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  1. ANATOMIC PATHOLOGY Original Article Sialolithiasis Differential Diagnostic Problems in Fine-Needle Aspiration Cytology MICHAEL W. STANLEY, MD,1 RICARDO H. BARDALES, MD,4 JANET BENEKE, MD,3 SOHEILA KOROURIAN, MD,1 AND SCOTT J. STERN, MD2 Downloaded from by guest on 04 May 2020 Sialolithiasis with obstruction of major salivary gland ducts can lead to clinical tumefaction related to cystic dilatation. In addition to mucus accumulation, these pseudoneoplasms feature hyperplasia and squa- mous metaplasia of the ductal lining epithelium, with varying degrees of inflammation. The authors report five examples of this lesion aspirated from two males and three females ranging in age from 45 to 80 years (median 65 years). Three were in the submaxillary gland, and two were in the parotid. In three cases, stone fragments were identified, and diag- noses of sialolithiasis were rendered; two of these patients underwent surgical excision. The remaining two cases showed prominent foam cells and metaplastic squamous cells in a mucoid background that mim- icked low grade mucoepidermoid carcinoma. Stone fragments were not identified and a differential diagnoses of sialolithiasis versus low grade mucoepidermoid carcinoma were suggested. Surgical excision revealed sialolithiasis in both instances. When stone fragments arc identified in aspirated material, these cases pose little diagnostic difficulty. Mow- ever, when this material is not present, epithelial changes and mucus accumulation may be difficult to distinguish from low grade mucoepi- dermoid carcinoma. Cautious interpretation is suggested in this setting. (Key word: Parotid; Salivary gland; Cytology; Fine-needle aspiration; Stones; Sialolithiasis; Mucoepidermoid carcinoma) Am J Clin Pathol 1996;106:229-233. The true incidence of sialolithiasis is difficult to deter- mine, as many cases are apparently asymptomatic. Some examples are incidentally discovered at the time of den- tal radiography, but up to 20% are not radiopaque.K2 Stone formation in the salivary glands (SG) is not associ- ated with abnormalities of calcium metabolism. Those symptomatic cases that lack the clinical features of a sec- ondary bacterial infection usually feature recurrent pain and swelling associated with meals. Many patients are symptomatic for years, and a few with large stones may describe nearly continuous pain. Sialolithiasis is most common in the submaxillary glands, with the parotid less commonly involved.'"3 Fine-needle aspirations (FNA) from stone-bearing salivary gland are rarely re- ported.4 Chronic salivary gland duct obstruction (of which si- alolithiasis is one cause) leads to parenchymal atrophy, and periductal chronic inflammation. Fibrosis can make these glands very firm, leading to clinically alarming physical findings that may suggest malignancy to the ex- amining physician. The involved ducts may become di- lated, and their lining cells show various combinations of mucinous, ciliated and squamous metaplasia. In the absence of suppuration, this type of obstructive lesion can form a tumefaction that consists mostly of a dilated duct and surrounding fibrous tissue. The duct contains secreted material and a stone or stone fragments. Fine- needle aspiration (FNA) of such a lesion will yield extra- cellular mucus and a small number of mucinous, foamy, or metaplastic squamous cells.5 The latter may be ma- ture, or can be less fully developed and resemble imma- ture squamous metaplastic elements seen in a variety of cytologic preparations from different body sites. Thus, the expected FNA picture of sialolithiasis closely mimics that of low grade mucoepidermoid carcinoma (LGMEC). Aspirates of this relatively common salivary gland malignancy also show spare cellularity, a mu- cinous background, and various combinations of foam cells and squamous cells. Low grade mucoepidermoid carcinoma also shows small "intermediate cells" that cy- tologically resemble the immature squamous metaplas- tic cells that can be associated with duct obstruction due to stones or other causes. We describe our experience with aspiration of sialoli- thiasis. The findings will be contrasted with those of a From the Departments of'' Pathology and Otolaryngology. Univer- sity of Arkansas for Medical Sciences: *Department of Pathology at the Hennepin County Medical Center, Minneapolis. Minnesota: and "De- partment of Pathology. McClellan Veterans Administration Center. Little Rock. Arkansas. Medical Manuscript received December 4. 1995: revision accepted February 14, 1996. Address reprint requests to Dr. Stanley: University of Arkansas for Medical Sciences. Department of Pathology, Mail Slot-517, 4301 W. Markham. Little Rock, AR 72205. 229

