aspirate showing the small flat sheets of oncocytes, scattered lymphocytes, and a granular cystic background. The oncocytes display abundant granular cytoplasm with sharp cytoplasmic borders and bland nuclear features (Papanicolaou, 400).

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Pathology Patterns Reviews

granularity and eosinophilia, characteristic features of oncocytes, may be difficult to detect on rapid Romanowsky and Papanicolaou-stained FNA material, but they are obvious on H&E-stained cell-block material. The accompanying lymphoid component of Warthin tumor shows mostly small, mature background lymphocytes. Occasionally elements of a reactive follicle germinal center may be identified. The fluid of Warthin tumor often imparts a dirty background appearance that may be confused with tumor necrosis. In addition to the 3 main components, other elements that can be encountered in FNA smears of Warthin tumor include, albeit rarely, metaplastic squamous and sebaceous gland cells. The differential diagnoses for Warthin tumor are wide Table 3 . 16,43 In most cases (>80%), the presence and combination of the 3 main cytologic elements establish the diagnosis without difficulty. However, as is well known, oncocytes, lymphocytes, and a fluid background are not pathognomonic of Warthin tumor, as they are encountered in several other conditions. Cysts (lymphoepithelial cysts) of the salivary glands and chronic inflammatory and obstructive duct lesions can accumulate fluid, show oncocytic metaplasia, and contain numerous lymphocytes and can easily be confused with Warthin tumor.44-46 Oncocytoma and oncocytic carcinoma are rare salivary gland tumors that may be confused with Warthin tumor, as oncocytes are common to all 3 entities, and the former 2 tumors may contain variable numbers of lymphocytes. In oncocytic neoplasms, the cell clusters are bigger and 3-dimensional and are 3 or more cell layers thick. The intermediate squamous cells of mucoepidermoid carcinoma, the uncommon oncocytic metaplasia of pleomorphic adenoma, and metaplastic cells of squamous cell carcinoma may all be confused with Warthin tumor.47 The cells of acinic cell carcinoma may show cytoplasmic eosinophilia, thus resembling oncocytes and leading to diagnostic confusion. However, the presence of large zymogen granules, prominent nucleoli, significant pleomorphism, cytoplasmic vacuolation, and prominent large-caliber vessels

favors the diagnosis of acinic cell carcinoma over Warthin tumor. It is important to always reaspirate any residual mass after initial drainage of fluid from Warthin tumor cases or any other cystic lesions to obtain more representative material, which may provide clues to the diagnosis. Oncocytic Neoplasms While nonneoplastic oncocytes are common and seen regularly in the FNA biopsy smears of salivary gland lesions, oncocytic neoplasms are rare.48 Exclusive populations of oncocytic cells showing abundant and finely granular cytoplasm characterize oncocytic neoplasms seen in many endocrine and other organs of the body, including the salivary glands. Most oncocytic neoplasms represent benign oncocytoma, while the malignant counterpart, oncocytic carcinoma (malignant oncocytoma) is extremely rare.4,49 In FNA smears of salivary gland oncocytic neoplasms, oncocytes are present as cohesive 3dimensional clusters and are 3 or more cells thick Image 7. The nuclei often exhibit mild atypia and prominent nucleoli.47 However, occasionally significant nuclear pleomorphism may be seen, but mitotic figures are uncommon. On air-dried, rapid Romanowskystained material, the cytoplasm may appear dense bluish gray, and the cytoplasmic granules, representing numerous mitochondria, may be difficult to detect. The accuracy rate for the diagnosis of oncocytoma on FNA biopsy material is high, about 92%, while false-positive diagnoses are largely due to incorrectly diagnosed cases of Warthin tumor.25 In general, the cell clusters in Warthin tumor are smaller and flat, while those of oncocytoma present as thicker 3-dimensional groups. In addition, aspiration of Warthin tumor often yields brownish fluid, which imparts the dirty cyst fluid appearance on the smears, while oncocytoma is less likely to be cystic or to contain as much fluid. As already noted, the majority of oncocytic neoplasms are benign, even if nuclear atypia is present. Nevertheless, the cytologic distinction of oncocytoma from the extremely rare oncocytic carcinoma is difficult and may be impossible on FNA material.49 While the presence of significant nuclear

