BRIEF REPORTS Spontaneous Infarction of Pleomorphic Adenoma: Report of a Case Simulating Malignancy on Fine-Needle Cytology Sample Franco Fulciniti, M.D., Ph.D.,1* Nunzia Simona Losito, M.D.,1 Gerardo Botti, M.D.,1 Marco Manola, M.D.,2 and Franco Ionna, M.D.2 Ischemic or hemorrhagic infarction has been described as an uncommon but possible complication of fine-needle cytology sampling in numerous organs, more frequently the thyroid, the salivary glands, the breast, the lymph node, and the kidney. In these situations, infarction appears to be directly related to the vascular disturbances caused by needle sampling, though fine this latter might be. One case of a spontaneous infarction of a parotid pleomorphic adenoma in a 46-year-old lady is here described in which the cytopathologic findings, which were related to ischemic infarction, preceded fine-needle cytology sampling and mimicked malignancy. The cytopathologic picture showed a quizzical mixture of necrosis and inflammation coupled to hyperplastic changes of the acinar cells, oncocytic metaplasia, and atypical squamous metaplasia of extreme degree simulating high-grade epidermoid- or mucoepidermoid carcinoma. Due to the cytologically suggestive changes, a nerve-sparing radical parotidectomy was performed. The differential diagnostic problems encountered in this case are discussed together to the possible medical–legal implications originating from such striking atypias as to closely simulate malignancy. Diagn. Cytopathol. 2010;38:430–434. ' 2009 Wiley-Liss, Inc. Key Words: salivary gland pathology; spontaneous infarction of pleomorphic adenoma; ischemic changes following fineneedle sampling; head and neck pathology 1 S.S.D. di Citopatologia, A.F. di Anatomia Patologica, Istituto Nazionale Tumori ‘‘Fondazione G. Pascale,’’ Naples, Italy 2 S.C. di Chirurgia Maxillo-Facciale-O.R.L, Istituto Nazionale Tumori ‘‘Fondazione G. Pascale,’’ Naples, Italy *Correspondence to: Franco Fulciniti, M.D., Ph.D., S.S.D. di Citopatologia, A.F. di Anatomia Patologica, Istituto Nazionale Tumori ‘‘Fondazione G. Pascale,’’ Via M. Semmola, Naples 80131, Italy. E-mail: franco.fulciniti@gmail.com Received 4 August 2009; Accepted 28 August 2009 DOI 10.1002/dc.21229 Published online 5 November 2009 in Wiley InterScience (www. interscience.wiley.com). 430 Diagnostic Cytopathology, Vol 38, No 6 Vascular disturbances following Fine-needle cytology (FNC) sampling, with or without aspiration, have been described in numerous organs mainly in the thyroid,1–6 where their relative frequency deserved an histo- and cytopathologic codification,2,3 the salivary glands,7–12 the breast,13–16 lymph nodes,17,18 and the kidney.19 Due to the widespread diffusion of FNC of the thyroid and to the rich vascularity of this gland, vascular disturbances following FNC have first been described and elegantly codified by LiVolsi and Merino4 and by Kini in this organ.5 Briefly, partial or total infarction of thyroid neoplasms following FNC may impede or endanger the histopathological diagnosis in surgical samples because of their following massive fibrosis, coagulative necrosis, or to the residual presence of only a small rim of viable tumor tissue at the periphery of a malignant neoplasm. This small rim of tissue may be more easily overlooked by the histopathologist, especially if he is unaware of the cytopathologic diagnosis.1–3,5 Moreover, even when a true infarct is lacking, myofibroblastic proliferation may ensue FNC as a post-traumatic response. These lesions are very cellular and, although entirely benign, may cause differential diagnostic problems with other lesions containing spindle cells, like medullary or anaplastic carcinoma.4 In the salivary glands, partial or total infarction may be caused by FNC sampling7,9 or may be a spontaneous event and may concern benign tumors or malignancies.8,11 In Warthin’s tumor, post-FNC infarction may lead to sudden increase in volume of the affected gland, coupled to pain or tenderness.7 In analogy to what described in the thyroid, infarction of malignant tumors may impede the histopathological diagnosis.10 Moreover, infarcted organs may be prone to secondary infection. To our knowledge only two cases of spontaneous infarction of pleomorphic adenoma have been previously ' 2009 WILEY-LISS, INC. Diagnostic Cytopathology DOI 10.1002/dc SPONTANEOUS INFARCTION OF PLEOMORPHIC ADENOMA described8,11 that underwent FNC. In both the cases, the cytopathologic picture was puzzling due to the presence of inflammation, coagulative necrosis, acinar cell hyperplasia, and of atypical squamous cells mimicking malignancy. In the case described by Layfield et al.,8 both the cytological and radiographic findings had simulated a primary malignancy. In this article, we report on an additional case of spontaneously infarcted pleomorphic adenoma that showed