Diagnostic value of core needle biopsy and fine-needle aspiration in salivary gland lesions

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1 ORIGINAL ARTICLE Diagnostic value of core needle biopsy and fine-needle aspiration in salivary gland lesions Eva Novoa, MD, 1 * Nicolas G urtler, MD, 2 Andre Arnoux, MD, 1 Marcel Kraft, MD 3 1 Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital AG, Aarau, Switzerland, 2 Department of Otorhinolaryngology, Head and Neck Surgery, University Hospital of Basel, Basel, Switzerland, 3 Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital Baselland, Liestal, Switzerland. Accepted 6 January 2015 Published online 6 July 2015 in Wiley Online Library (wileyonlinelibrary.com). DOI /hed ABSTRACT: Background. Core needle biopsy (CNB) has gained acceptance as a minimally invasive procedure in the head and neck. Nevertheless, many concerns arise regarding the value and safety of this method in the assessment of salivary gland lesions. Methods. This prospective study comprises 111 patients with a salivary gland lesion. The results of ultrasound-guided CNB were compared with those of fine-needle aspiration (FNA) in the 103 histologically verified cases. Results. CNB achieved a higher accuracy than FNA in identifying true neoplasms (98% vs 91%) and detecting malignancy (99% vs 87%), and was also superior to FNA providing a specific diagnosis (93% vs 74%). In both methods, no complications, such as bleeding, infection, nerve injury, or tumor-cell seeding, occurred. Conclusion. CNB is a simple, safe, and highly accurate procedure, which should be considered as an additional diagnostic tool in the assessment of salivary gland lesions. VC 2015 Wiley Periodicals, Inc. Head Neck 38: E346 E352, 2016 KEY WORDS: core needle biopsy, fine-needle aspiration, ultrasound, salivary gland, tumor-cell seeding INTRODUCTION Core needle biopsy (CNB) is a minimally invasive procedure, which is routinely applied in the assessment of breast and liver tumors. When approaching head and neck lesions, CNB is known to yield a significantly higher sensitivity and specificity compared to other diagnostic methods, such as fine-needle aspiration (FNA). 1 Unfortunately, FNA supplies nondiagnostic material in 3% to 30% of procedures despite a good puncture technique. Additionally, the latter is associated with a falsenegative rate of 10% in the detection of malignant head and neck lesions. 2 These figures largely vary depending on the availability of an experienced cytopathologist, the quantity and quality of smears, and the access for immediate processing of the aspirated material. 2 CNB constitutes an additional diagnostic tool in head and neck lesions of uncertain character, especially in nonsurgical patients or when extensive surgery is to be discussed in advance. 3 However, many concerns arise regarding the value and safety of CNB. Potential risks, such as bleeding, infection, nerve injury, or tumor-cell seeding, are the main reasons why many physicians are still reluctant to routinely implement this promising method in the assessment of salivary gland lesions. 1 *Corresponding author: E. Novoa, Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital AG, Grenzstrasse 17, CH-5430 Aarau, Switzerland. eva.novoa@gmail.com The purpose of the present study was to compare ultrasound-guided CNB with FNA in the assessment of salivary gland lesions. MATERIALS AND METHODS After approval by the local ethics commission, a prospective study was performed including 111 patients with a salivary gland lesion who underwent ultrasound-guided CNB and FNA as part of their diagnostic investigation. The latter consisted in the collection of a medical history, physical examination, sonography of the neck, and information about a bleeding tendency or intake of antiplatelets and/or anticoagulants. Each patient received ultrasound-guided FNA and CNB in separate schedules. The sonographers (N.G. and M.K.) had 15 years of experience. In general, FNA was carried out with a 24-gauge needle after a modified technique, as described elsewhere. 4 In addition to common smears, liquid-based cytology was routinely used. The cytopathologist was present during the FNA procedure. The latter prepared and fixed the smears himself before he took all the samples to the department of pathology for immediate staining, microscopic examination, and diagnosis. According to the study protocol, CNB was performed with a 20-gauge needle with the patient under general anesthesia immediately before surgical excision of the salivary gland lesion, as previously described. 5 In patients, who were not surgical candidates, this procedure was carried out while they were under local anesthesia on an outpatient basis. In this regard, the study protocol met the ethical standards of the Declaration of Helsinki in its current version. E346 HEAD & NECK DOI /HED APRIL 2016