Table 3 Differential Diagnoses for Warthin Tumor

Cytologic Finding (Warthin Tumor) Cyst fluid not obvious; oncocytes only Rare oncocytes and lymphocytes Atypical metaplastic squamous cells Oncocytic cells and lymphocytes Differential Diagnosis Oncocytoma Various cystic lesions Lymphoma SCC MEC Acinic cell carcinoma (lymphocyte-rich stroma) Diagnostic Hints Warthin tumor unlikely if only 1 cell seen; oncocytoma usually not cystic and has fewer lymphocytes than Warthin tumor Reaspirate any residual mass Consider flow cytometric analysis Warthin tumor unlikely if high-grade nuclear features, no oncocytes in SCC Intermediate and mucous cells favor MEC Papillary and acinar structures, cytoplasmic vacuoles, necrosis favor acinic cell carcinoma

MEC, mucoepidermoid carcinoma; SCC, squamous cell carcinoma.

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atypia, mitosis, and necrosis suggests malignancy, a definitive diagnosis of carcinoma may require surgical excision and histologic evaluation. Other lesions in the same differential category are acinic cell carcinoma, mucoepidermoid carcinoma with oncocytic metaplasia, and oncocytosis seen in normal salivary glands or metaplastic oncocytes associated with inflammatory lesions (Table 3). Myoepithelioma Myoepithelioma is an uncommon benign neoplasm that occurs in the parotid, submandibular gland, and the palate. The tumor is composed exclusively of plasmacytoid or spindled cells representing myoepithelial cells (and not accompanied by an epithelial or ductal component).50,51 Cytologically, spindleshaped or uniform plasmacytoid cells containing moderate amounts of cytoplasm and showing distinct cytoplasmic borders characterize the smears of myoepithelioma. Stromal material is minimal or absent, while necrosis, mitosis, and nuclear atypia are virtually never seen in this neoplasm.43,52 Pleomorphic adenoma and the malignant myoepithelioma are the chief differential considerations for myoepithelioma (Table 1). Identification of plasmacytoid myoepithelial cells intimately mixed with metachromatic stroma favors pleomorphic adenoma, although stroma-poor cases may be difficult to distinguish from myoepithelioma. The cytologic features of the extremely rare malignant myoepithelioma have not been well reported, but the presence of significant 52,53 nuclear atypia and mitosis may suggest such a diagnosis. Low-Grade Neoplasms Low-Grade Mucoepidermoid Carcinoma Mucoepidermoid carcinoma (MEC) is generally divided into 2 histologic grades, low and high, the former characterized by a cystic growth pattern Image 8 and an abundance of mucous cells, while high-grade MEC is defined by dominance of the solid component. Some workers recognize an intermediate histologic grade of MEC.54-56 Proper assignment of grade requires evaluation of the entire tumor, a difficult proposition on FNA material because of sampling problems. While grading of the tumor is difficult on cytologic material, a more serious problem is failing to correctly diagnose low-grade MEC. Low-grade MEC accounts for about 80% of all MECs and is well recognized for its potential false-negative diagnostic pitfall, apparently owing to the bland cytologic features and hypocellular nature of many of these tumors. MEC occurs at any age, can involve both the major and minor salivary glands, and is the most common malignant salivary gland tumor in children.56,57 The aspiration of low-grade MEC usually yields fluid, which may be mucoid, and the smears are typically hypocellular. Again, to obtain more representative material in any
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Image 7 Oncocytoma. Smear showing exclusively oncocytic cells forming cohesive clusters. No lymphocytes or other cell types are present (rapid Romanowsky, 400).

