complicaciones biopsia parotida

Pathology Patterns Reviews

S100 Am J Clin Pathol 2002;118(Suppl 1):S100-S115 S100 DOI: 10.1092/5FECYJ9639CMQM0L

© American Society for Clinical Pathology

A b s t r a c t

The widespread use of fine-needle aspiration (FNA)biopsy of salivary gland lesions in many centers istestimony to its usefulness and acceptance as adiagnostic technique. Many pertinent questionsconcerning a mass arising in the salivary gland can beanswered by evaluation of FNA cytologic material, andthese include whether the mass is truly of salivarygland origin, whether the lesion is inflammatory orneoplastic, and if neoplastic, whether benign ormalignant. On diagnosis of a neoplastic salivary glandlesion, the next important issue is to correctly classifythe tumor, particularly if malignant. Specific cytologicdiagnoses can be achieved in the majority of cases, thusenabling the clinician and patient to make appropriateinformed decisions. The cytologic evaluation of salivarygland tumors, however, is limited by the wide range andheterogeneous nature of benign and malignant tumorsarising in this area, many of which share similar orshow overlapping cytologic features, making thediagnosis of rare tumors problematic. In this review, thecytologic features of the major salivary glandneoplasms, the differential diagnoses, and the salientpoints that, if examined carefully, help achieve aspecific diagnosis are discussed.

Fine-needle aspiration (FNA) biopsy as a diagnosticprocedure is well established and widely used to evaluatepalpable lesions and, with the aid of imaging studies, isequally applicable to deep-seated lesions.1,2 In the head andneck area, lesions of the salivary glands frequently are evalu-ated by this technique; in fact in many centers, this is the firsttissue-based procedure applied to establish a diagnosis beforeany surgical intervention. While use of needles to aspiratepalpable lesions of the salivary glands is not new, this tech-nique (coupled with the availability of improved fast stains onair-dried smears) has been refined over the years with the useof very thin needles.3,4 Nowadays, in many centers trainedcytopathologists rather than surgeons perform FNA of sali-vary gland lesions using 23- or 25-gauge needles.5,6

The usefulness of salivary gland FNA relates to the factthat it is easy to perform, is minimally invasive, smear evalu-ation is immediate, and the procedure can be repeated severaltimes to obtain more tissue for diagnosis or special studies.7,8

When a malignant diagnosis is given, the surgeon and thepatient are in a better position to discuss and plan for the nextcourse of action, while the diagnosis of a benign lesionprovides immediate relief to the patient, sparing the anxietyof waiting several days for a surgical biopsy diagnosis.2,9

A review of the FNA cytologic findings of salivarygland lesions is presented, starting with a brief discussion ofnormal salivary gland cytology, comments on diagnosticaccuracy, and post-FNA–related tissue changes. The reviewfocuses on the detailed cytologic findings of each of themajor neoplasms of the salivary glands and the differentialpossibilities that need consideration in particular situations.In addition, a synoptic discussion of nonneoplastic inflam-matory lesions that clinically and cytologically can mimicmalignancy is given.

Review of Fine-Needle Aspiration Cytology of SalivaryGland Neoplasms, With Emphasis on Differential Diagnosis

Perkins Mukunyadzi, MD

Key Words: Salivary gland; Neoplasm; Fine-needle aspiration; Differential diagnosis

DOI: 10.1309/5FECYJ9639CMQM0L


Am J Clin Pathol 2002;118(Suppl 1):S100-S115 S101S101 DOI: 10.1092/5FECYJ9639CMQM0L S101


Accuracy of Salivary Gland FNA

It is generally agreed by many cytopathologists thatFNA of salivary glands is a good diagnostic test withreasonable sensitivity and specificity, ranging from 60%to 100% and 90% to 100%, respectively.5 However, aspointed out by Stanley10 and Schwarz et al,11 it is difficultto compare the accuracy of statistical data because manyof the published series are small and, in others, unsatisfac-tory or nondiagnostic cases were excluded in the overallfigures. False-negative and false-positive results occur insalivary gland FNA. False-negative results are due mainlyto errors of underdiagnosing low-grade tumors because oftheir bland cytologic features and the difficult evaluationof 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 associ-ated inflammatory reactions.12,13 But perhaps more prob-lematic and challenging is the heterogeneity of benign andmalignant tumors, whose underlying cytologic featuresare similar, with differences in some cases being quantita-tive rather than qualitative. The shared cytomorphologicfeatures account for the indeterminate or “suspicious”diagnoses and long lists of differential possibilities givenat times. However, in the hands of experiencedcytopathologists ensuring proper sampling and specimenhandling, the diagnosis of many salivary gland lesions ispossible.14-16

Normal Salivary Gland FNA Cytology

Normal salivary glands are rarely aspirated. However,normal salivary gland tissue is observed in the inadver-tently aspirated normal tissue obtained together withabnormal tissue or in cases in which the target lesion ismissed.17,18 Normal salivary gland FNA cytology recapitu-lates the normal histologic features ❚ Image 1❚ and shows amixture of acinar cells, duct cells, adipose tissue ❚ Image

2❚ , and scattered inflammatory cells. The acinar cells aredisposed of in grape-like arrangements, composed ofround or pyramidal cells, usually with uniform eccentricnuclei and abundant granular or vacuolated cytoplasm.Duct cells often form small groups or linear arrangementsand appear crowded compared with acinar cells because ofthe lesser amount of cytoplasm that they possess. Ductcells are smaller than acinar cells, and if they lose theircytoplasm, they can easily be confused with lymphocytes.It is not uncommon to observe adipocytes, normalconstituents of salivary gland tissue, associated with tissuefragments, particularly in FNA samples of the parotidgland.17,19

FNA-Related Tissue Changes

The issue of post-FNA–related tissue changes is impor-tant, as these changes may affect the histologic interpretationof resected specimens. However, Mukunyadzi et al6 foundthat the use of very thin (25-gauge) needles leads to insignifi-cant bleeding and minor tissue damage. Potential tissuechanges include tumor infarction, hemorrhage, granulationtissue, and metaplastic changes.20,21 Granulation tissue andmetaplastic cellular changes potentially can be confused withsarcoma, carcinosarcoma, or both.22 Post-FNA tumor infarc-tion and other changes have been reported in the literature,although most tissue changes often were focal and insignifi-cant.23 Seeding of the needle tract by tumor cells, a potentialserious complication of FNA, has been reported in the litera-ture but remains extremely rare.24 In a study of 94 salivarygland masses, when 25-gauge needles were exclusively usedin the aspiration of salivary gland lesions, the resultant tissuechanges were, in many cases, minor and did not precludehistologic 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 toavoid potential diagnostic errors in the histologic interpreta-tion of the resected specimens.