on FNC sample diffuse coagulative necrosis, oncocytic metaplasia, acinar cell hyperplasia, and the presence of numerous markedly atypical squamous cells that simulated malignancy. Due to the following inconclusive cytopathologic diagnosis and also to the clinically suggestive features of the mass (tenderness of recent duration, warmness, and redness of the overlying skin), a nerve-sparing radical parotidectomy was performed, and the histopathological diagnosis was of infarcted pleomorphic adenoma. The differential diagnosis of this rare condition is discussed with a special effort to underline the most predictive cytopathologic findings useful, in our view, to make a correct diagnosis on FNC samples. Case Report A 46-year-old lady presented at the FNC Clinic of our Institution for the diagnostic evaluation of a 2.5 3 1.8 cm mass in her left parotid. The mass was slightly tender on palpation and the overlying skin was erythematous. The patient referred that the lesion had been present for about 1 year, but recently there had been a phase of accelerated growth and some spontaneous pain, as well as tenderness on self-palpation had recently appeared. Her routine blood tests were normal except for a slight leukocytosis (19,000 WBC/mm3, 80% neutrophilic granulocytes) and elevated erythrocyte sedimentation rate of 55 mm. The mass had an elastic consistency and was warmer than the contralateral parotid. FNC was performed using a 23G needle without aspiration. Three separate passes were done, and several smears were obtained that were partly air-dried, stained with Diff QuikTM, partly fixed in 95% ethanol, and stained with Papanicolaou. The smears contained several small tissue fragments at a naked eye inspection, and the obtained material had a chalky appearance. Cytological Findings Low-power microscopic magnification showed richly cellular smears in which several cell types could be recognized in a background of coagulative necrosis: (1) hyperplastic serous acinar cells of normal appearance. These were present as small lobular units in which they showed normal polarity and smooth nuclei with finely granular heterochromatin, small nucleoli, and moderately ample, vacuolated cytoplasms (Fig. C-1); (2) sheets of small size oncocytes alternating to normal acinar cells (Fig. C-2). These had pyknotic nuclei and the background was rich in inflammatory cells. (3) Some dense, anucleated orangiophylic fragments could be seen that were interpreted as being anucleated squamous cells or freely lying keratin; these were variably interspersed to the other cellular components; (4) clusters of metaplastic squamous cells with varying degree of cellular atypias. They showed heavily keratinized spiky cytoplasms that had a bluish to greenish tinge in DQ stained smears. Their nuclei showed from moderate to marked variation in size and shape (Fig. C-3). The smear background was rich in inflammatory cells and in fragments of keratin (Figs. C-1 and C-4). In PAP stained smears, several of the squamoid cells observed in DQ stained smears had extremely atypical nuclei of ovoid to elongated shape, with prominent nucleoli of irregular shape and size that closely mimicked malignancy (Fig. C-4). An inconclusive cytological diagnosis was made in which a strong worry for malignancy was substantiated by the really striking atypias observed in the (metaplastic) squamous cells (Figs. C-3 and C-4). The only other lesions considered in the differential diagnosis were epidermoid- or mucoepidermoid carcinoma, and spontaneous infarction of a benign salivary gland neoplasm. Histopathological Findings A nerve sparing radical parotidectomy was performed. The superficial lobe of the parotid gland contained a cystic lesion measuring 2.5 3 1.8 cm (Fig. C-5). The cyst lumen contained numerous anucleated squames and fragments of keratin, whereas the cystic wall was lined by metaplastic squamous cells with various degrees of cytopathologic atypias, from moderate to extreme (Fig. C-6). The salivary gland parenchyma surrounding the cystic lesion showed areas of gland tissue with diagnostic features of pleomorphic adenoma in which an abrupt transition between viable, well preserved tissue and infarcted tissue with massive squamous metaplasia with formation of ghost cells and cholesterol clefts could be seen (Fig. C-7). The atypias in the squamous lining of the cystic area were really notable; nevertheless, in no case could in situ or invasive carcinomatous transformation be observed. A histopathological diagnosis of infarcted pleomorphic adenoma with extremely atypical squamous metaplasia was made. The patient’s recovery after the operation was uneventful and she is well at a 1-year follow-up. Diagnostic Cytopathology, Vol 38, No 6 431 Diagnostic Cytopathology DOI 10.1002/dc FULCINITI ET AL. Figs. C-1–C-4. Fig. C-1. FNC sample. Acinar