Image 8 Low-grade mucoepidermoid carcinoma. Histologic examination reveals the predominantly microcystic pattern and numerous mucous cells (H&E, 400).

cystic lesion, the residual mass, following initial fluid aspiration, should be reaspirated. The cellular component of MEC will show a mixture of mucus-secreting cells and intermediate cells Image 9. Both cell types show bland cytologic features. Mucus-secreting cells exhibit abundant foamy or vacuolated cytoplasm, low N/C ratios, and loose cellular groups. Careful examination of the smears may reveal the presence of goblet cells (Image 9), cells frequently seen in lowgrade MEC.25,57 When the mucous cells are present as single cells, they can be easily confused with foamy histiocytes.
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Pathology Patterns Reviews

usually is not seen in MEC, although metastasis of low-grade MEC to the neck and intraparotid lymph nodes may result in a very confusing picture. Obstructive duct lesions are particularly problematic as mucous and squamous metaplasia can be seen, mimicking the mixed cell pattern of low-grade MEC. Identification of stone fragments excludes MEC, but this, in the experience of many, is not a common finding in cases of sialolithiasis. The mucoid stroma of pleomorphic adenoma may be mistaken for the mucin of MEC, but the mucin/stroma of the latter does not show metachromasia. A careful search for the myoepithelial cells will help avoid making the wrong diagnosis.10,60 Acinic Cell Carcinoma Acinic cell carcinoma, the third major common malignant tumor of the salivary gland, is seen in adults and children and occurs mainly in the parotid gland, although the submandibular glands can be involved as well. Ten percent of acinic cell carcinomas will recur despite wide resection, but the overall prognosis is good, with a 10-year survival rate of about 90%. Several histologic growth patterns of acinic cell carcinoma are recognized, including the solid, follicular (resembles thyroid follicles), microcystic, papillary Image 10, and mixed patterns.61,62 Cytologically, acinic cell carcinoma can be divided into well-, moderately, and poorly differentiated forms, but the cytologic diagnosis depends on the identification of acinar cells and/or recognition of the acinar-glandular arrangement. In many cases, the FNA smears are quite cellular (cystic cases may be hypocellular), showing both single cells and large irregular clusters; the central portions of the latter often contain large-caliber vessels, while the periphery demonstrates frayed borders Image 11.63-65 The tumor cells in well-differentiated acinic cell carcinoma closely resemble normal acinar cells, are large and polyhedral with abundant bluish gray vacuolated Image 12 and granular cytoplasm on rapid Romanowskystained material, and have eccentric nuclei. The cytoplasmic granules are much larger than the granules of oncocytic cells. In some cases, however, the granules may be degranulated and, therefore, may not be identified. The cytoplasm is delicate and can rupture easily

Image 9 Smear of low-grade mucoepidermoid carcinoma showing clusters of mucous cells, smaller intermediate cells, and prominent goblet cells (rapid Romanowsky, 600).

Intermediate cells are small uniform cells with scant cytoplasm and frequently are present in tight cohesive clusters. Cells showing true or mature squamous cell differentiation (keratinization) are almost never seen in low-grade MEC.10,19,56 As stated before, underdiagnosis of low-grade MEC is a common problem because the malignant nature of the lesion may be overlooked for reasons mentioned before and because the foamy cells resemble histiocytes.1,9,10,58 One should always first exclude the possibility of low-grade MEC before a specific diagnosis is given in the cytologic evaluation of any cystic lesion of the salivary glands. The differential diagnosis of low-grade MEC includes Warthin tumor, benign salivary gland cysts (lymphoepithelial cysts), branchial cleft cyst, sialolithiasis or chronic sialadenitis complicated by cystic dilatation, and pleomorphic adenoma with excess mucoid stroma Table 4.49,54,59 To differentiate Warthin tumor from low-grade MEC, one should look for the presence of numerous oncocytes (especially in cohesive clusters), the dirty cystic background, and lymphocytes. The presence of oncocytes and lymphocytes in large numbers
Table 4 Differential Diagnoses for Low-Grade MEC*
Cytologic Finding (MEC) Squamous and mucous cells, cyst fluid, foamy cells Hypocellular mucoid smears (with or without foamy cells) Oncocyte-like cells (rare) Differential Diagnosis Metaplastic cells seen in sialolithiasis and Kuttner tumor (submandibular) Cysts Warthin tumor

Diagnostic Hints Goblet cells favor MEC; painful aspirate and stone fragments favor inflammation (may defer to histologic examination) Mixed cellsgoblet and goblet cellsfavor MEC True oncocytes favor Warthin tumor; mucous and intermediate cells favor MEC

MEC, mucoepidermoid carcinoma. * The differential diagnosis of low-grade mucoepidermoid carcinoma is particularly difficult and warrants extreme caution.