Classification of Salivary Gland Lesions

Any tumefacient lesion of the salivary glands isamenable to evaluation by FNA cytology. The salivary gland

❚ Image 1❚ Normal salivary gland tissue showing acinarstructures and the ductal system. Note the presence ofadipose tissue (H&E, ×200).

Mukunyadzi / FINE-NEEDLE ASPIRATION CYTOLOGY OF SALIVARY GLAND NEOPLASMS



mass lesions can be broadly classified into inflammatory,nonneoplastic, and neoplastic tumors. A listing of the sali-vary gland tumors includes the more common pleomorphicadenoma, Warthin tumor, adenoid cystic carcinoma,mucoepidermoid carcinoma, acinic cell carcinoma, variouscystic entities, and many rare tumors that are infrequentlyencountered in FNA cytology. This review focuses on thediscussion of neoplastic salivary gland tumors.

Benign Salivary Gland Neoplasms

This group of salivary gland tumors constitutes themajority of salivary gland tumors, accounting for about 85%,63% and 14% in the parotid, submandibular, and sublingualglands, respectively. More than 50% of the tumors of theminor salivary glands are adenomas. They include thecommon pleomorphic adenoma and Warthin tumor and otherrelatively rare tumors such as myoepithelioma, oncocytoma,sebaceous adenoma, cystadenoma, and papillomas.10,25,26

Pleomorphic AdenomaA great number of salivary gland FNA aspirates, partic-

ularly of the parotid gland, will turn out to be pleomorphicadenomas, synonymously and more appropriately known asbenign mixed tumor. In the parotid gland, pleomorphicadenoma accounts for more than 70% of all the tumors, but itis rare in the sublingual gland.1,19 More cases of pleomorphicadenoma are seen in females than males and usually mani-fest during the fourth decade as slow-growing masses. Onpalpation, the tumor feels firm, round, or bosselated and maybe movable. In rare situations or cases of long duration, pleo-morphic adenoma may be fixed to the underlying tissues,show ulceration, or manifest with pain, clinical findings thatare highly suggestive of malignancy.27-29

The appearance of the aspirated material of pleomor-phic adenoma (if the specimen is not too bloody) is charac-teristic, showing droplets of thick or pasty mucoid material,and the material should be grossly inspected. Smear cellu-larity is variable, but many cases are usually quite cellular.Cytologically, the smears show 3 main components: extra-cellular matrix, myoepithelial and ductal cells present invarious proportions, and stroma. In many cases, myoepithe-lial cells dominate the smear, forming irregular tissue frag-ments and scattered background single cells. The myoep-ithelial cells have tremendous potential for differentiatinginto various cytomorphologic forms, a finding that is morestriking in cytologic smears than in histologic sections andincludes plasmacytoid ❚ Image 3❚ , spindled, and stellate cellsand clear cell changes. Ductal cells are less conspicuous andusually show flat sheets composed of small cuboidal cellswith round nuclei. The third component of pleomorphicadenoma, the stroma, is seen often as the metachromaticmagenta chondromyxoid matrix (Image 3).27,28 This matrix

usually is mixed intimately with the cellular elements andmay be so abundant as to obscure the latter. On Papanico-laou-stained slides, the matrix is cyanophilic and appearsfibrillary ❚ Image 4❚ .29 In rare cases, additional minor compo-nents such as metaplastic squamous cells, cystic fluid, seba-ceous cells, inflammatory cells, and even tyrosine crystalsmay be identified.30,31

❚ Image 2❚ Smear of normal salivary gland aspirate demon-strating acinar cells arranged as a “bunch of grapes” cluster.Smaller ductal cells can be identified in the center of thecluster, while fragments of adipose tissue also are present(Papanicolaou, ×200).

❚ Image 3❚ Pleomorphic adenoma. This very cellular smearshows loose clusters of plasmacytoid myoepithelial cells andmetachromatic chondromyxoid stroma (rapid Romanowsky,×400).




The diagnosis of pleomorphic adenoma is usuallyobvious after the identification of the 3 components justdescribed.15 However, the considerable variation in theproportions of the constituent elements is a challengebecause of the resultant long list of differential diagnoses❚ Table 1❚ . Stroma-deficient or cellular cases may be difficultto recognize as pleomorphic adenoma and may be confusedwith other tumors of the salivary gland. The differential diag-noses include low-grade carcinomas, and the monomorphicadenoma, metastases, and the plasmacytoid appearance ofthe myoepithelial cells may be mistaken for malignantlymphoma or plasma cell proliferations.8,32,33

Monomorphic Adenoma (Basal Cell Adenoma)

Monomorphic adenoma, also synonymously known asbasal cell adenoma, represents a group of benign salivarygland neoplasms characterized by a monomorphic popula-tion of small blue or basaloid cells. The histologic subclassi-fication of basal cell adenomas is based on the growthpatterns, hence the recognition of several types: tubular,trabecular, solid, membranous or dermal analogue, andcanalicular.19,33-35 The diagnostic dilemma in the evaluationof monomorphic adenomas relates to their resemblance toother primary or secondary small blue cell tumors that maybe encountered in the salivary glands. The list of such tumorsincludes adenoid cystic carcinoma (particularly the solidvariant), cellular variant of pleomorphic adenoma, basaladenocarcinoma, metastatic cutaneous basal cell carcinoma,metastatic small cell carcinoma, and pilomatrixoma.32,33,36,37