2 VALUE OF CORE NEEDLE BIOPSY IN SALIVARY GLAND LESIONS The results of CNB were compared with those of FNA in the 103 histologically verified cases, whereas clinical follow-up was performed on the remaining 8 patients who were not surgical candidates. In order to decrease bias, CNB was always analyzed before the surgical specimen. Additionally, tumor-cell seeding after CNB was investigated by histologic examination of 103 excised needle tracks and clinical follow-up. Although antiplatelets and anticoagulants do not represent an absolute contraindication to CNB and FNA, patients were asked to stop their medication or convert it into unfractionated or low-molecular weight heparin at least 1 week before the procedure. The diagnostic value of CNB and FNA was evaluated separately in the following 3 situations: (1) to identify true neoplasms; (2) to detect malignancy; and (3) to supply a specific diagnosis. Sensitivity, specificity, accuracy, and positive and negative predictive values were calculated for the previously described situations. In accord with the literature, neoplastic and malignant lesions were classified as positive, whereas nonneoplastic and benign lesions were calculated as negative. Samples able to provide a presumptive diagnosis were considered adequate, whereas inadequate samples were those with insufficient material for a histologic or cytologic analysis or when the target was missed. Fisher s exact test was used for statistical analysis. A value of p <.05 was considered statistically significant, whereas values of p <.01 were defined as highly significant. Additionally, receiver operating characteristic (ROC) curves and the area under the ROC curve (AUC) with SE and 95% confidence interval (CI) were used to evaluate the diagnostic performance of CNB and FNA. The nonparametric Wilcoxon signed-rank test was used to compare the ROC and AUC curves of both diagnostic tests, whereas the SPSS version 21.0 (IBM, Armonk, NY) was used to calculate the ROC and AUC curves. RESULTS Clinical data There were 60 male (54%) and 51 female patients (46%). The mean age at diagnosis was 54 years (range, years). In keeping with the World Health Organization classification, 6 a total of 99 neoplastic (89%) and 12 nonneoplastic (11%) lesions were observed in our series, of which 25 were malignant (23%) and 86 benign (77%). Ninety-six lesions (86%) were located in the parotid gland, 14 (13%) in the submandibular gland, and a single lesion (1%) in the sublingual gland. Based on sonographic measurements, 7 lesions (6%) were <1 cm in their greatest dimension, 86 (78%) were between 1 and 3 cm, and 18 (16%) measured >3 cm. Histopathology The 25 malignant tumors consisted of 20 salivary gland carcinomas (8 mucoepidermoid carcinomas, 2 basal cell adenocarcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas, 2 acinic cell carcinomas, 2 poorly differentiated carcinomas, 1 carcinoma ex pleomorphic adenoma, and 1 basaloid squamous cell carcinoma), 3 intraglandular lymph node metastases (2 squamous cell carcinomas, and 1 leiomyosarcoma), and 2 intraglandular malignant lymphomas (2 marginal zone lymphomas). The 74 benign tumors included 44 salivary gland adenomas (41 pleomorphic adenomas, and 3 basal cell adenomas), 26 Warthin tumors, 2 intraglandular lipomas, 1 myoepithelioma, and 1 intraglandular schwannoma. The 12 nonneoplastic lesions consisted of 7 chronic sialadenitis (4 chronic sclerosing sialadenitides, 2 chronic sialadenitis with abscess-formation, and 1 chronic sialadenitis with lipomatosis), 2 epidermoid cysts, 1 mucous retention cyst, 1 acute sialadenitis with abscess-formation, and 1 sarcoidosis. Sample adequacy In our series, CNB was performed only once per patient with 2 separate needle passes per lesion resulting in 104 adequate (94%) and 7 inadequate (6%) samples. Five of the latter were located in the