  2. ANATOMIC PATHOLOGY Original Article 230 TABLE 1. CLINICAL AND HISTOPATHOLOGIC FINDINGS IN FIVE SIALOLITHIASIS PATIENTS EVALUATED BY FINE-NEEDLE ASPIRATION Location of Mass Stones Noted in Smears Patient No. Age (years)/Sex Symptom* Duration Surgical Pathology Findings f 51/M 48/F 65/F 80/F Mass/pain, 2 months Mass, 1 year NA Mass, 3 years 1 2 3 4 Submandibular Parotid Parotid Submandibular No No Yes Yes Single 1 cm stone 0.5 cm thickening with small stones No surgery performed Mucoid material not sectioned; stones not grossly identified 2.5 cm lobulated area of fibrosis with punctate calcifications 5 68/M Submandibular Mass, NA Yes Downloaded from by guest on 04 May 2020 NA = not applicable. * Only in case I did the clinical record specifically address asking the patient about the mealtime pain; this individual did not have this symptom. t Cases 1. 2. 4 and 5 showed evidence of chronic duct obstruction, featuring duct obstruction, fibrosis, chronic inflammation, and acinar atrophy. typical archival example of LGMEC. The primary goal of this report is to illustrate the difficulty in distinguish- ing these two entities in FNA material. tures as noted in FNA smear material. All cases showed readily identifiable mucus mixed with foam cells (Fig. 1). Immature squamous cells were also present in cases 1, 2, and 5. Epithelial cell groups showed various combina- tions of foam cells, columnar cells, and immature squa- mous metaplastic elements (Fig. 2). Neither stones nor ciliated metaplasia were identified in cases 1 and 2, mak- ing their resemblance to LGMEC complete. The preop- erative FNA diagnoses in these two cases were "benign duct obstructive process versus LGMEC." As noted previously, smear material from cases 3 through 5 also showed mucus and foam cells. However, in these examples stone fragments were easily identified (Fig. 3), and case 5 showed numerous ciliated columnar cells (Fig. 4). These indicators of benignancy eliminated consideration of LGMEC, leading to FNA diagnoses of sialolithiasis. This was confirmed surgically in cases 4 and 5, and by clinical follow-up of 6 years in case 3. Chronic inflammatory cells were noted in four cases, but were especially prominent in cases 3 and 4, in which they were accompanied by a moderate number of neutro- phils. Comparison of cells from sialolithiasis with those of LGMEC shows the similarities between these two types of cyst linings (Fig. 5). Histologically, the lining of dilated MATERIALS AND METHODS Each of the five patients was referred for FNA of a sal- ivary gland mass. Aspirations were performed with 25 gauge needles mounted on 10 cc syringes. Smears were prepared by the aspirating pathologist and either air dried for a Diff-Quik stain (StatLab Medical Products, Lewisville, TX) or alcohol fixed for a Papanicolaou stain. In one case, a formalin-fixed cell block supplemented the smears. All subsequently obtained surgical specimens were fixed in 10% buffered formalin, embedded in par- affin, sectioned at 4 /xm, and stained with hematoxylin and eosin. The patients' medical charts were reviewed. A surgically confirmed archival example of LGMEC is used for illustrative purposes. This neoplasm presented as a 1.5 cm parotid mass in a 14-year-old male, and was aspirated by one of the authors (MWS) in the manner described above. RESULTS The clinical and histopathologic findings are summa- rized in the Table 1. Table 2 reviews the cytologic fea- TABLE 2. CYTOLOGIC FINDINGS IN FIVE SIALOLITHIASIS PATIENTS EVALUATED BY FINE-NEEDLE ASPIRATION Patient No. Background Mucus Foam Cells Chronic Inflammatory Cells Immature Squamous Cells Stone Fragments Cellularity Cilia _ - - - + _ - + + + + + + + - - + + - +* +* + 1 2 3 4 5 Abundant Abundant Abundant Moderate Abundant 2+/3+ 1+/3+ 1+/3+ 2+/3+ 2+/3+ Numerousf + Numerous + = present: - = not present; 1+/3+ = sparse smear cellularity; 2+/3+ = moderate smear cellularity. * Acute inflammatory cells were also noted. t Stone fragments were also seen in cell block sections prepared by embedding the centrifuge pellet from 1 mL of tubid fluid. A.J.C.P.'August 1996