As a group, the basal cell adenomas are ratheruncommon tumors (2% of all salivary gland neoplasms) andare encountered infrequently in FNA of the salivaryglands.25,38 The smears of monomorphic adenomas often arecellular but variable, showing cohesive, irregular, jigsawpuzzle configurations or flat trabecular patterns and scattered(naked) single cells. A hint of peripheral palisading may bepresent in some clusters. Individual cells appear small andbasaloid, exhibiting high nuclear/cytoplasmic (N/C) ratiosand scant cytoplasm. The nuclei appear round to ovoid,show even distribution of fine chromatin, and are withoutobvious nucleoli. Basal cell adenomas may containmetachromatic collagenous matrix, analogous to the matrixof 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 adenomafrom adenoid cystic carcinoma ❚ Table 2❚ . However, thematrix of basal cell adenoma tends to show interdigitation

❚ Table 1❚Differential Diagnoses for Pleomorphic Adenoma*

Cytologic Finding (Pleomorphic Adenoma) Differential Diagnosis Diagnostic Hints

Plasmacytoid myoepithelial cells Malignant lymphoma Identify myoepithelial cellsPlasmacytoma Matrix and nuclear detail; no lymphoglandular bodies

Increased duct cells Low-grade carcinoma Careful characterization of matrixMatrix-poor tumor cells Monomorphic adenoma Matrix

Low-grade carcinoma Nuclear detailMyoepithelioma Difficult to excludeMetastases Necrosis, mitosis, nuclear detail, history

Increased stroma with or Adenoid cystic carcinoma Identify myoepithelial cellswithout hyaline globules Polymorphous low-grade adenocarcinoma Evaluate stroma-cell interface

Nuclear atypia (mild to moderate Carcinoma ex pleomorphic adenoma Identify typical myoepithelial cell featuresand focal)

Mucoid background Low-grade mucoepidermoid carcinoma Different staining characteristics on rapid Romanowsky/ MGG stains; no mucous and intermediate cells

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

❚ Image 4❚ Smear of pleomorphic adenoma showing thecharacteristic fibrillary appearance of the matrix. Note thepresence of myoepithelial cells intimately admixed with thestroma (Papanicolaou, ×400).




with tumor cells at the periphery, and, in addition, delicatevessels and spindle cells may be present, embedded in thestroma. In contrast, in adenoid cystic carcinoma, thestroma–tumor cell interface is sharply defined; the matrix iscommonly acellular and devoid of blood vessels. The dermalanalogue subtype of basal cell adenoma is virtually indistin-guishable cytologically from adenoid cystic cell carci-noma.10,36,39 Clinical history and imaging studies are crucialin the diagnosis of metastatic small cell carcinoma and cuta-neous basal cell carcinoma, entities that cytologicallyresemble basal cell adenomas. Presence of high-gradenuclear features, mitosis, nucleoli, and necrosis are moresuggestive of carcinoma than of monomorphic adenoma.40,41

Warthin TumorWarthin tumor is a benign tumor commonly encountered

in salivary gland FNA specimens. Warthin tumor occurs

frequently in the parotid gland, is slightly more common infemales, shows an association with cigarette smoking, and maybe bilateral in about 10% of the cases. On palpation, mostWarthin tumors feel soft or boggy but in situations of increasedfluid accumulation they may feel quite tense and firm.1,10,42

Histologic examination of Warthin tumor reveals thecharacteristic cystic spaces lined by a bilayer of oncocyticcells 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 quitehypocellular owing to fluid dilution. The 3 main componentsthat characterize the FNA cytology of Warthin tumor areoncocytes, lymphocytes, and the fluid background ❚ Image 6❚ .Oncocytes usually are seen as flat, cohesive sheets 2 to 3cells in thickness and often devoid of stroma. The oncocyteshave abundant dense cytoplasm, relatively large but blandnuclei, and uniformly low N/C ratios.19 The cytoplasmic

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

Cytologic Finding (Mono-morphic Adenoma) Differential Diagnosis Diagnostic Hints

Basaloid small cells Basal cell adenocarcinoma Necrosis, mitosis, high-grade nuclear features, pleomorphism favors malignancy; may be impossible to distinguish

Adenoid cystic carcinoma Abnormal nuclear detail, necrosis favors malignancyPolymorphous low-grade adenocarcinoma May be impossible to distinguish; palisading favors adenoma; site of

(problem: hyaline globules of stroma) tumor originCellular pleomorphic adenoma Identify myoepithelial cells; naked nuclei favor monomorphic adenomaMetastatic small cell carcinoma Clinical data, nuclear molding, necrosis, no stroma favor malignancy

❚ Image 5❚ Warthin tumor. Histologic examination reveals abilayer of oncocytes lining the cyst wall and abundantlymphocytes in the subepithelial stroma (H&E, ×400).

❚ Image 6❚ Smear of Warthin tumor aspirate showing thesmall flat sheets of oncocytes, scattered lymphocytes, and agranular “cystic” background. The oncocytes displayabundant granular cytoplasm with sharp cytoplasmic bordersand bland nuclear features (Papanicolaou, ×400).




granularity and eosinophilia, characteristic features of onco-cytes, may be difficult to detect on rapid Romanowsky– andPapanicolaou-stained FNA material, but they are obvious onH&E-stained cell-block material.

The accompanying lymphoid component of Warthintumor shows mostly small, mature background lymphocytes.Occasionally elements of a reactive follicle germinal centermay be identified. The fluid of Warthin tumor often impartsa dirty background appearance that may be confused withtumor necrosis. In addition to the 3 main components, otherelements that can be encountered in FNA smears of Warthintumor include, albeit rarely, metaplastic squamous and seba-ceous gland cells.