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Image 10 Acinic cell carcinoma. Histologic section showing papillary configuration. Vacuolation and clear cytoplasm are apparent in the tumor cells. This appearance could be confused with metastatic renal cell carcinoma (H&E, 600).

Image 11 Tumor cells of acinic cell carcinoma are seen attached to the centrally placed vessels (rapid Romanowsky, 600).

during the smearing process, leading to the presence of numerous naked nuclei and a granular background. The lessdifferentiated tumors show smaller cells that may appear cuboidal. Nuclear atypia remains minimal to moderate, but necrosis may be present. On occasion, cells with clear cytoplasm may be identified.63,64 A major differential diagnostic consideration of acinic cell carcinoma is normal salivary gland acinar cells or sialosis Table 5.66 Normal acinar cells are usually seen as 3-dimensional cohesive clusters of cells like a bunch of grapes and may be mixed with groups of smaller ductal cells and adipose tissue fragments, whereas in acinic cell carcinoma, in addition to clusters, there are relatively more single cells. Furthermore, the clusters of cells in acinic cell carcinoma are larger and more irregular than those of normal acini. Because the tumor grows in an expansive manner, all normal tissues (including adipose and ductal cells) are pushed away to the periphery and generally are not represented in the smears. Neoplasms in the differential diagnosis of acinic cell carcinoma include epithelial-myoepithelial carcinoma, MEC, Warthin tumor, pleomorphic adenoma, oncocytoma, and metastatic renal carcinoma.4,67 The presence of clear cells or vacuolated cells should lead to the consideration of epithelial-myoepithelial carcinoma and metastatic renal cell carcinoma. However, the identification of acellular hyaline stroma (and spindle-shaped myoepithelial cells) favors epithelial-myoepithelial carcinoma, whereas the presence of numerous naked nuclei in the background favors acinic cell carcinoma. Clinical history of a kidney carcinoma should lead to strong consideration of metastasis.
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The vacuolated cells of low-grade MEC may be confused with acinic cell carcinoma. An effort should be made to look for mucus-producing and goblet cells that are characteristic of low-grade MEC. In addition, zymogen granules are not seen in low-grade MEC but may be present in acinic cell carcinoma. Identification of the strikingly metachromatic stroma and plasmacytoid cells will help in the distinction of cellular pleomorphic adenoma from acinic cell carcinoma. The tumor cells of acinic cell carcinoma may appear oncocytic and,

Image 12 Another irregular cluster of acinic cell carcinoma showing cytoplasmic vacuoles, eccentric nuclei, and occasional nucleoli (rapid Romanowsky, 600).

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Table 5 Differential Diagnoses for ACC

Cytologic Finding (ACC) Eosinophilic, oncocyte-like cells, cytoplasmic vacuoles Oncocyte-like cells and lymphocytes Hypocellular (cystic ACC) Acinar cells, normal looking (well-differentiated ACC) Papillary structures, vacuolated or clear cytoplasm
ACC, acinic cell carcinoma.