parotid gland and 2 in the submandibular gland. CNB missed the target in 6 lesions. Two of them were located in the superficial parotid lobe, 1 in the deep parotid lobe, 1 in an accessory parotid gland, which was smaller than 1 cm and hypermobile, and 2 in the submandibular gland measuring 1 cm and located behind the mandible impeding the correct placement of the needle. In the last case, CNB was only able to biopsy necrotic tissue in a myoepithelioma (Table 1). FNA correctly diagnosed 6 of the aforementioned lesions, however, an acinic cell carcinoma was suspected in a basal cell adenoma (Table 2). There were 103 surgical patients (96 cases with adequate and 7 with inadequate CNB material) and 8 nonsurgical candidates (Table 1). FNA was performed in all patients with a minimum of 2 separate needle passes per lesion, and was repeated in 20 lesions (18%) because of nondiagnostic material or a questionable result. Thus, adequate FNA samples were obtained in 108 lesions, whereas 3 remained nondiagnostic. Again, there were 103 surgical patients (101 cases with adequate and 2 with inadequate FNA material) and 8 nonsurgical candidates (Table 2). Comparison of core needle biopsy and fine-needle aspiration CNB achieved a significantly higher accuracy than FNA in identifying true neoplasms (98% vs 91%) and detecting malignancy (99% vs 87%) in salivary gland lesions (Tables 3 and 5). No false-positive and only 2 false-negative results of true neoplasm were seen in CNB. In these cases, CNB suspected a branchial cyst and chronic sialadenitis with necrosis instead of a Warthin tumor (Tables 1 and 4). Because of the small number of nonneoplastic lesions in our series, low negative predictive values were observed for both CNB and FNA (78% vs 33%; Table 3). On the other hand, FNA showed 3 false-positive results (1 chronic sialadenitis with abscessformation, 1 epidermoid cyst, and 1 mucous retention cyst) and 6 false-negative results (1 basal cell adenocarcinoma, 1 marginal zone lymphoma, and 4 Warthin tumors) in identifying true neoplasms (Tables 2 and 4). In detecting malignancy, CNB did not produce any false-positive results and only 1 false-negative result. In HEAD & NECK DOI /HED APRIL 2016 E347

3 NOVOA ET AL. TABLE 1. Incorrect or inadequate diagnosis of core needle biopsy in salivary gland lesions. Definitive histology (n 5 103) Incorrect or inadequate diagnosis of CNB (location) Malignant tumors (n 5 22) 5/22 5 (4/19 PG, 1/3 SG) Mucoepidermoid carcinoma 2/7 5 1 poorly differentiated carcinoma (PG),* 1 CNB- (PG) Basal cell adenocarcinoma 1/2 5 1 basal cell adenoma (PG)*, Adenocarcinoma Adenoidcystic carcinoma 0/2 5 (0/1 PG, 0/1 SG) Acinic cell carcinoma 1/2 5 0/1 (PG), 1 CNB- (SG) Poorly differentiated carcinoma 1/1 5 1 adenocarcinoma (PG)* Basaloid squamous cell carcinoma Squamous cell carcinoma Leiomyosarcoma Marginal zone lymphoma Benign tumors (n 5 74) 7/74 5 (6/69 PG, 1/5 SG) Pleomorphic adenoma 3/ CNB- (2/37 PG, 1/4 SG) Basal cell adenoma 1/3 5 1 CNB- (PG) Warthin tumor 2/ branchial cyst (PG),*, 1 chronic sialadenitis with necrosis (PG)*, Intraglandular lipoma Myoepithelioma 1/1 5 1 CNB- (PG) Intraglandular schwannoma Nonneoplastic lesions (n 5 7) 2/7 5 (2/4 PG, 0/3 SG) Chronic sclerosing sialadenitis Chronic sialadenitis with abscess-formation 1/2 5 1 coagulation necrosis and granulation tissue (PG),* 0/1 (SG) Chronic sialadenitis with lipomatosis Epidermoid cyst 1/2 5 1 vascularized elastic and fatty tissue (PG),* 0/1 (SG) Mucous retention cyst Abbreviations: CNB, core needle biopsy; PG, parotid gland; SG, submandibular gland; CNB-, inadequate samples. * Incorrect specific diagnosis. False negative result in detecting malignancy. False negative result in identifying true neoplasms. False positive result in identifying true neoplasms. k False positive result in detecting malignancy. this case, both CNB and FNA led to a diagnosis of basal cell adenoma, whereas histopathology revealed a lowgrade basal cell adenocarcinoma because of a discrete infiltration of tumor margins. This final diagnosis was only possible after surgical excision of the entire lesion and a second opinion from an expert pathologist (Tables 1 and 6). In contrast, FNA showed 5 false-positive results (3 pleomorphic adenomas, and 2 basal cell adenomas) and 8 false-negative results (3 mucoepidermoid carcinomas, 2 basal cell adenocarcinomas, 1 acinic