The differential diagnoses for Warthin tumor are wide❚ Table 3❚ .16,43 In most cases (>80%), the presence andcombination of the 3 main cytologic elements establish thediagnosis without difficulty. However, as is well known,oncocytes, lymphocytes, and a fluid background are notpathognomonic of Warthin tumor, as they are encountered inseveral other conditions. Cysts (lymphoepithelial cysts) ofthe salivary glands and chronic inflammatory and obstructiveduct lesions can accumulate fluid, show oncocytic meta-plasia, and contain numerous lymphocytes and can easily beconfused with Warthin tumor.44-46 Oncocytoma and onco-cytic carcinoma are rare salivary gland tumors that may beconfused with Warthin tumor, as oncocytes are common toall 3 entities, and the former 2 tumors may contain variablenumbers of lymphocytes. In oncocytic neoplasms, the cellclusters are bigger and 3-dimensional and are 3 or more celllayers thick. The intermediate squamous cells of mucoepi-dermoid carcinoma, the uncommon oncocytic metaplasia ofpleomorphic adenoma, and metaplastic cells of squamouscell carcinoma may all be confused with Warthin tumor.47

The cells of acinic cell carcinoma may show cytoplasmiceosinophilia, thus resembling oncocytes and leading to diag-nostic confusion. However, the presence of large zymogengranules, prominent nucleoli, significant pleomorphism,cytoplasmic vacuolation, and prominent large-caliber vessels

favors the diagnosis of acinic cell carcinoma over Warthintumor. It is important to always reaspirate any residual massafter initial drainage of fluid from Warthin tumor cases orany other cystic lesions to obtain more representative mate-rial, which may provide clues to the diagnosis.

Oncocytic NeoplasmsWhile nonneoplastic oncocytes are common and seen

regularly in the FNA biopsy smears of salivary gland lesions,oncocytic neoplasms are rare.48 Exclusive populations of onco-cytic cells showing abundant and finely granular cytoplasmcharacterize oncocytic neoplasms seen in many endocrine andother organs of the body, including the salivary glands. Mostoncocytic neoplasms represent benign oncocytoma, while themalignant counterpart, oncocytic carcinoma (malignant onco-cytoma) is extremely rare.4,49 In FNA smears of salivary glandoncocytic neoplasms, oncocytes are present as cohesive 3-dimensional 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 maybe seen, but mitotic figures are uncommon. On air-dried, rapidRomanowsky–stained material, the cytoplasm may appeardense bluish gray, and the cytoplasmic granules, representingnumerous mitochondria, may be difficult to detect.

The accuracy rate for the diagnosis of oncocytoma onFNA biopsy material is high, about 92%, while false-positivediagnoses are largely due to incorrectly diagnosed cases ofWarthin tumor.25 In general, the cell clusters in Warthintumor are smaller and flat, while those of oncocytomapresent as thicker 3-dimensional groups. In addition, aspira-tion of Warthin tumor often yields brownish fluid, whichimparts the dirty cyst fluid appearance on the smears, whileoncocytoma is less likely to be cystic or to contain as muchfluid. As already noted, the majority of oncocytic neoplasmsare benign, even if nuclear atypia is present. Nevertheless,the cytologic distinction of oncocytoma from the extremelyrare oncocytic carcinoma is difficult and may be impossibleon FNA material.49 While the presence of significant nuclear

❚ Table 3❚Differential Diagnoses for Warthin Tumor

Cytologic Finding (Warthin Tumor) Differential Diagnosis Diagnostic Hints

Cyst fluid not obvious; Oncocytoma Warthin tumor unlikely if only 1 cell seen; oncocytoma usually not cystic andoncocytes only has fewer lymphocytes than Warthin tumor

Rare oncocytes and Various cystic lesions Reaspirate any residual masslymphocytes Lymphoma Consider flow cytometric analysis

Atypical metaplastic SCC Warthin tumor unlikely if high-grade nuclear features, no oncocytes in SCCsquamous cells MEC Intermediate and mucous cells favor MEC

Oncocytic cells and Acinic cell carcinoma Papillary and acinar structures, cytoplasmic vacuoles, necrosis favor aciniclymphocytes (lymphocyte-rich stroma) cell carcinoma

MEC, mucoepidermoid carcinoma; SCC, squamous cell carcinoma.




atypia, mitosis, and necrosis suggests malignancy, a defini-tive diagnosis of carcinoma may require surgical excisionand histologic evaluation. Other lesions in the same differen-tial category are acinic cell carcinoma, mucoepidermoidcarcinoma with oncocytic metaplasia, and oncocytosis seenin normal salivary glands or metaplastic oncocytes associ-ated with inflammatory lesions (Table 3).

MyoepitheliomaMyoepithelioma is an uncommon benign neoplasm that

occurs in the parotid, submandibular gland, and the palate. Thetumor is composed exclusively of plasmacytoid or spindledcells representing myoepithelial cells (and not accompanied byan epithelial or ductal component).50,51 Cytologically, spindle-shaped or uniform plasmacytoid cells containing moderateamounts of cytoplasm and showing distinct cytoplasmicborders characterize the smears of myoepithelioma. Stromalmaterial is minimal or absent, while necrosis, mitosis, andnuclear atypia are virtually never seen in this neoplasm.43,52

Pleomorphic adenoma and the malignant myoepithe-lioma are the chief differential considerations for myoepithe-lioma (Table 1). Identification of plasmacytoid myoepithelialcells intimately mixed with metachromatic stroma favorspleomorphic adenoma, although stroma-poor cases may bedifficult to distinguish from myoepithelioma. The cytologicfeatures of the extremely rare malignant myoepitheliomahave not been well reported, but the presence of significantnuclear atypia and mitosis may suggest such a diagnosis.