Differential Diagnosis High-grade mucoepidermoid carcinoma Warthin tumor; oncocytoma Variety of cystic lesions Normal salivary gland tissue; sialosis Metastasis: renal cell carcinoma (rare but known to go to unusual sites)

Diagnostic Hints No mixed cell pattern in ACC Acinar arrangements and naked nuclei favor ACC Reaspirate No normal elements (adipocytes and ductal cells), favor ACC Clinical history and imaging studies

together with the presence of scattered naked nuclei (resembling lymphocytes), acinic cell carcinoma may be confused with oncocytoma and Warthin tumor. However, more commonly, acinar cell arrangements are seen in acinic cell carcinoma but not in oncocytoma or Warthin tumor, and, in addition, lymphocytes rather than naked nuclei typify Warthin tumor. Adenoid Cystic Carcinoma Adenoid cystic carcinoma is one of the major and more common malignant salivary gland neoplasms. It occurs mainly in the minor glands and submandibular gland, accounting for about 10% of all salivary gland and 3% of parotid tumors. Adenoid cystic carcinoma manifests as a slow-growing mass, and, in about 10% of the cases, patients may complain of pain or show facial muscle weakness (clinical findings strongly suggestive of malignancy), and the clinical behavior is characterized by persistent growth and recurrences.10,68 Cytologically, the smear patterns of adenoid cystic carcinoma are characterized by a mixture of small, uniform, basaloid cells with high N/C ratios and metachromatic stroma. The cytologic architecture frequently mimics the histologic patterns Image 13, showing cribriform or tubular structures, while exclusively solid sheets of tumor cells are seen in the solid variant or anaplastic adenoid cystic carcinoma. The chromatin appears coarse but uniform without identifiable nucleoli, and nuclear pleomorphism is minimal. Necrosis is a rare cytologic finding, but when seen usually is indicative of the anaplastic variant of adenoid cystic carcinoma. The background of adenoid cystic carcinoma usually is populated by scattered naked nuclei of tumor cells. Although the stroma of adenoid cystic carcinoma is characteristic, it can be seen in several other salivary gland tumors. In the classic cribriform or tubular adenoid cystic carcinoma, balls or spheres and cylinders of magenta stroma are seen on air-dried, rapid Romanowskystained material Image 14. The interface between tumor cells and stroma often is

sharply demarcated. On Papanicolaou staining, the stroma appears cyanophilic but shows no fibrillary architecture, an important distinguishing feature when the differential consideration is pleomorphic adenoma (Image 13).15,69 The diagnosis of the well-differentiated or cribriform type of adenoid cystic carcinoma is relatively straightforward. The microcystic spaces containing the hyaline globules and cylinders of metachromatic stroma are easily identified in such cases. However, metachromatic stroma is not specific for or unique to adenoid cystic carcinoma; it also is found in cases of polymorphous low-grade adenocarcinoma, basal cell adenoma, and pleomorphic adenoma and even in epithelial-myoepithelial carcinoma and basal cell carcinoma. 36 Thus, cases of adenoid cystic carcinoma lacking cribriform architecture may be impossible to distinguish from other basaloid tumors. The identification of hyaline stroma is, however, always critical to the diagnosis of adenoid cystic carcinoma, as most cases almost always (excerpt the solid variant) show its presence.70 There are no clear nuclear and cytoplasmic features that permit discrimination of adenoid cystic carcinoma from its mimics. Because the surgical treatment of adenoid cystic carcinoma may involve sacrificing the facial nerve, it is crucial to make the correct cytologic diagnosis. In addition, the overall prognosis between different tumor types may be vastly different. In difficult cases, definitive diagnosis may need to be deferred to the surgical specimen (or frozen section) evaluation. Adenoid cystic carcinoma always should be considered in the differential diagnosis of any basaloid small blue cell tumors of the salivary gland (Table 2). Polymorphous Low-Grade Adenocarcinoma Polymorphous low-grade adenocarcinoma occurs predominantly in the minor salivary glands, in particular on the hard palate and other intraoral sites. In rare instances, the major salivary glands and neck lymph nodes may be involved. The average age of patients with polymorphous low-grade adenocarcinoma is 60 years.71-73

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Image 13 Adenoid cystic carcinoma. A, The typical cribriform architecture seen on histologic sections (H&E, 400). B, Aspirate smear indicating the nonfibrillary cyanophilic cylinders and globules of the matrix and showing tumor cells lined up on the outer aspect of the matrix (Papanicolaou, 400).