cell carcinoma, 1 poorly differentiated carcinoma, and 1 marginal zone lymphoma; Tables 2 and 6). CNB was also superior to FNA providing a specific diagnosis (93% vs 74%), but failed to correctly diagnose 3 malignant tumors (1 mucoepidermoid carcinoma, 1 basal cell adenocarcinoma, and 1 poorly differentiated carcinoma), 2 benign tumors (2 Warthin tumors) and 2 nonneoplastic lesions (1 chronic sialadenitis with abscessformation, and 1 epidermoid cyst; Tables 1 and 7). On the other hand, FNA failed to correctly diagnose 12 malignant tumors (6 mucoepidermoid carcinomas, 2 basal cell adenocarcinomas, 1 acinic cell carcinoma, 1 poorly differentiated carcinoma, and 2 marginal zone lymphomas), 10 benign tumors (3 pleomorphic adenomas, 3 basal cell adenomas, and 4 Warthin tumors), and 4 nonneoplastic lesions (2 chronic sialadenitides with abscess-formation, 1 epidermoid cyst, and 1 mucous retention cyst; Tables 2 and 7). A correlation between the puncture site and the number of failed diagnoses could not be determined because of the small number of submandibular lesions. However, except for an inflammatory lesion of the submandibular gland in which FNA failed to correctly provide a specific diagnosis, all false diagnoses of CNB and FNA were located in the parotid gland (Tables 1 and 2). In identifying true neoplasms, the AUC amounted to (95% CI, ) for CNB and (95% CI, ) for FNA (p 5.727). In detecting malignancy, the AUC amounted to (95% CI, ) for CNB and (95% CI, ) for FNA (p ). The ROC and AUC curves in both diagnostic tests reached the range of good accuracy and their performance did not show any significant differences. Nonsurgical candidates CNB was performed with the patients under local anesthesia in 8 nonsurgical patients, and was well tolerated. Based on the results of CNB, these patients were able to avoid open surgery. Three multimorbid elderly women received palliative treatment after diagnosing an advanced mucoepidermoid carcinoma of the sublingual gland, a carcinoma ex pleomorphic adenoma, and a poorly differentiated carcinoma of the parotid gland, respectively. Additionally, 3 cases of chronic sialadenitis of the submandibular gland, 1 sarcoidosis of the parotid gland, and 1 acute parotitis with abscess-formation were correctly diagnosed by CNB and therefore treated conservatively. E348 HEAD & NECK DOI /HED APRIL 2016

4 VALUE OF CORE NEEDLE BIOPSY IN SALIVARY GLAND LESIONS TABLE 2. Incorrect or inadequate diagnosis of fine-needle aspiration in salivary gland lesions. Definitive histology (n 5 103) Incorrect or inadequate diagnosis of CNB (location) Malignant tumors (n 5 22) 12/22 5 (11/19 PG, 1/3 SG) Mucoepidermoid carcinoma 6/7 5 1 monomorphic benign epithelial neoplasia (PG),*, 1 Warthin tumor (PG),*, 1 basaloid neoplasia (PG),*, 1 squamous cell carcinoma (PG),* 1 malignant necrotic neoplasia (PG),* 1 malignant mucigenous neoplasia (PG)* Basal cell adenocarcinoma 2/2 5 1 cystic lesion (PG),*, 1 basal cell adenoma (PG)*, Adenocarcinoma Adenoidcystic carcinoma 0/2 5 (0/1 PG, 0/1 SG) Acinic cell carcinoma 1/2 5 0/1 (PG), 1 pleomorphic adenoma (SG)*, Poorly differentiated carcinoma 1/1 5 1 benign epithelial neoplasia (PG)*, Basaloid squamous cell carcinoma Squamous cell carcinoma Leiomyosarcoma Marginal zone lymphoma 2/2 5 1 retention cyst (PG),*, 1 atypical lymphocytes (PG)* Benign tumors (n 5 74) 11/74 5 (11/69 PG, 0/5 SG) Pleomorphic adenoma 3/ carcinoma ex pleomorphic adenoma (PG),*, 2 myoepithelial neoplasias with possible malignancy (PG)*, Basal cell adenoma 3/3 5 1 basal cell carcinoma (PG),*, 1 acinic cell carcinoma (PG),*, 1 myoepithelioma (PG)* Warthin tumor 5/ branchial cysts (PG),*, 2 cystic lesions (PG),*, 1 FNA- (PG) Intraglandular lipoma Myoepithelioma Intraglandular schwannoma Nonneoplastic lesions (n 5 7) 5/7 5 (3/4 PG, 2/3 SG) Chronic sclerosing sialadenitis 1/1 5 1 FNA- (SG) Chronic sialadenitis with abscess-formation 2/2 5 1 Warthin tumor (PG),*, 1 acute inflammation with necrosis (SG)* Chronic sialadenitis with lipomatosis Epidermoid cyst 1/2 5 1 pilomatrixoma (PG),*, 0/1 (SG) Mucous retention cyst 1/1 5 1 Warthin tumor (PG)*, Abbreviations: CNB, core needle biopsy; PG, parotid gland; SG, submandibular gland; FNA-, inadequate samples. * Incorrect specific diagnosis. False negative result in detecting malignancy. False negative result in identifying true neoplasms. False positive