Application of Sal classification to parotid gland fine-needle aspiration cytology: 10-year retrospective analysis of 312 patients

Received: 19 October 2016 Revised: 10 September 2017 Accepted: 22 November 2017 DOI: 10.1002/hed.25056 ORIGINAL ARTICLE Application of Sal classification to parotid gland fine-needle aspiration cytology: 10-year retrospective analysis of 312 patients Ahmet Erdem Kilavuz MD 1 Murat Songu MD 2 Abdulkadir _Imre MD 2 Secil Arslanoglu MD 2 Yilmaz Ozkul MD 2 Ercan Pinar MD 2 D uzg un Ateş MD 2 1 Department of Otorhinolaryngology, Acibadem Healthcare Group Taksim Hospital, Istanbul, Turkey 2 Department of Otorhinolaryngology, Izmir Katip Celebi University, Ataturk Training and Research Hospital, Izmir, Turkey Correspondence Ahmet Erdem Kilavuz, Department of Otorhinolaryngology, Acibadem Healthcare Group Taksim Hospital, Istanbul, Turkey. Email: aekilavuz@gmail.com Abstract Background: The accuracy of fine-needle aspiration biopsy (FNAB) is controversial in parotid tumors. We aimed to compare FNAB results with the final histopathological diagnosis and to apply the Sal classification to our data and discuss its results and its place in parotid gland cytology. Methods: The FNAB cytological findings and final histological diagnosis were assessed retrospectively in 2 different scenarios based on the distribution of nondefinitive cytology, and we applied the Sal classification and determined malignancy rate, sensitivity, and specificity for each category. Results: In 2 different scenarios FNAB sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were found to be 81%, 87%, 54.7%, and 96.1%; and 65.3%, 100%, 100%, and 96.1%, respectively. The malignancy rates and sensitivity and specificity were also calculated and discussed for each Sal category. Conclusion: We believe that the Sal classification has a great potential to be a useful tool in classification of parotid gland cytology. KEYWORDS fine-needle aspiration biopsy, histopathological diagnosis, parotidectomy, parotid gland, Sal classification 1 INTRODUCTION Salivary gland tumors account for 3% of all head and neck tumors. The majority of salivary gland tumors (60%-85%) originate from the parotid gland and 60%-80% of these are histologically benign. 1,2 Determining the best treatment plan involves supporting the results of a physical examination with diagnostic evidence, such as ultrasound, CT, MRI, or fine-needle aspiration biopsy (FNAB). 3,4 The FNAB is a widely used safe, easy-to-perform, and cost-effective diagnostic technique that is essential for the examination of head and neck masses. 5,6 However, the accuracy of FNAB for the diagnosis of parotid tumors is controversial because of the variable histomorphological appearance and the overlapping cytological features of benign and malignant parotid tumors. These issues are reflected in various investigations of the sensitivity and specificity of FNAC for the diagnosis of parotid tumors. 7 9 Furthermore, there is the limiting issue of nondefinitive cytology, which cannot be overlooked, because their exclusion or, if included, their incorporation to malignant or benign cytology contributes to the variability in study results. 8,10 Classification systems for cytologic diagnosis add more clarity and depth to cytology reporting and naturally provide an algorithm for clinical management. However, although these systems work easily for thyroid and breast cytology, applying them to salivary gland pathology is challenging because of its heterogeneity and rarity. 11 Bajwa et al 12 proposed the Sal classification for parotid gland cytology in order to better predict malignancy possibility and determine the final treatment decision. One of the main contributions of their study is that it provides us a better chance to predict the Head & Neck. 2018;40:937 942. wileyonlinelibrary.com/journal/hed VC 2018 Wiley Periodicals, Inc. 937

938 KILAVUZ ET AL. TABLE 1 Sal classification defined by Bajwa et al 12 Sal classification Definition SAL 1I Inadequate samples SAL 1C Cyst contents only SAL 2I Benign inflammatory (nonneoplastic) SAL 2N Benign neoplastic lesions SAL 3 Atypical cytology TABLE 2 Accuracy of fine-needle aspiration biopsy when nondefinitive cases are regarded as malignant cytology of malignancy of nonmalignancy malignancy histopathology benign histopathology Total 40 33 73 9 222 231 SAL 4 SAL 5P SAL 5NOS SAL 5M Suspicious cytology with remarks of malignancy possibility Primary salivary gland malignancy Malignancy not otherwise specified Metastatic diseases Total 49 255 304 Sensitivity 81.6% Specificity 87% PPV 54.7% NPV 96.1% Abbreviations: FNAB, fine-needle aspiration biopsy; NPV, negative predictive value; PPV, positive predictive value. Republished as adapted with permission from Bajwa MS, Rose SJ, Mairembam P, et al. Feasibility of a novel classification for parotid gland cytology: a retrospective review of 512 cytology reports taken from 4 United Kingdom general hospitals. Head Neck. 2016;38(11):1596 1603, VC 2017 John Wiley and Sons. outcomes of the cases that have nondefinitive cytology, which are harder to manage and predict the final results. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the FNAB for 2 separate scenarios and created 2 contingency tables, and we applied Sal classification (Table 1) to our data and discussed the results and its place in the management of parotid gland diseases. 2 MATERIALS AND METHODS Our study protocol was approved by the local ethics committee. We retrospectively enrolled 312 patients who underwent primary surgery for parotid gland tumors in our tertiary center between January 2006 and March 2016. Demographic characteristics (age and sex), clinical history, preoperative findings, FNAB cytological findings, and final histopathological diagnosis retrospectively by review of the patients charts. The FNAB was performed with ultrasound guidance by a radiologist and histopathological, and the analysis of the material was assessed by a cytopathologist. We assessed the correlations between the FNAB report and the final histopathological diagnosis in 2 different steps. First, we calculated sensitivity, specificity, PPV, and NPV according to the classic Galen and Gambino 13 method for 2 different scenarios. In the first scenario, we incorporated the cases with suspicious cytology into the malignant cytology group, therefore, a false-positive result was a lesion that was either suspicious or malignant on FNAB and resulted to be benign in final histopathology, whereas false-negative cases were benign on FNAB and resulted to be malignant in final histopathology. In the second scenario, we excluded suspicious cytology from the statistical analysis, so a falsepositive result was a lesion that was malignant on FNAB and resulted to be benign in final histopathology, whereas falsenegative cases were benign on FNAB and resulted to be malignant in final histopathology. We also prepared contingency tables for each scenario. Finally, we applied the Sal classification to our data and calculated malignancy rates, sensitivity, specificity, PPV, and NPV for each category and discussed its applications and benefits. 3 RESULTS The study population consisted of 312 patients (174 men and 138 women) with a mean age of 54.12 6 15.41 years (range 10-80 years). Ultrasound and preoperative FNAB were performed in all cases. Of the 312 final histological results, the most common benign tumor type was pleomorphic adenoma (n 5 127; 40.7%), followed by Warthin s tumor (n 5 95; 30.4%). The most common malignant tumor type was mucoepidermoid carcinoma (n 5 12; 3.84%). In the first scenario, in which we regarded nondefinitive cytology as malignant, FNAB sensitivity was found to be 81%, specificity 87%, PPV 54.7%, and NPV 96.1% (Table 2). We excluded 8 cases with inadequate cytology in these scenarios because they did not correspond to a final histopathological diagnosis. In the second scenario, we also excluded nondefinitive cytology alongside inadequate cytology and we calculated sensitivity 65.3%, specificity 100%, PPV 100%, and NPV 96.1% (Table 3). We used the Sal classification to further categorize the cytology results as: Sal 1I (n 5 8; 2.6%) inadequate sample; Sal 1C (n 5 20; 6.4%) cyst content; Sal 2I (n 5 18; 5.8%) nonneoplastic, inflammatory lesions; Sal 2N (n 5 193; 61.9%) benign neoplastic lesions; Sal 3 (n 5 29; 9.3%)

KILAVUZ ET AL. 939 TABLE 3 Accuracy of fine-needle aspiration biopsy when nondefinitive cases are excluded from statistical analysis of malignancy of nonmalignancy malignancy histopathology benign histopathology Total 17 0 17 9 222 231 Total 26 222 248 Sensitivity 65.3% Specificity 100% PPV 100% NPV 96.1% Abbreviations: FNAB, fine-needle aspiration biopsy; NPV, negative predictive value; PPV, positive predictive value. atypical; Sal 4 (n 5 27; 8.6%) suspicious; Sal 5p (n 5 8; 2.6%) primary salivary gland malignancy; Sal 5 not otherwise specified (NOS; n 5 6; 1.9%) and malignancy NOS; and Sal 5M metastatic lesions (n 5 3; 0.9%). The malignancy rate in Sal 5P, Sal 5NOS, and Sal 5M were all 100%. The Sal 3 and Sal 4 categories were derived from the nondefinitive cytology cases. Nondefinitive cytology results, which included no malignant differential diagnosis, were classified as Sal 3 and cases that included malignancy as a possibility were classified as Sal 4. The malignancy rates in Sal 3 and Sal 4 were 17.3% and 66.6%, respectively. Sensitivity, specificity, PPV, and NPV were also calculated for each group except Sal 1I, Sal 3, and Sal 4 because the data obtained from these groups did not correspond with the final histopathological results. For example, in the Sal 2N category, a true-positive result was considered to be a lesion that was a definite benign neoplasm on cytology and confirmed by the final histological diagnosis. A false-positive result was when the final histological diagnosis was anything other than a benign neoplasm (ie, a nonneoplastic or malignant lesion). The results for each Sal category are listed in Table 4. 