Image 14 The brightly metachromatic matrix forming hyaline cylinders and spheres with a sharp interface between the matrix and tumor cells are characteristic findings for adenoid cystic carcinoma (rapid Romanowsky, 400).

Mixed patterns of irregular sheets and pseudopapillary or papillary fragments of tumor cells and metachromatic stroma characterize the cytology of polymorphous low-grade adenocarcinoma. The tumor cells are oval or polyhedral with moderate amounts of nonvacuolated cytoplasm. Because the cytoplasm is delicate, naked nuclei of tumor cells often are seen in the background. The nuclei appear uniform, show delicate chromatin, and contain small or inconspicuous nucleoli. The stroma may be mixed intimately with tumor cells or may form hyaline globules that closely resemble the hyaline globules of adenoid cystic carcinoma.74 The chief differential considerations for polymorphous low-grade adenocarcinoma include adenoid cystic carcinoma, epithelial-myoepithelial carcinoma, and pleomorphic adenoma (Table 2). The distinction of polymorphous low-grade adenocarcinoma from adenoid cystic carcinoma may be quite difficult, because, when present, the stromal hyaline globules are similar. However, the tumor cells of polymorphous low-grade adenocarcinoma generally are larger and more uniform than the cells of adenoid cystic carcinoma, and in addition, the presence of pseudopapillary fragments is uncommon in adenoid cystic carcinoma. Epithelial-myoepithelial carcinoma may be impossible to distinguish from polymorphous lowgrade adenocarcinoma when the 2 cell types, ductal and myoepithelial cells, that characterize this tumor are not seen together. The metachromatic stroma of polymorphous lowgrade adenocarcinoma may lead to the consideration of a cellular pleomorphic adenoma; however, the globular hyaline deposits are less common in the latter. In addition, the tumor
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cells of pleomorphic adenoma usually show plasmacytoid features of the myoepithelial cells, and the cells do not form the well-defined pseudopapillary or tubular structures typical of polymorphous low-grade adenocarcinoma.25,73 High-Grade Neoplasms High-Grade MEC The diagnosis of high-grade MEC, in contrast with that of low-grade MEC, is relatively easy, as more atypical cells showing squamoid features are seen.10 Nevertheless, other constituent elements such as intermediate cells and mucusproducing or goblet cells should be sought and identified to complete the diagnostic picture. It should be noted, however, that the histologic classification of high-grade MEC is not based primarily on the presence of high-grade nuclear features; rather it is dependent on the extent of the solid component.10,73 The implication of this requirement with regard to FNA cytology is thorough sampling of the lesion to obtain representative material. The differential diagnosis of high-grade MEC includes squamous cell carcinoma. Primary squamous cell carcinoma of the salivary glands is rare, while metastasis or contiguous involvement from cutaneous or intraoral locations is more common.26 As noted by Schindler et al19 and Feldman et al,75 both highgrade MEC and squamous cell carcinoma can show cystic components, making this feature nondiscriminative. Squamous cell carcinoma metastatic from the tonsillar crypts is particularly likely to show cystic metastasis19,75 Table 6.
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Table 6 Differential Diagnoses for High-Grade Neoplasms

Neoplasm SDC (may be impossible to distinguish from metastatic breast carcinoma) High-grade mucoepidermoid carcinoma SCC (primary rare, intraparotid lymph node metastasis or contiguous spread from skin) Metastasis: adenocarcinoma, undifferentiated carcinoma
SCC, squamous cell carcinoma; SDC, salivary duct carcinoma.

Cytologic Finding High-grade nuclear features; cribriform pattern; necrosis and hyalinized collagen bands Mixture of cells: intermediate, squamous differentiation, and mucous cells; nuclear atypia not as severe as in SDC or SCC Pleomorphic cells with high-grade nuclei; dense keratinized cytoplasm; keratin debris Difficulty differential; need full clinical data and imaging studies