result in detecting malignancy. False positive result in identifying true neoplasms. On the other hand, FNA failed to correctly diagnose 3 of the aforementioned lesions. First, FNA led to a diagnosis of pleomorphic adenoma in what was really sarcoidosis. Second, the carcinoma ex pleomorphic adenoma was held for a mesenchymal neoplasia. Finally, the lack of representative material in the acute parotitis with abscessformation resulted in inadequate FNA material. Complications The medical history was negative for a bleeding tendency or the intake of antiplatelets and/or anticoagulants in 87 patients. Only 3 of 6 patients with antiplatelets could stop their medication before performing CNB and FNA. Oral anticoagulants were present while performing CNB in 1 patient and FNA in 7 patients. One patient was under low-molecular weight heparin while performing FNA, and, in 7 cases, unfractionated heparin was stopped 4 hours before CNB. In a case of factor XI deficiency, both methods were performed under a spontaneous prothrombin time of 56%. All patients were asked to compress the puncture site for at least 15 minutes. In such a manner, no bleeding, major hematomas, local infections, or nerve injuries were encountered in our study. Histologic examination of the excised needle tracks either revealed no tumor displacement in 65 cases (63%) or was not identified on the surgical specimen from another 38 patients (37%). Furthermore, a complete histologic analysis of the specimen did not show any displaced tumor tissue. Ten of the needle tracks examined were related to malignant tumors (2 mucoepidermoid carcinomas, 2 adenocarcinomas, 2 adenoid cystic carcinomas, 2 TABLE 3. Identification of true neoplasms in salivary gland lesions. Method Sensitivity Specificity Accuracy PPV NPV CNB (n 5 96) 98% (p 5.161) 100% (p 5.070) 98%* (p 5.035) 100% (p 5.134) 78% (p 5.077) FNA (n 5 101) 94% 50% 91% 97% 33% Abbreviations: PPV, positive predictive value; NPV, negative predictive value; CNB, core needle biopsy; FNA, fine-needle aspiration. * Statistical significance (p <.05). High statistical significance (p <.01). Note: The results of CNB are compared to those of FNA. True neoplasms are classified as positive, nonneoplastic lesions as negative for the calculation of sensitivity, specificity, accuracy, and positive and negative predictive values. HEAD & NECK DOI /HED APRIL 2016 E349

5 NOVOA ET AL. TABLE 4. Method Identification of true neoplasms in salivary gland lesions. Truepositive Falsepositive Falsenegative Truenegative Total CNB FNA Abbreviations: CNB, core needle biopsy; FNA, fine-needle aspiration. Note: The results of CNB are compared to those of FNA. True neoplasms are classified as positive, nonneoplastic lesions as negative for the calculation of sensitivity, specificity, accuracy, and positive and negative predictive values. squamous cell carcinomas, 1 leiomyosarcoma, and 1 marginal zone lymphoma), 50 benign tumors (27 pleomorphic adenomas, 1 basal cell adenoma, 20 Warthin tumors, 1 intraglandular lipoma, and 1 myoepithelioma), and 5 to nonneoplastic lesions (1 chronic sialadenitis with abscessformation, 1 chronic sialadenitis with lipomatosis, 2 epidermoid cysts, and 1 mucous retention cyst). A clinical and sonographic follow-up of up to 6 years failed to show any tumor recurrence as well. DISCUSSION To our knowledge, the present study constitutes the largest and only prospective study comparing ultrasoundguided CNB with FNA in the assessment of salivary gland lesions in the same case series. In other investigations, CNB was carried out after failed FNA. 3 This negative selection does not allow for a real comparison between both methods. Additionally, all lesions were verified histologically, whereas tumor-cell seeding after CNB was investigated by histologic examination of the needle tracks and clinical follow-up. The evaluation of a new method, such as CNB, should be based on histopathology after surgical excision of the entire lesion, which is the gold standard in this field. Therefore, we chose a different study design. In contrast to other investigations, we included patients already listed for salivary gland surgery. In such a manner, we performed CNB with the patients under general anesthesia immediately before surgical excision of the lesion. This particular design allows for a histologic diagnosis of all lesions, which has not been fulfilled in previous CNB publications. However, from a technical point of view, it makes no difference if ultrasound-guided CNB is performed with the patient under local or general anesthesia. In a recent meta-analysis on the diagnostic value of CNB in head and neck lesions, the latter was able to identify true neoplasms and detect malignancy with an accuracy of 94% and 96%, respectively. 