52,53

Low-Grade Neoplasms

Low-Grade Mucoepidermoid CarcinomaMucoepidermoid carcinoma (MEC) is generally divided

into 2 histologic grades, low and high, the former character-ized by a cystic growth pattern ❚ Image 8❚ and an abundanceof mucous cells, while high-grade MEC is defined by domi-nance of the solid component. Some workers recognize anintermediate histologic grade of MEC.54-56 Proper assign-ment of grade requires evaluation of the entire tumor, a diffi-cult proposition on FNA material because of sampling prob-lems. While grading of the tumor is difficult on cytologicmaterial, a more serious problem is failing to correctly diag-nose low-grade MEC. Low-grade MEC accounts for about80% of all MECs and is well recognized for its potentialfalse-negative diagnostic pitfall, apparently owing to thebland cytologic features and hypocellular nature of many ofthese tumors. MEC occurs at any age, can involve both themajor and minor salivary glands, and is the most commonmalignant 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 hypocel-lular. Again, to obtain more representative material in any

cystic lesion, the residual mass, following initial fluid aspira-tion, should be reaspirated. The cellular component of MECwill show a mixture of mucus-secreting cells and interme-diate cells ❚ Image 9❚ . Both cell types show bland cytologicfeatures. Mucus-secreting cells exhibit abundant foamy orvacuolated cytoplasm, low N/C ratios, and loose cellulargroups. Careful examination of the smears may reveal thepresence of goblet cells (Image 9), cells frequently seen in low-grade MEC.25,57 When the mucous cells are present as singlecells, they can be easily confused with foamy histiocytes.

❚ Image 7❚ Oncocytoma. Smear showing exclusivelyoncocytic cells forming cohesive clusters. No lymphocytes orother cell types are present (rapid Romanowsky, ×400).

❚ Image 8❚ Low-grade mucoepidermoid carcinoma. Histologicexamination reveals the predominantly microcystic patternand numerous mucous cells (H&E, ×400).




Intermediate cells are small uniform cells with scant cytoplasmand frequently are present in tight cohesive clusters. Cellsshowing true or mature squamous cell differentiation (kera-tinization) are almost never seen in low-grade MEC.10,19,56

As stated before, underdiagnosis of low-grade MEC is acommon problem because the malignant nature of the lesionmay be overlooked for reasons mentioned before andbecause the foamy cells resemble histiocytes.1,9,10,58 Oneshould always first exclude the possibility of low-grade MECbefore a specific diagnosis is given in the cytologic evalua-tion of any cystic lesion of the salivary glands. The differen-tial diagnosis of low-grade MEC includes Warthin tumor,benign salivary gland cysts (lymphoepithelial cysts),branchial cleft cyst, sialolithiasis or chronic sialadenitiscomplicated by cystic dilatation, and pleomorphic adenomawith excess mucoid stroma ❚ Table 4❚ .49,54,59 To differentiateWarthin tumor from low-grade MEC, one should look for thepresence of numerous oncocytes (especially in cohesive clus-ters), the dirty cystic background, and lymphocytes. Thepresence of oncocytes and lymphocytes in large numbers

usually is not seen in MEC, although metastasis of low-gradeMEC to the neck and intraparotid lymph nodes may result ina very confusing picture. Obstructive duct lesions are partic-ularly problematic as mucous and squamous metaplasia canbe seen, mimicking the mixed cell pattern of low-gradeMEC. Identification of stone fragments excludes MEC, butthis, in the experience of many, is not a common finding incases of sialolithiasis. The mucoid stroma of pleomorphicadenoma may be mistaken for the mucin of MEC, but themucin/stroma of the latter does not show metachromasia. Acareful search for the myoepithelial cells will help avoidmaking the wrong diagnosis.10,60

Acinic Cell CarcinomaAcinic cell carcinoma, the third major common malig-

nant tumor of the salivary gland, is seen in adults and chil-dren and occurs mainly in the parotid gland, although thesubmandibular glands can be involved as well. Ten percentof acinic cell carcinomas will recur despite wide resection,but the overall prognosis is good, with a 10-year survival rateof about 90%. Several histologic growth patterns of aciniccell 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 intowell-, moderately, and poorly differentiated forms, but thecytologic diagnosis depends on the identification of acinarcells and/or recognition of the acinar-glandular arrangement.In many cases, the FNA smears are quite cellular (cysticcases may be hypocellular), showing both single cells andlarge irregular clusters; the central portions of the latter oftencontain large-caliber vessels, while the periphery demon-strates frayed borders ❚ Image 11❚ .63-65 The tumor cells inwell-differentiated acinic cell carcinoma closely resemblenormal acinar cells, are large and polyhedral with abundantbluish gray vacuolated ❚ Image 12❚ and granular cytoplasm onrapid Romanowsky–stained material, and have eccentricnuclei. The cytoplasmic granules are much larger than thegranules of oncocytic cells. In some cases, however, thegranules may be degranulated and, therefore, may not beidentified. The cytoplasm is delicate and can rupture easily

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

❚ Table 4❚Differential Diagnoses for Low-Grade MEC*

Cytologic Finding (MEC) Differential Diagnosis Diagnostic Hints

Squamous and mucous cells, Metaplastic cells seen in sialolithiasis Goblet cells favor MEC; painful aspirate and stone fragmentscyst fluid, foamy cells and Kuttner tumor (submandibular) favor inflammation (may defer to histologic examination)

Hypocellular mucoid smears Cysts Mixed cells—goblet and goblet cells—favor MEC (with or without foamy cells)

Oncocyte-like cells (rare) Warthin tumor 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.




during the smearing process, leading to the presence ofnumerous naked nuclei and a granular background. The less-differentiated tumors show smaller cells that may appearcuboidal. Nuclear atypia remains minimal to moderate, butnecrosis may be present. On occasion, cells with clear cyto-plasm may be identified.63,64

A major differential diagnostic consideration of aciniccell carcinoma is normal salivary gland acinar cells orsialosis ❚ Table 5❚ .66 Normal acinar cells are usually seen as3-dimensional cohesive clusters of cells like a bunch ofgrapes and may be mixed with groups of smaller ductal cellsand adipose tissue fragments, whereas in acinic cell carci-noma, in addition to clusters, there are relatively more singlecells. Furthermore, the clusters of cells in acinic cell carci-noma are larger and more irregular than those of normalacini. Because the tumor grows in an expansive manner, allnormal tissues (including adipose and ductal cells) arepushed away to the periphery and generally are not repre-sented in the smears. Neoplasms in the differential diagnosisof acinic cell carcinoma include epithelial-myoepithelialcarcinoma, MEC, Warthin tumor, pleomorphic adenoma,oncocytoma, and metastatic renal carcinoma.4,67 The pres-ence of clear cells or vacuolated cells should lead to theconsideration of epithelial-myoepithelial carcinoma andmetastatic renal cell carcinoma. However, the identificationof acellular hyaline stroma (and spindle-shaped myoepithe-lial cells) favors epithelial-myoepithelial carcinoma, whereasthe presence of numerous naked nuclei in the backgroundfavors acinic cell carcinoma. Clinical history of a kidneycarcinoma should lead to strong consideration of metastasis.