Salivary Duct Carcinoma Salivary duct carcinoma is a rare, high-grade malignant tumor, accounting for about 2.8% of the salivary gland malignant tumors. More than 80% of the cases occur in the parotid gland of older men. At diagnosis, the majority of the patients will have local lymph node metastases and/or extra parotid extension into adjacent soft tissue. The histologic similarities of salivary duct carcinoma to mammary duct carcinoma have been well described and include the cribriform pattern of tumor growth Image 15 and the presence of comedo-type necrosis.26,76,77 Cytologically, the diagnosis of a malignant process is straightforward in these cases because the nuclear features are often high-grade and easy to recognize as such. However, recognizing the tumor as a primary tumor of the salivary gland and correctly classifying it may be difficult. The smears of salivary duct carcinoma usually are very cellular, showing tumor cell groups disposed of in cribriform or pseudopapillary formations Image 16, often associated with necrosis.

Nuclei are large and irregular with thickened membranes and prominent nucleoli. The cytoplasm is generally moderate to abundant and appears eosinophilic.78 A nonspecific but useful diagnostic feature seen in invasive salivary duct carcinoma is the presence of bands of hyalinized collagen (Image 16), a stromal response to tumor infiltration.79-81 Initial recognition of salivary duct carcinoma as a highgrade neoplasm is crucial as this tumor carries a dismal prognosis. However, salivary duct carcinoma should be differentiated from high-grade MEC, squamous cell carcinoma, and metastatic breast carcinoma (Table 6). MEC consists of a mixture of cell types, including mucous cells, intermediate cells, and cells showing squamous differentiation. The squamous differentiation seen in MEC is subtle and does not usually show full maturation, and the degree of nuclear atypia is often mild. The cytoplasm of salivary duct carcinoma may appear dense and squamoid, but obvious squamous differentiation and the presence of keratin material and high-grade nuclei are more consistent with squamous cell carcinoma Image 17

Image 15 Salivary duct carcinoma. A histologic section demonstrates the cribriform and infiltrative growth pattern of this high-grade tumor (H&E, 400).

Image 16 The smear pattern of salivary duct carcinoma shows irregular clusters of high-grade nuclei tumor cells and bands of hyalinized collagen (rapid Romanowsky, 600).

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papillary cystic adenoma, and papillary adenocarcinoma, true malignant mixed tumors, mesenchymal lesions such as schwannoma, and others. Proper recognition of the individual cell constituents and correlation with the clinical picture is critical in making the correct diagnosis.83,84

FNA of Lymphoid Lesions

Lymphoid lesions of the salivary gland include normal intraparotid lymph node, benign lymphoepithelial lesions, and malignant lymphoma.26,85-88 The presence of lymphocytes in Warthin tumor and many epithelial salivary gland neoplasms has been described. Malignant lymphoma accounts for about 5% of all salivary gland tumors. Secondary involvement of the salivary gland or intraparotid lymph nodes can be suspected in patients known to have lymphoma. Of the primary lymphomas, the high-grade type is relatively easy to diagnose. However, follicular lymphomas and lymphomas of mucosa-associated tissue type (MALT) may be very difficult to identify.89 A high index of suspicion is required whenever an abundance of lymphoid cells is identified, and flow cytometric analysis should be performed. MALT lymphomas are low-grade tumors that occur in association with benign lymphoepithelial lesions and, therefore, will show a polymorphous picture composed of reactive or benign and malignant lymphoid cells. Flow cytometric analysis and histologic evaluation are required for the definitive diagnosis of lymphomas.86-88

Image 17 Squamous cell carcinoma of the parotid gland. In this smear tumor cells with obvious high-grade nuclei, pleomorphism, and keratinized cytoplasm are present. This degree of atypia and squamous maturation is not seen in mucoepidermoid carcinoma (rapid Romanowsky, 600).