1 However, different results were found depending on the anatomic site in the head and neck. Therefore, we included only salivary gland lesions in our series and excluded other neck lumps. In the site-specific meta-analysis, CNB detected true neoplasms and malignancy in salivary gland lesions even with an accuracy of 98% confirming the results obtained in the present study. 1 This emphasizes the excellent diagnostic value of CNB, which is similar to frozen section biopsy and clearly superior to FNA. The failures in diagnostic accuracy of FNA have been previously analyzed. 2 Our results confirm the fact that diagnostic difficulties with FNA are presented in paucicellular cysts, lesions with overlapping features (eg, cellular pleomorphic adenoma, basal cell adenoma, and adenoid cystic carcinoma), lesions with low cytologic atypia (eg, low-grade mucoepidermoid carcinoma and acinic cell carcinoma), and uncommon lesions, such as malignant lymphomas. 7 Similarly, false-positive diagnoses may originate from overestimation of reactive changes occurring in the setting of associated inflammatory reactions. 8 Intraoperative frozen section biopsy, which is more accurate than FNA in the assessment of salivary gland lesions, generally helps surgeons to decide the extent of surgery based on the specific diagnosis, set operative margins, and determine nerve or neck involvement. Therefore, this method is an alternative option in patients with nondiagnostic FNA already listed for surgery. The analysis of frozen section biopsy has recently shown an accuracy of 99% in the differentiation between malignant and benign parotid lesions. 9,10 However, a significant lower accuracy of 63% in the diagnosis of malignant tumors and 5% of deferred diagnosis has also been described with this method. 11 Furthermore, frozen section biopsy can only be performed intraoperatively and shows a higher rate of false-positive and false-negative results than CNB. This may lead to an unjustified overtreatment (eg, nerve sacrifice and neck dissection) or undertreatment (eg, need for a second surgery) resulting in a higher morbidity than that reported after CNB. Especially because the performance of revision surgery in a previously operated patient generates higher costs and is related with increased technical difficulties. As not all surgical decisions can be made intraoperatively without an informed consent of our patients, a correct preoperative diagnosis is of particular importance for patient counseling and planning of the operative procedure. 12 In such a manner, the need for a more accurate, less invasive, preoperative diagnostic tool has been considered. CNB could also help to avoid unnecessary surgery in cases of TABLE 5. Detection of malignancy in salivary gland lesions. Method Sensitivity Specificity Accuracy PPV NPV CNB (n 5 96) 95%* (p 5.015) 100%* (p 5.032) 99% (p 5.001) 100%* (p 5.023) 99%* (p 5.021) FNA (n 5 101) 64% 94% 87% 74% 90% Abbreviations: PPV, positive predictive value; NPV, negative predictive value; CNB, core needle biopsy; FNA, fine-needle aspiration. * Statistical significance (p <.05). High statistical significance (p <.01). Note: The results of CNB are compared to those of FNA. Malignancy is classified as positive, benignity as negative for the calculation of sensitivity, specificity, accuracy, and positive and negative predictive values. E350 HEAD & NECK DOI /HED APRIL 2016