The vacuolated cells of low-grade MEC may be confusedwith acinic cell carcinoma. An effort should be made to lookfor mucus-producing and goblet cells that are characteristicof low-grade MEC. In addition, zymogen granules are notseen in low-grade MEC but may be present in acinic cellcarcinoma. Identification of the strikingly metachromaticstroma and plasmacytoid cells will help in the distinction ofcellular pleomorphic adenoma from acinic cell carcinoma. Thetumor cells of acinic cell carcinoma may appear oncocytic and,

❚ Image 10❚ Acinic cell carcinoma. Histologic section showingpapillary configuration. Vacuolation and clear cytoplasm areapparent in the tumor cells. This appearance could beconfused with metastatic renal cell carcinoma (H&E, ×600).

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

❚ Image 12❚ Another irregular cluster of acinic cell carcinomashowing cytoplasmic vacuoles, eccentric nuclei, andoccasional nucleoli (rapid Romanowsky, ×600).




together with the presence of scattered naked nuclei (resem-bling lymphocytes), acinic cell carcinoma may be confusedwith oncocytoma and Warthin tumor. However, morecommonly, acinar cell arrangements are seen in acinic cellcarcinoma but not in oncocytoma or Warthin tumor, and, inaddition, lymphocytes rather than naked nuclei typifyWarthin tumor.

Adenoid Cystic CarcinomaAdenoid cystic carcinoma is one of the major and more

common malignant salivary gland neoplasms. It occursmainly in the minor glands and submandibular gland,accounting for about 10% of all salivary gland and 3% ofparotid tumors. Adenoid cystic carcinoma manifests as aslow-growing mass, and, in about 10% of the cases, patientsmay complain of pain or show facial muscle weakness (clin-ical findings strongly suggestive of malignancy), and theclinical behavior is characterized by persistent growth andrecurrences.10,68

Cytologically, the smear patterns of adenoid cysticcarcinoma are characterized by a mixture of small, uniform,basaloid cells with high N/C ratios and metachromaticstroma. The cytologic architecture frequently mimics thehistologic patterns ❚ Image 13❚ , showing cribriform or tubularstructures, while exclusively solid sheets of tumor cells areseen in the solid variant or anaplastic adenoid cystic carci-noma. The chromatin appears coarse but uniform withoutidentifiable nucleoli, and nuclear pleomorphism is minimal.Necrosis is a rare cytologic finding, but when seen usually isindicative of the anaplastic variant of adenoid cystic carci-noma. The background of adenoid cystic carcinoma usuallyis populated by scattered naked nuclei of tumor cells.Although the stroma of adenoid cystic carcinoma is charac-teristic, 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 onair-dried, rapid Romanowsky–stained material ❚ Image 14❚ .The interface between tumor cells and stroma often is

sharply demarcated. On Papanicolaou staining, the stromaappears cyanophilic but shows no fibrillary architecture, animportant distinguishing feature when the differentialconsideration is pleomorphic adenoma (Image 13).15,69

The diagnosis of the well-differentiated or cribriformtype of adenoid cystic carcinoma is relatively straightfor-ward. The microcystic spaces containing the hyaline glob-ules and cylinders of metachromatic stroma are easily identi-fied in such cases. However, metachromatic stroma is notspecific for or unique to adenoid cystic carcinoma; it also isfound in cases of polymorphous low-grade adenocarcinoma,basal cell adenoma, and pleomorphic adenoma and even inepithelial-myoepithelial carcinoma and basal cellcarcinoma.36 Thus, cases of adenoid cystic carcinomalacking cribriform architecture may be impossible to distin-guish from other basaloid tumors. The identification ofhyaline stroma is, however, always critical to the diagnosis ofadenoid cystic carcinoma, as most cases almost always(excerpt the solid variant) show its presence.70 There are noclear nuclear and cytoplasmic features that permit discrimi-nation of adenoid cystic carcinoma from its mimics. Becausethe surgical treatment of adenoid cystic carcinoma mayinvolve sacrificing the facial nerve, it is crucial to make thecorrect cytologic diagnosis. In addition, the overall prognosisbetween different tumor types may be vastly different. Indifficult cases, definitive diagnosis may need to be deferredto the surgical specimen (or frozen section) evaluation.Adenoid cystic carcinoma always should be considered inthe differential diagnosis of any basaloid small blue celltumors of the salivary gland (Table 2).

Polymorphous Low-Grade AdenocarcinomaPolymorphous low-grade adenocarcinoma occurs

predominantly in the minor salivary glands, in particular onthe hard palate and other intraoral sites. In rare instances, themajor salivary glands and neck lymph nodes may beinvolved. The average age of patients with polymorphouslow-grade adenocarcinoma is 60 years.71-73

❚ Table 5❚Differential Diagnoses for ACC

Cytologic Finding (ACC) Differential Diagnosis Diagnostic Hints

Eosinophilic, oncocyte-like cells, High-grade mucoepidermoid carcinoma No mixed cell pattern in ACCcytoplasmic vacuoles

Oncocyte-like cells and lymphocytes Warthin tumor; oncocytoma Acinar arrangements and naked nuclei favor ACCHypocellular (cystic ACC) Variety of cystic lesions ReaspirateAcinar cells, normal looking Normal salivary gland tissue; sialosis No normal elements (adipocytes and ductal cells),

(well-differentiated ACC) favor ACCPapillary structures, vacuolated Metastasis: renal cell carcinoma Clinical history and imaging studies

or clear cytoplasm (rare but known to go to unusual sites)

ACC, acinic cell carcinoma.