than salivary duct carcinoma. Pleomorphic adenoma is distinguished from salivary duct carcinoma by the identification of plasmacytoid myoepithelial cells, lack of high-grade nuclear features, and the absence of necrosis. Metastasis from breast carcinoma to the parotid gland is uncommon, but both entities frequently involve neck lymph nodes, making the cytologic differentiation from lymph node aspiration material difficult if not impossible. Thus, historic clinical data and immunostaining for androgen receptors (positive in salivary duct carcinoma) may assist in making the correct diagnosis.80 Carcinoma Ex Pleomorphic Adenoma Carcinoma ex pleomorphic adenoma accounts for about 2.2% of all salivary gland tumors, and the malignant component can manifest synchronously or metachronously with pleomorphic adenoma. The malignant component often is high-grade and includes MEC, salivary duct carcinoma, undifferentiated carcinoma, and others. Low-grade tumors also can arise from pleomorphic adenoma. Cytologically, in the synchronous type, the benign pleomorphic adenoma and the malignant component may be identified in the same smear, but more likely one component is present or dominates the smear pattern.11,44,82 Other Rare Neoplasms and Nonneoplastic Tumefacient Lesions There are many extremely uncommon neoplastic tumors that can occur in salivary glands and, therefore, may be encountered in FNA cytologic material. These include sebaceous adenoma, sebaceous lymphadenoma, papilloma,
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Chronic Sialadenitis and Sialolithiasis

Nonneoplastic inflammatory lesions, including the tumefacient Kuttner tumor (chronic sclerosing sialadenitis) of the submandibular gland, frequently are encountered in FNA of the salivary glands. Included in this group is sialolithiasis with duct obstruction.18,88 Clinically, such lesions appear neoplastic. Long-standing chronic inflammation and sialolithiasis, as alluded to previously, may lead to metaplastic changes in the ductal epithelium including squamous, mucous Image 18, and oncocytic metaplasia. These cytologic changes result from a sequence of events initiated by duct obstruction, followed by continued accumulation of secretions (mucus) distally, eventually leading to cystic dilatation, atrophy of the acinar cell component, fibrosis, and metaplastic changes. Duct obstruction may be due to production of viscid secretions or calculi. Regardless of the pathogenesis, the importance of the cytologic changes relates to the fact that they potentially may be confused with a variety of salivary gland neoplasms. Metaplastic squamous and mucous cells may be mistaken for intermediate or squamous cells and mucus-producing cells of MEC, and when these cells
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Image 18 Chronic sialadenitis and sialolithiasis. Scattered chronic inflammatory infiltrate cells, fibrosis, mucous metaplasia of the ductal epithelium. Acinar atrophy and dilatation of some ducts are obvious in this histologic section (H&E, 400).

Image 19 Atypical squamous metaplasia in an aspirate smear from a case of sialolithiasis and chronic sialadenitis (rapid Romanowsky, 600).

are seen in situations where there is cystic dilatation with fluid accumulation, an erroneous diagnosis of MEC is reinforced. Squamous metaplastic cells with atypia Image 19 also may raise the possibility of squamous cell carcinoma, although the degree of atypia usually is mild in the former. When oncocytic metaplasia is accompanied by chronic inflammatory cells (small lymphocytes), an incorrect diagnosis of Warthin tumor may be made. FNA of chronic sialadenitis may yield fibrotic stroma that may show metachromasia on rapid Romanowsky stain and, when seen together with ductal cells (which dominate such smears because of acinar cell atrophy) showing metaplastic squamous differentiation, a diagnosis of pleomorphic adenoma may be considered. Although rare, identification of stone fragments in FNA smears of the salivary glands should dissuade one from a diagnosis of a neoplastic tumor.

From the Department of Pathology, University of Arkansas for Medical Sciences and Central Arkansas Veterans Healthcare System, Little Rock. Address reprint requests to Dr Mukunyadzi: Dept of Pathology, Slot LR/113, Central Arkansas Veterans Healthcare System, 4301 W 7th St, Little Rock, AR 72205.

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FNA biopsy is a minimally invasive technique that has a pivotal role in the diagnosis and management of patients with salivary gland tumors. When performed properly, FNA cytology can provide useful preoperative information about a mass lesion arising in the salivary gland, permitting the clinician to appropriately manage the patient. However, extreme care and recognition of the limitations of cytology are essential in the evaluation of salivary gland FNA material to achieve the correct diagnoses, as there are many common and rare tumors that can cause diagnostic confusion.

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