6 VALUE OF CORE NEEDLE BIOPSY IN SALIVARY GLAND LESIONS TABLE 6. Method Detection of malignancy in salivary gland lesions. Truepositive Falsepositive Falsenegative Truenegative Total CNB FNA Abbreviations: CNB, core needle biopsy; FNA, fine-needle aspiration. Note: The results of CNB are compared to those of FNA. Malignancy is classified as positive, benignity as negative for the calculation of sensitivity, specificity, accuracy, positive and negative predictive value. nondiagnostic FNA in which a conservative treatment rather than surgical is being considered (eg, malignant lymphomas, and nonneoplastic lesions). 3 In our opinion, there is no absolute indication for salivary gland surgery in elderly and/or multimorbid patients with a benign tumor. However, one has to be sure about the correct diagnosis before performing a wait-and-scan policy, and CNB is the best method to do so. CNB provides diagnostic advantages in cases in which FNA must be repeated, where the cytologic diagnosis is not concordant with clinical and radiological findings, or where malignancy is suspected. Especially nonsurgical candidates profit from CNB confirming the clinical diagnosis and justifying conservative treatment. 3 Although, in our case series, only adults were included. CNB could be easily applied in the pregnant or pediatric population where a delay in surgery because of misdiagnosed malignancy may correlate with a higher morbidity. A complete patient counseling and preoperative consent information might include the possibility for extensive surgery in case of malignancy, but the psychological stress of this diagnosis and the unnecessary complexity of the surgical planning could be avoided by using CNB as a confirmatory preoperative diagnostic method. 12 CNB is more expensive and time-consuming than FNA. 13,14 This is mainly because of the time required for local anesthesia and the costs of the biopsy gun with its special needles. However, the costs of intraoperative frozen section biopsy or revision surgery in case of a falsenegative result of FNA strongly counterbalance the costs of CNB. In our study, CNB showed only 1 false-negative result in a low-grade basal cell adenocarcinoma, where a complete excision of the entire lesion was necessary for diagnosis. In this case, a lateral parotidectomy was performed and no further therapy was required (Table 1). On the contrary, the false-negative results of FNA could have delayed the timing for surgery without a correct CNB diagnosis. This was the case in 8 patients of our series where FNA suspected benign disease in a malignant salivary gland tumor (Table 2). Technical difficulties with CNB occur in hypermobile lesions with a diameter of 1 cm or less. In these cases, we suggest a bimanual technique with fixation of the lesion during the procedure. Lesions located behind the mandible or in the deep parotid lobe also constitute a challenge because of the difficulties in placing a straight needle under bony surfaces or in narrow spaces with poor visibility, such as the oral cavity. Furthermore, biopsy of cystic lesions should include solid components or the wall of the cyst to increase the possibility of an adequate sampling. In these cases, FNA is clearly superior to CNB. 1 Although seeding constitutes a potential complication of any biopsy method, it does not seem to affect prognosis, given that displaced tumor cells can be surgically removed. In this connection, 2 cases of tumor displacement (1 adenoid cystic carcinoma of the submandibular gland, and 1 pleomorphic adenoma of the parotid gland) after FNA have recently been reported. 15,16 Nevertheless, FNA is widely accepted in the assessment of salivary gland lesions. In contrast, the potential risk of seeding accounts for one of the major reasons why many physicians still avoid CNB. Displaced tumor cells have been found within the needle track or in the skin beneath the puncture site. 17,18 However, tumor-cell seeding after CNB is extremely rare and seems to be related to the needle diameter, the tumor type, and the anatomic site of puncture. 19 Additionally, multiple punctures seem to have an adverse effect on needle-track seeding. 20 Previous studies in breast cancer showed the incidence and amount of tumor displacement to be inversely related to the interval between CNB and excision of the needle track. Hence, these authors concluded that tumor cells probably do not survive displacement. 17 In our study, we did not encounter any displaced tumor cells after performing an average of 2 needle passes per lesion by using a 20-gauge needle and histologic analysis of the needle tracks. However, the excision of needle tracks does not definitively exclude tumor-cell seeding. To our knowledge, there is no reliable method to evidence displaced tumor cells except for long-term follow-up studies over a time course as long as 20 years. 