Mixed patterns of irregular sheets and pseudopapillaryor papillary fragments of tumor cells and metachromaticstroma characterize the cytology of polymorphous low-gradeadenocarcinoma. The tumor cells are oval or polyhedral withmoderate amounts of nonvacuolated cytoplasm. Because thecytoplasm is delicate, naked nuclei of tumor cells often areseen in the background. The nuclei appear uniform, showdelicate chromatin, and contain small or inconspicuousnucleoli. The stroma may be mixed intimately with tumorcells or may form hyaline globules that closely resemble thehyaline globules of adenoid cystic carcinoma.74

The chief differential considerations for polymorphouslow-grade adenocarcinoma include adenoid cystic carcinoma,epithelial-myoepithelial carcinoma, and pleomorphic adenoma(Table 2). The distinction of polymorphous low-grade adeno-carcinoma from adenoid cystic carcinoma may be quite diffi-cult, because, when present, the stromal hyaline globules aresimilar. However, the tumor cells of polymorphous low-gradeadenocarcinoma generally are larger and more uniform thanthe cells of adenoid cystic carcinoma, and in addition, thepresence of pseudopapillary fragments is uncommon inadenoid cystic carcinoma. Epithelial-myoepithelial carcinomamay be impossible to distinguish from polymorphous low-grade adenocarcinoma when the 2 cell types, ductal andmyoepithelial cells, that characterize this tumor are not seentogether. The metachromatic stroma of polymorphous low-grade adenocarcinoma may lead to the consideration of acellular pleomorphic adenoma; however, the globular hyalinedeposits are less common in the latter. In addition, the tumor

cells of pleomorphic adenoma usually show plasmacytoidfeatures of the myoepithelial cells, and the cells do not formthe well-defined pseudopapillary or tubular structures typicalof polymorphous low-grade adenocarcinoma.25,73

High-Grade Neoplasms

High-Grade MECThe diagnosis of high-grade MEC, in contrast with that

of low-grade MEC, is relatively easy, as more atypical cellsshowing squamoid features are seen.10 Nevertheless, otherconstituent elements such as intermediate cells and mucus-producing or goblet cells should be sought and identified tocomplete the diagnostic picture. It should be noted,however, that the histologic classification of high-gradeMEC is not based primarily on the presence of high-gradenuclear features; rather it is dependent on the extent of thesolid component.10,73 The implication of this requirementwith regard to FNA cytology is thorough sampling of thelesion to obtain representative material. The differentialdiagnosis of high-grade MEC includes squamous cell carci-noma. Primary squamous cell carcinoma of the salivaryglands is rare, while metastasis or contiguous involvementfrom cutaneous or intraoral locations is more common.26 Asnoted by Schindler et al19 and Feldman et al,75 both high-grade MEC and squamous cell carcinoma can show cysticcomponents, making this feature nondiscriminative. Squa-mous cell carcinoma metastatic from the tonsillar crypts isparticularly likely to show cystic metastasis19,75 ❚ Table 6❚ .

A B

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

❚ Image 14❚ The brightly metachromatic matrix forminghyaline cylinders and spheres with a sharp interface betweenthe matrix and tumor cells are characteristic findings foradenoid cystic carcinoma (rapid Romanowsky, ×400).




Salivary Duct CarcinomaSalivary duct carcinoma is a rare, high-grade malignant

tumor, accounting for about 2.8% of the salivary glandmalignant tumors. More than 80% of the cases occur in theparotid gland of older men. At diagnosis, the majority of thepatients will have local lymph node metastases and/or extraparotid extension into adjacent soft tissue. The histologicsimilarities of salivary duct carcinoma to mammary ductcarcinoma have been well described and include the cribri-form pattern of tumor growth ❚ Image 15❚ and the presence ofcomedo-type necrosis.26,76,77

Cytologically, the diagnosis of a malignant process isstraightforward in these cases because the nuclear features areoften high-grade and easy to recognize as such. However,recognizing the tumor as a primary tumor of the salivarygland and correctly classifying it may be difficult. The smearsof salivary duct carcinoma usually are very cellular, showingtumor cell groups disposed of in cribriform or pseudopapil-lary formations ❚ Image 16❚ , often associated with necrosis.

Nuclei are large and irregular with thickened membranes andprominent nucleoli. The cytoplasm is generally moderate toabundant and appears eosinophilic.78 A nonspecific but usefuldiagnostic feature seen in invasive salivary duct carcinoma isthe presence of bands of hyalinized collagen (Image 16), astromal response to tumor infiltration.79-81

Initial recognition of salivary duct carcinoma as a high-grade neoplasm is crucial as this tumor carries a dismal prog-nosis. However, salivary duct carcinoma should be differenti-ated from high-grade MEC, squamous cell carcinoma, andmetastatic breast carcinoma (Table 6). MEC consists of amixture of cell types, including mucous cells, intermediatecells, and cells showing squamous differentiation. The squa-mous differentiation seen in MEC is subtle and does notusually show full maturation, and the degree of nuclear atypiais often mild. The cytoplasm of salivary duct carcinoma mayappear dense and squamoid, but obvious squamous differentia-tion and the presence of keratin material and high-grade nucleiare more consistent with squamous cell carcinoma ❚ Image 17❚

❚ Table 6❚Differential Diagnoses for High-Grade Neoplasms

Neoplasm Cytologic Finding

SDC (may be impossible to distinguish from metastatic High-grade nuclear features; cribriform pattern; necrosis and hyalinized breast carcinoma) collagen bands

High-grade mucoepidermoid carcinoma Mixture of cells: intermediate, squamous differentiation, and mucous cells; nuclear atypia not as severe as in SDC or SCC

SCC (primary rare, intraparotid lymph node metastasis Pleomorphic cells with high-grade nuclei; dense keratinized cytoplasm;or contiguous spread from skin) keratin debris

Metastasis: adenocarcinoma, undifferentiated carcinoma Difficulty differential; need full clinical data and imaging studies

SCC, squamous cell carcinoma; SDC, salivary duct carcinoma.

❚ Image 15❚ Salivary duct carcinoma. A histologic sectiondemonstrates the cribriform and infiltrative growth pattern ofthis high-grade tumor (H&E, ×400).