4 DISCUSSION Pleomorphic adenoma is the most common benign tumor of the salivary glands accounting for 51%-85% of all benign parotid tumors. 1,2,7 However, Lim et al 14 reported that 36% of the tumors in their series were pleomorphic adenomas and 40% were Warthin s tumors. Pleomorphic adenoma was the most common benign tumor in our study with a rate of 40.7%, followed by Warthin s tumor with a rate of 30.6%, which was consistent with previous reports. Only 1 in 6 parotid gland tumors is malignant. 15 Mucoepidermoid carcinoma is the most common malignant parotid tumor 16 with a reported incidence between 3% and 18%. However, some studies report adenoid cystic carcinomas 17 or acinic cell carcinomas 18 as the most common malignant tumors. In the present study, the incidence of mucoepidermoid carcinoma was 3.46%, whereas those of acinic cell and adenoid cystic carcinomas were 1.48% and 1%, respectively. These rates were similar with those reported previously. TABLE 4 Application of Sal classification to our data Sal classification Definition No. of cases (% of total cases) No. of benign cases (% of category) No. of malignant cases (% of category) Sensitivity Specificity SAL 1I Inadequate 8 (2.6) 8 (100) 0 (0)...... SAL 1C Cyst contents 20 (6.4) 19 (95) 1 (5) 100% 95% SAL 2I Inflammatory (nonneoplastic) 18 (5.8) 18 (100) 0 (0) 52% 97% SAL 2N Benign neoplastic 193 (61.9) 185 (96) 8 (4) 83% 84% SAL 3 Atypical 29 (9.3) 24 (82.7) 5 (17.3)...... SAL 4 Suspicious 27 (8.6) 9 (33.3) 18 (66.6)...... SAL 5P SAL 5NOS Primary salivary gland malignancy Malignancy not otherwise specified 8 (2.6) 0 (0) 8 (100) 22% 99% 6 (1.9) 0 (0) 6 (100) 18% 98% SAL 5M Metastatic 3 (0.9) 0 (0) 3 (100) 30% 100% 312 263 49

940 KILAVUZ ET AL. The FNAB is a widely used rapid, safe, easy-to-perform, well-tolerated, and cost-effective diagnostic procedure that is essential for the examination of head and neck masses. Potential complications of FNAB are bleeding, hematoma, and infection at the site of the biopsy. These complications were not observed in our study. The limitation of FNAB in the parotid gland is that there is not yet a widely accepted classification like the ones we use in thyroid or breast cytology. 19,20 The sensitivity and specificity of FNABs for parotid tumors have been reported to be 57%-98% and 39.1%-100%, respectively, leading some authors to contend that the accuracy of the technique is not sufficient to determine the final treatment decision. 6,8,21 The FNABs were an interpreterdependent test result in this wide range in sensitivity and specificity. In addition, the sense of obligation to define the cytology result as benign or malignant in FNAB may lead to incoherence between the FNAB and the postoperative histopathology results. The Galen and Gambino 13 method is accepted as the gold standard in calculating a diagnostic test s sensitivity and specificity. Literature search revealed that reporting of data on nondefinitive results was often ambiguous and their rates average at 14%-18%, 22 24 in 1 study, 25 the rate of nondefinitive cytology was reported as 56% but, in that study, FNAB was performed freehand, without ultrasound guidance. Several studies did not even mention such results, and it was unclear whether there were no results of this type, whether they were excluded, or whether they were incorporated as malignant or benign cytology. We feel that this uncertainty and lack of proper reporting of these results leads to bias. There were some studies that acknowledged the nondefinitive cytology and acted accordingly. Bajwa et al 12 accepted them as benign and calculated sensitivity as 61.4%, whereas Ers oz et al, 26 Das et al, 27 and Atula et al 28 ruled them as malignant cytology and reported sensitivity as 93%, 94.3%, and 52%, respectively. Fakhry et al 9 accepted suspicious cytology as malignant, but ruled out 39 patients with indeterminate cytology before calculating sensitivity (79.6%) and specificity. Henrys and Grigg, 29 Tew et al, 30 and Araujo Filho et al 31 also excluded nondefinitive