  3. STANLEY ET AL. FNA of Sialolithiasis 231 5 *V M * c #. Downloaded from by guest on 04 May 2020 • ^ & V ^ •-••*•• FlG. 1. Case 1. Low power examination of FNA smears from sialolithi- ais shows abundant mucus, as well as cells that lie both singly and in clusters. Considerable dissociation can be noted adjacent to the large cell group. Most of the cells entrapped within the mucus are foam cells (Diff-Quik stain, 40X). FIG. 3. Case 3. Stone fragments were readily identified in FNA material from three cases, and some were laminated (arrow). In this example, acute inflammatory cells are also present (cell block sections, hematox- ylin and eosin, X400). ducts associated with sialolithiasis showed various com- binations of squamous cells, vacuolated cells, immature squamous metaplastic cells, and ciliated metaplasia (Fig. 6). In those cases lacking cilia, these epithelia resembled LGMEC (Fig. 7). DISCUSSION The FNA findings in our examples of sialolithiasis in- clude mucus, with small numbers of foam cells, imma- ture squamous metaplastic cells, and more mature squa- mous cells. The cells of immature squamous metaplasia resemble the "intermediate cells" of LGMEC. Thus, for those aspirates that do not yield either ciliated metaplasia 3VJP B ••v- FIG. 2. Case 1. A, This complex epithelial cell group was depicted at low magnification in Figure 1. Columnar cells and a foam cell are present. In other areas, cells with dense cytoplasm are arranged in fiat sheets with the pattern of immature squamous metaplasia. The latter pattern mimics the intermediate cells of low grade mucoepidermoid carcinoma (Diff-Quik stain, X600). Case 5. B, This cell group from an example of sialolithiasis shows immature squamous metaplasia that mimics the intermediate cells of low grade mucoepidermoid carcinoma. These cells lie in a flat sheet and feature bland nuclei, moderate amounts of cytoplasm, sharp cell borders, and slight vacuolization (Papanicolaou, X600). m* * % • FlG. 4. Case 5. FNA smears from this example of sialolithiasis showed numerous groups of ciliated columnar cells (Papanicolaou. X600). Vol. 106-No. 2

  4. 232 ANATOMIC PATHOLOGY Original Article Downloaded from by guest on 04 May 2020 FIG. 5. This archival example of low grade mucoepidermoid carcinoma showed the same low-magnification picture illustrated in sialolithiasis (Fig. 1). At higher magnification, these squamoid and vacuolated cells are similar to those of sialolithiasis (Papanicolaou, X600). FIG. 7. Shows the epithelium in an archival example of low grade mucoepidermoid carcinoma (hematoxylin and eosin, X400). architectural. In Evans' scheme, neoplasms that are min- imally cystic with more than 90% solid growth are con- sidered high grade.7 In cytologic samples, this is reflected in the well-known spare cellularity of LGMEC and the abundant cellularity of the high grade neoplasms. Several groups have described their experience with FN A of MEC,9"15 but many do not provide grading data for the subsequently obtained histologic material. Cyto- logically, high grade MEC is often readily recognized as carcinoma, but may be difficult to classify more fully.5'9 However, LGMEC can be a very challenging diagnosis because many aspirates are sparsely cellular, show only bland tumor cells, and raise the possibility of other mu- cinous or cystic salivary gland masses (pleomorphic ade- noma,"16 acinic cell carcinoma, Warthin's tumor,"13 or stone fragments, one may seriously consider the ma- lignant, albeit low grade interpretation.6'7 Several grading schemes have been developed, but di- visions more complex than high grade MEC and LGMEC seem to add little of clinical relevance.7 High grade cases lead to more instances of local recurrence, regional metastasis and distant spread. Furthermore, high grade tumors are more likely to be extensive and to be incompletely removed at the time of initial surgery. Tumors with marked nuclear pleomorphism, prominent mitotic activity, or all but focal necrosis are usually in- terpreted as some other type of malignancy.8 Thus, the distinction between high grade MEC and LG is largely FIG. 6. Cases 2 and 5. A-C, Examples of cyst linings from cases of sialolithia- sis are shown here. A and B show squa- mous and ciliated cells, respectively. C shows a more complex epithelium con- taining goblet cells, finely vacuolated foam cells, and immature metaplastic cells that mimic the intermediate cells of low grade mucoepidermoid carci- noma (hematoxylin and eosin, X400). >* - . < * A.J.C.P.-August 1996