cells of normal appearance can be seen as lobular units. Notice small nucleoli and finely vacuolated cytoplasms and twoo deeply orangiophylic fragments (top of the image). Papanicolaou, 3600. Fig. C-2. FNC sample. Low power microscopic magnification showing a peculiar mixture of hyperplastic acinar cells mixed with small-size oncocytes (lower right corner). Also notice the inflammatory type of background and several deeply orangiophylic dense bodies. Papanicolaou, 3100. Fig. C-3. FNC sample. One cluster of atypical metaplastic squamous cells can be observed. Notice the irregular nuclei showing moderate variation in size and shape and the presence of prominent chromocenters. The cytoplasms are mostly well defined and have a bluish to greenish tinge. Diff Quik, 3400. Fig. C-4. FNC sample. A sheets of extremely atypical squamous (metaplastic) cells is shown. Notice the extreme variability of nuclear shape, from round-oval to cigar-shaped, as well as nuclear hypechromasia associated to prominent, multiple chromocenters. The background is inflammatory and contains dense, keratinized bodies. Papanicolaou, 3600. Discussion In analogy to what happens with other organs, FNC sampling—with or without suction—may induce various histopathological changes also in the salivary glands. These changes have been extensively analyzed by Li et al.12 and vary from acute and chronic inflammation, cholesterol cleft formation and granulomatous reaction to capsular pseudo-infiltration, extensive squamous metaplasia and infarction. These changes may have a variable impact on 432 Diagnostic Cytopathology, Vol 38, No 6 the histopathological picture following the excision of the salivary gland tumor, but rarely do they interfere with the diagnosis except that in cases in which the presence of exuberant squamous metaplasia coupled to subepithelial stromal hyalinization and/or necrosis leads the histopathologist to the suspicion of a malignancy, like squamous cell- or mucoepidermoid carcinoma. Spontaneous infarction of salivary gland tumors is extremely rare and the present case may be, to our knowledge, the third one described in the cytologic literature. Like in the two cases Diagnostic Cytopathology DOI 10.1002/dc SPONTANEOUS INFARCTION OF PLEOMORPHIC ADENOMA described previously,8,11 the cytological atypias in the squamous metaplastic cells were of extreme degree and caused a justified worry for malignancy that conducted, in our case, to a radical, nerve sparing parotidectomy. In the case here described, frozen-section histopathological examination of the surgical sample would have probably conducted to a correct diagnosis: this possibility had been discussed with the surgeon right before the operation and the deliberate choice to dissect preoperatively the intraglandular portion of the facial nerve was justified by the possible finding of a malignancy in the definitive histopathological sample, in the face of a possible negative intraoperative diagnosis. With hindsight, considering also the descriptions of the two previously published cases, the cytopathologic diagnosis of infarction could have been formulated in our case. In fact, a peculiar mixture of benign acinar cells and small oncocytic cells with pyknotic nuclei had been observed, combined to the presence of heavily keratinized anucleated squamous and metaplastic cells—also with remarkable nuclear atypias—in an inflammatory background devoid of true cellular necrosis. This combination of features could have probably been also useful to exclude epidermoid carcinoma (in which a certain degree of cellular necrosis is always present) and mucoepidermoid carcinoma because at least some mucous or intermediate-type cells should be observed in this entity. However, as mucoepidermoid carcinoma, among salivary gland tumors, is the most commonly underdiagnosed lesion in FNC samples,20–22 the cytopathologists are particularly alerted (and hence negatively biased) in the diagnostic evaluation of atypical squamous or metaplastic squamous cells in a salivary gland FNC. So, the fear of underevaluating a possible malignancy, may lead, as in our case, to (justified) overestimation of the cytopathologic picture. In conclusion, it is our opinion that though spontaneous infarct of pleomorphic adenoma may be correctly diagnosed on FNC samples, this condition may lengthen rather than shorten the list of possible pitfalls in salivary gland cytopathology.23,24 Figs. C-5–C-7. Fig. C-5. Surgical sample. Low power magnification showing an empty cystic structure. Adjacent to the cyst the nodular solid growth (center of the picture) represents the residual noninfarcted plemorphic adenoma. Numerous serous acini can be seen at the periphery of the gland. H&E, reduced from 340. Fig. C-6. Surgical sample. High power microscopic magnification of the cyst wall showing extremely atypical