❚ Image 16❚ The smear pattern of salivary duct carcinomashows irregular clusters of high-grade nuclei tumor cells andbands of hyalinized collagen (rapid Romanowsky, ×600).




than salivary duct carcinoma. Pleomorphic adenoma is distin-guished from salivary duct carcinoma by the identification ofplasmacytoid myoepithelial cells, lack of high-grade nuclearfeatures, and the absence of necrosis. Metastasis from breastcarcinoma to the parotid gland is uncommon, but both entitiesfrequently involve neck lymph nodes, making the cytologicdifferentiation from lymph node aspiration material difficult ifnot impossible. Thus, historic clinical data and immunostainingfor androgen receptors (positive in salivary duct carcinoma)may assist in making the correct diagnosis.80

Carcinoma Ex Pleomorphic AdenomaCarcinoma ex pleomorphic adenoma accounts for about

2.2% of all salivary gland tumors, and the malignant componentcan manifest synchronously or metachronously with pleomor-phic adenoma. The malignant component often is high-gradeand includes MEC, salivary duct carcinoma, undifferentiatedcarcinoma, and others. Low-grade tumors also can arise frompleomorphic adenoma. Cytologically, in the synchronous type,the benign pleomorphic adenoma and the malignant componentmay be identified in the same smear, but more likely onecomponent is present or dominates the smear pattern.11,44,82

Other Rare Neoplasms and Nonneoplastic TumefacientLesions

There are many extremely uncommon neoplastictumors that can occur in salivary glands and, therefore, maybe encountered in FNA cytologic material. These includesebaceous adenoma, sebaceous lymphadenoma, papilloma,

papillary cystic adenoma, and papillary adenocarcinoma,true malignant mixed tumors, mesenchymal lesions such asschwannoma, and others. Proper recognition of the indi-vidual cell constituents and correlation with the clinicalpicture is critical in making the correct diagnosis.83,84

FNA of Lymphoid Lesions

Lymphoid lesions of the salivary gland include normalintraparotid lymph node, benign lymphoepithelial lesions, andmalignant lymphoma.26,85-88 The presence of lymphocytes inWarthin tumor and many epithelial salivary gland neoplasmshas been described. Malignant lymphoma accounts for about5% of all salivary gland tumors. Secondary involvement of thesalivary gland or intraparotid lymph nodes can be suspected inpatients known to have lymphoma. Of the primary lymphomas,the high-grade type is relatively easy to diagnose. However,follicular lymphomas and lymphomas of mucosa-associatedtissue type (MALT) may be very difficult to identify.89 A highindex of suspicion is required whenever an abundance oflymphoid cells is identified, and flow cytometric analysisshould be performed. MALT lymphomas are low-grade tumorsthat occur in association with benign lymphoepithelial lesionsand, therefore, will show a polymorphous picture composed ofreactive or benign and malignant lymphoid cells. Flow cyto-metric analysis and histologic evaluation are required for thedefinitive diagnosis of lymphomas.86-88

Chronic Sialadenitis and Sialolithiasis

Nonneoplastic inflammatory lesions, including thetumefacient Kuttner tumor (chronic sclerosing sialadenitis)of the submandibular gland, frequently are encountered inFNA of the salivary glands. Included in this group issialolithiasis with duct obstruction.18,88 Clinically, suchlesions appear neoplastic. Long-standing chronic inflamma-tion and sialolithiasis, as alluded to previously, may lead tometaplastic changes in the ductal epithelium including squa-mous, mucous ❚ Image 18❚ , and oncocytic metaplasia. Thesecytologic changes result from a sequence of events initiatedby duct obstruction, followed by continued accumulation ofsecretions (mucus) distally, eventually leading to cysticdilatation, atrophy of the acinar cell component, fibrosis, andmetaplastic changes. Duct obstruction may be due to produc-tion of viscid secretions or calculi. Regardless of the patho-genesis, the importance of the cytologic changes relates tothe fact that they potentially may be confused with a varietyof salivary gland neoplasms. Metaplastic squamous andmucous cells may be mistaken for intermediate or squamouscells and mucus-producing cells of MEC, and when these cells

❚ Image 17❚ Squamous cell carcinoma of the parotid gland. Inthis smear tumor cells with obvious high-grade nuclei,pleomorphism, and keratinized cytoplasm are present. Thisdegree of atypia and squamous maturation is not seen inmucoepidermoid carcinoma (rapid Romanowsky, ×600).




are seen in situations where there is cystic dilatation with fluidaccumulation, an erroneous diagnosis of MEC is reinforced.Squamous metaplastic cells with atypia ❚ Image 19❚ also mayraise the possibility of squamous cell carcinoma, although thedegree of atypia usually is mild in the former. When oncocyticmetaplasia is accompanied by chronic inflammatory cells(small lymphocytes), an incorrect diagnosis of Warthin tumormay be made. FNA of chronic sialadenitis may yield fibroticstroma that may show metachromasia on rapid Romanowskystain and, when seen together with ductal cells (which domi-nate such smears because of acinar cell atrophy) showingmetaplastic squamous differentiation, a diagnosis of pleomor-phic adenoma may be considered. Although rare, identifica-tion of stone fragments in FNA smears of the salivary glandsshould dissuade one from a diagnosis of a neoplastic tumor.

Conclusion

FNA biopsy is a minimally invasive technique that has apivotal role in the diagnosis and management of patients withsalivary gland tumors. When performed properly, FNAcytology can provide useful preoperative information about amass lesion arising in the salivary gland, permitting the clini-cian to appropriately manage the patient. However, extremecare and recognition of the limitations of cytology are essen-tial in the evaluation of salivary gland FNA material toachieve the correct diagnoses, as there are many commonand rare tumors that can cause diagnostic confusion.

From the Department of Pathology, University of Arkansas forMedical Sciences and Central Arkansas Veterans HealthcareSystem, Little Rock.

Address reprint requests to Dr Mukunyadzi: Dept ofPathology, Slot LR/113, Central Arkansas Veterans HealthcareSystem, 4301 W 7th St, Little Rock, AR 72205.

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