  5. STANLEY ET AL. FNA ofS 233 REFERENCES or nonneoplastic cysts'3). Clear cell change and onco- cytic differentiation (focal or diffuse) are additional un- common cytologic alterations that might further expand our differential diagnostic thinking, but that have not yet been extensively described in FNA material.17'18 Low grade mucoepidermoid carcinoma is a relatively frequent cause of false-negative salivary gland FNAs.10 Furthermore, false-positive diagnoses of this tumor can occur in cases of sialadenitis." The latter difficulty is complicated by the fact that chronic inflammatory cells may be prominent in LGMEC,5'7-13 limiting the diagnos- tic utility of this finding. To this already complex prob- lem, we add the difficulties occasioned by salivary gland duct obstruction. The sialolithiasis cases we have de- scribed are a special instance of what is probably a more general problem. For example, we have seen similar FNA findings related to salivary gland duct obstruction in patients with compression of the superficial lobe by tumors in the deep parotid lobe. Frierson and Fechner4 have made the interesting ob- servation that psammoma bodies and nonpsammoma- tous calcifications are commonly present in submaxil- lary glands that are normal, inflamed or irradiated. In some of their cases, excision revealed a clinically inap- parent stone, whereas some examples of sialolithiasis were recognized preoperatively. The importance of rec- ognizing that psammoma bodies occur in a normal sali- vary gland is obvious in the FNA setting. Whether some laminated calcifications represent early stone formation is not clear. Some of the historical information obtained by review of the patients' medical records is incomplete. However, the data summarized in Table 1 suggest that referral of sialolithiasis patients for FNA is weighted toward those individuals who lack the expected symptoms. Thus, this diagnosis may not be prominent in our differential diag- nostic thinking at the time of aspiration. This may make the danger of confusing these cases with LGMEC even greater. We suggest that when FNA findings consistent with LGMEC are encountered, one should consider the possibility of sialolithiasis or other duct-obstructive le- sions. Not all cases will show stones in cytologic material, or radiographs. Further clinical investigation may be warranted before institution of surgical therapy. 1. Hume WJ. The mouth, salivary glands, jaws, and teeth. In: McGee JO, Isaacson PG, Wright NA. eds. Oxford Textbook of Pathol- ogy, vol 2a. Pathology of Systems. New York: Oxford University Press, 1992, pi 070. 2. Levy DM, ReMine WH. Devine KD. Salivary gland calculi: Pain. swelling associated with eating. JAMA 1962:181:1115-1119. 3. Blatt I. Studies in sialolithiasis. III. Pathogenesis, diagnosis and treatment. Southern Med J 1964;57:723-729. 4. Frierson HF, Fechner RE. Chronic sialadenitis with psammoma bodies mimicking neoplasia in a fine-needle aspiration speci- men from the submandibular gland. Am J Clin Pathol 1991:95: 884-888. 5. Lowhagen TL, Tani EM, Skoog L. Salivary glands and rare head and neck lesions. In: Bibbo, ed. Comprehensive Cytopathology. Philadelphia: W. B. Saunders Co., 1991. pp 624-625, 634-636. 6. Kumar N. Kapila K, Verma K. Fine-needle aspiration cytology of mucoepidermoid carcinoma: A diagnostic problem. Acta Cviol 1991;35:357-359. 7. Evans HL. Mucoepidermoid carcinoma of salivary glands: A study of 69 cases with special attention to histologic grading. Am J Clin Pathol 1984; 81:696-701. 8. Stanley MW, Bardales RH, Farmer CE. et al. Primary metastatic high-grade carcinomas of the salivary glands: A cytologic-histo- logic correlation study of twenty cases. 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Cohen MB, Fisher PE, Holly EA, et al. Fine-needle aspiration bi- opsy diagnosis of mucoepidermoid carcinoma: Statistical anal- ysis. Acta Cytol 1990;34:43-49. 16. Stanley MW. Lowhagen T. Mucin production by pleomorphic ad- enomas of the parotid gland: A cytologic spectrum. Diagn Cvto- pathol 1990;6:49-52. 17. Hamed G, Shmookler BM, Ellis GL, Punja U, Feldman D. Onco- cytic mucoepidermoid carcinoma of the parotid gland. Arch Pa- tholLabMed 1994; 118:313-314. 18. Layfield LJ. Glasgow BJ. Aspiration cytology of clear-cell lesions of the parotid gland: Morphologic features and differential diag- nosis. Diagn Cvtopathol 1993:9:705-712. Downloaded from by guest on 04 May 2020