12 None of the previous CNB publications has achieved this goal nor did those on FNA and salivary gland surgery. In a review of 438 head and neck lesions with 7 years of clinical follow-up, no evidence of tumor-cell seeding in salivary gland lesions was observed after CNB. 1 When performing superficial parotidectomy for pleomorphic adenoma, the risk of recurrence is estimated between 1% and 3%. Although there is a little risk of seeding after CNB, the latter is certainly lower than that TABLE 7. Correct specific diagnosis in salivary gland lesions. Method Malignant tumors Benign tumors Nonneoplastic lesions Total verified lesions CNB 85%* (17/20) (p 5.008) 97% (67/69) (p 5.020) 71% (5/7) (p 5.209) 93%* (89/96) (p <.001) FNA 45% (10/22) 86% (63/73) 33% (2/6) 74% (75/101) Abbreviations: CNB, core needle biopsy; FNA, fine-needle aspiration. * High statistical significance (p <.01). Statistical significance (p <.05). Note: The results of malignant, benign and nonneoplastic lesions are compared with those of all histologically verified lesions. HEAD & NECK DOI /HED APRIL 2016 E351

7 NOVOA ET AL. after parotid surgery. Whereas recurrences have been reported up to 20 years after tumor resection, the majority of them occur within the first 5 to 10 years. 12 Hence, a major criticism of our study regarding tumor displacement could be the relatively short follow-up of 6 years, but no recurrences were seen during this period. To be on the safe side, we suggest excising the puncture site with the attached needle tract during salivary gland surgery to minimize the risk of tumor-cell seeding. 3 Other complications of CNB, such as bleeding or hematoma, were not observed in our study. Atwell et al 21 reported a risk of major bleeding of 0.5% after imageguided percutaneous CNB of the liver, kidney, lung, and pancreas using 20-gauge needles. Additionally, they found no significant association between intake of aspirin and bleeding tendency after CNB in any of these organs. However, a serum platelet count of < and an international normalized ratio of >1.6 were identified as important risk factors for significant bleeding, although the mean values for each of them remained well within accepted ranges for percutaneous biopsy. 21 In our study, serum platelet count and international normalized ratio were not routinely ordered before CNB or FNA. Occasionally, we performed CNB and FNA under abnormal coagulation standards without bleeding complications in patients with antiplatelets or anticoagulants. A superficial compression of the puncture site for at least 15 minutes may also have reduced the risk of hematoma. However, in case of nonurgent biopsy, scheduling CNB 7 to 10 days after the last dose of aspirin or converting oral anticoagulants into unfractionated or low-molecular weight heparin seems to be a reasonable, but not a necessary precaution. 1 In conclusion, CNB constitutes a simple, safe, and highly accurate procedure, which should be considered as an additional diagnostic tool in the assessment of salivary gland lesions. However, CNB is not an alternative to FNA nor does it replace excisional biopsy. FNA combined with ultrasound imaging should continue to be the investigation method of first choice for salivary gland lesions, reserving CNB for those cases in which surgery is not suitable or after repeated failures of FNA to provide an adequate diagnosis. In summary, we suggest the following procedure in salivary gland lesions: (1) in surgical patients with diagnostic FNA, no further investigation is required; (2) in surgical patients with nondiagnostic FNA, either preoperative CNB or intraoperative frozen section biopsy should be performed; and (3) in nonsurgical candidates with nondiagnostic FNA, we highly recommend the performance of CNB in local anesthesia to establish a specific diagnosis before developing a case-adapted treatment. Acknowledgment The authors thank Warren Jacobs for the correction of their manuscript. REFERENCES 1. Novoa E, G urtler N, Arnoux A, Kraft M. Role of ultrasound-guided core-needle biopsy in the assessment of head and neck lesions: a metaanalysis and systematic review of the literature. Head Neck 2012;34: Tandon S, Shahab R, Benton JI, Ghosh SK, Sheard J, Jones TM. Fine-needle aspiration cytology in a regional head and neck cancer center: comparison with a systematic review and meta-analysis. 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