squamous cells with prominent nucleoli, mimicking malignancy. H&E, 3600. Fig. C-7. Surgical sample. Interface between the cystic structure (lower left) and the residual plemorphic adenoma (right side of the image). Notice the abundance of heavily keratinized bodies on the left, lining the cyst wall and a cholesterol cleft (center of the image) abutting on the noninfarcted tumor. H&E, 3250. Diagnostic Cytopathology, Vol 38, No 6 433 Diagnostic Cytopathology DOI 10.1002/dc FULCINITI ET AL. Acknowledgments The authors gratefully acknowledge Ms. Ornella Sacco for her data managing skillfulness, the Lega Italiana per la Lotta ai Tumori, Sezione di Napoli, for its generous contribution to this paper and Drs. Rosario Romanelli and Alessandra Trocino for their excellent bibliographical services. References 1. Jayaram G, Aggarwal S. Infarction of thyroid nodule: A rare complication following fine needle aspiration. Acta Cytol 1989;33:940– 941. 2. Layfield LJ, Lones MA. Necrosis in thyroid nodules after fine-needle aspiration biopsy. Report of two cases. Acta Cytol 1991;35: 427–430. 3. Alejo M, Matias-Cruiu X, de las Heras Duran P. Infarction of papillary carcinoma after fine-needle aspiration. Acta Cytol 1991;35: 478–479. 4. LiVolsi VA, Merino MJ. Worrisome histological alterations following fine-needle aspiration of the thyroid (WHAFFT). Pathol Annu 1994;29(Part 2):99–120. 5. Kini SR. Post-fine-needle biopsy infarction of thyroid neoplasms: A review of 28 cases. Diagn Cytopathol 1996;15:211–220. 6. Sharma C, Krishnanand G. Histological analysis and comparison of techniques in fine needle aspiration-induced alterations in thyroid. Acta Cytol 2008;52:56–64. 7. Kern SB. Necrosis of a Warthin’s tumor following fine-needle aspiration. Acta Cytol 1988;32:207–208. 8. Layfield LJ, Reznicek M, Lowe M, Bottles K. Spontaneous infarction of a parotid gland pleomorphic adenoma. Report of a case with radiographic and cytological overlap with a primary salivary gland malignancy. Acta Cytol 1992;36:381–386. 9. Bayramoğlu H, Düzcan E, Akbulut M, Topuz B. Infarction after fine-needle aspiration biopsy of pleomorphic adenoma of the parotid gland. Acta Cytol 2001;45:1008–1010. 10. Rau AR, Pai RR, Nayak S. Infarction of acinic cell carcinoma in a patient infected with HIV: A complication of fine-needle aspiration cytology obscuring definitive diagnosis. Diagn Cytopathol 2003;29: 222–224. 434 Diagnostic Cytopathology, Vol 38, No 6 11. Behzatoglu K, Bahadir B, Huq GE, Kaplan HH. Spontaneous infarction of a pleomorphic adenoma in parotid gland: Diagnostic problems and review. Diagn Cytopathol 2005;32:367–369. 12. Li S, Baloch ZW, Tomaszewski JE, LiVolsi VA. Worrisome histological alterations following fine-needle aspiration of benign parotid lesions. Arch Pathol Lab Med 2000;124:87–91. 13. McCutcheon JM, Lipa M. Infarction of a fibroadenoma of breast following fine-needle aspiration. Cytopathology 1993;4:247–250. 14. Vargas MP, Merino MJ. Infarcted myxoid fibroadenoma following fine-needle aspiration. Arch Pathol Lab Med 1996;120:1069–1071. 15. Deshpande KM, Deshpande AH, Raut WK, Lele VR, Bobhate SK. Diagnostic difficulties in spontaneous infarction of a fibroadenoma in an adolescent: Case report. Diagn Cytopathol 2002;26: 26–28. 16. Lee KC, Chan JK, Ho LC. Histological changes in the breast after fine-needle aspiration. Am J Surg Pathol 1994;18:1039–1047. 17. Davies JD, Merino MJ. Segmental lymph-node infarction after fineneedle aspiration. J Clin Pathol 1982;35:855–877. 18. Nasuti JF, Gupta PK, Baloch ZW. Clinical implications and value of immunohistochemical staining in the evaluation of lymph node infarction after fine-needle aspiration. Diagn Cytopathol 2001;25:104– 107. 19. Fulciniti F, Mascolo M, Insabato L, Formichelli F, Botti G. Massive infarction of papillary carcinoma of the kidney after fine-needle aspiration biopsy: Report of a case with cytohistological correlation. Acta Cytol 2006;50:563–566. 20. Schindler S, Nayar R, Dutra J, Bedrossian CW. Diagnostic challenges in aspiration cytology of the salivary glands. Semin Diagn Pathol 2001;18:124–146 (Review). 21. Hughes JH, Volk EE, Wilbur DC. Cytopathology Resource Committee, College of American Pathologists. Pitfalls in salivary gland fine-needle aspiration cytology: Lessons from the College of American Pathologists Interlaboratory Comparison Program in Nongynecologic Cytology. Arch Pathol Lab Med 2005;129:26–31. 22. Edwards PC, Wasserman P. Evaluation of cystic salivary gland lesions by fine-needle aspiration: An analysis of 21 cases. Acta Cytol 2005;49:489–494. 23. Palombini L. Challenges in the interpretation of FNAs from the salivary glands. Diagn Cytopathol 1997;17:417–421. 24. Boccato P, Altavilla G, Blandamura S. Fine-needle aspiration biopsy of salivary gland lesions. A reappraisal of pitfalls and problems. Acta Cytol 1998;42:888–898.