cases from statistical analysis in their study. In our study, we utilized our data in 2 steps. In the first step, our 2 different scenarios constituted of solely changing the classification of nondefinitive cases. Sensitivity and specificity rates in 2 different scenarios in which the nondefinitive cytology were excluded from the study and accepted as malignant were 65%-100% and 81%-87%, respectively. This change that was inflicted by nondefinitive cytology suggests that nondefinitive cytology should be analyzed under a different group in cytology classifications. Results in our study support this suggestion; the change in classification itself was enough to change predictive values of the same data. In the second step, we applied the Sal classification to our data. Numbers in the Sal 1I group should be as low as it could be, because this category actually does not provide any assistance in determining a treatment plan, thus, the biopsy should be repeated to obtain an adequate result. Literature suggests that the rate of this category should not exceed 10%. 32 In our study, the Sal 1I category constituted of 2.6% of the total, which we believe is quite acceptable. We had only 1 malignant case in the Sal 1C category (5%). Given the 100% sensitivity and 95.1% specificity, FNAB proves to be very reliable in this category. Full aspiration of the cysts and planning a close follow-up to exclude any possible solid component of solid-cystic neoplasm seems to be logical in the management of these cases. 33 The FNAB seems to be very useful in the Sal 2N category, according to the results of our study. Low malignancy rate (4%) and acceptable sensitivity (82.7%) and specificity (83.7%) help us to develop an accurate treatment plan. Limited surgical options like extracapsular dissection or partial superficial parotidectomy could safely be considered in the surgical treatment of these cases because of its low malignancy rate. The Sal 3 category should probably be the main focus in the future development of this classification. With its remarkably unspecific nature and considerable malignancy rate (17.3%), a high clinical correlation is essential in handling of these cases. Moreover, we believe that the further prospective studies should focus on reducing the number or reforming this category. Sal 4 and its clinical implication possess more clarity than the Sal 3 category. Its significantly higher malignancy rate (66.6%) leads us to accept these cases as malignant and act accordingly. We believe limited surgical treatment options (ultrasound extracapsular dissection and partial superficial parotidectomy) would not be suitable for these cases. All cases in the Sal 5P, Sal 5NOS, and Sal 5M groups turned out to be malignant in our study. However, the sensitivity and specificity were significantly low in all Sal 5 subcategories. These lesions must be considered on a case-by-case basis. We recommend to utilize further imaging methods (CT, MRI, and positron emission tomography/ct) and pay a great deal of attention to the clinical properties to each case in this category to define whether it is a primary parotid malignancy, a metastasis, or any other malignant tumor located in the parotid region. 5 CONCLUSIONS We believe that the Sal classification has a great potential to be a useful tool in classification of parotid gland cytology. That being said, all new classification methods would initially have limitations and they all should be open to improvement. There are few limitations worthy of mention in our study and the classification itself. We feel that the Sal

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942 KILAVUZ ET AL. [29] Henrys CE, Grigg R. Use of fine-needle aspiration cytology in the diagnosis of parotid neoplasms. ANZ J Surg. 2015;85(11): 838-842. [30] Tew S, Poole AG, Philips J. Fine-needle aspiration biopsy of parotid lesions: comparison with frozen section. Aust N Z J Surg. 1997;67(7):438-441. [31] Araujo Filho VJF, Carlucci DD Jr, Sondermann A, Machado MTA, Carneiro PC, Ferraz AR. Fine needle aspirative biopsy in parotid gland diseases. Rev Col Bras Cir. 2001;28(3):189-192. [32] Eedes CR, Wang HH. Cost-effectiveness of immediate specimen adequacy assessment of thyroid fine-needle aspirations. Am J Clin Pathol. 2004;121(1):64-69. [33] Wong DS, Wong LY. Cystic parotid swelling on FNA: significance on clinical management. Otolaryngol Head Neck Surg. 2004;130(5):593-596. How to cite this article: Kilavuz AE, Songu M, _Imre A, et al. Application of Sal classification to parotid gland fine-needle aspiration cytology: 10-year retrospective analysis of 312 patients. Head & Neck. 2018;40:937 942. https://doi.org/10.1002/hed.25056