ACCURACY OF FINE-NEEDLE ASPIRATION CYTOLOGY OF SALIVARY GLAND LESIONS IN THE NETHERLANDS CANCER INSTITUTE

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1 ACCURACY OF FINE-NEEDLE ASPIRATION CYTOLOGY OF SALIVARY GLAND LESIONS IN THE NETHERLANDS CANCER INSTITUTE Rolf J. Postema, MD, 1 * Mari-Louise F. van Velthuysen, MD, PhD, 2 Michiel W. M. van den Brekel, MD, PhD, 1,3 Alfons J. M. Balm, MD, PhD, 1,3 Johannes L. Peterse, MD 2 1 Department of Head & Neck Oncology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands 2 Department of Pathology, The Netherlands Cancer Institute Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands. m.v.velthuysen@nki.nl 3 Department of Otorhinolaryngology, Academic Medical Center, Amsterdam, The Netherlands Accepted 5 November 2003 Published online 20 April 2004 in Wiley InterScience ( DOI: /hed Abstract: Background. To evaluate the accuracy of fineneedle aspiration cytology (FNAC) in salivary gland lesions in a tertiary referral center. Methods. A cytohistologic correlation study was performed using an automated pathology database of 1023 patients diagnosed with a salivary gland lesion. Results. In 388 cases, both cytology and histology were available. Using cytologic confirmation of malignancy as the starting point, the sensitivity, specificity, and accuracy of FNAC in this study were 88%, 99%, and 96%, respectively. Exact typespecific concordance of the malignant diagnosis was achieved in 66 (88%) of 75 cases and in 211 (95%) of 223 benign cases. Of the 19 cases with a cytologic diagnosis cyst, four proved to be Correspondence to: M. L. F. van Velthuysen *Present address: Department of Otorhinolaryngology, Groningen University Hospital, P.O. Box , 9700 RB Groningen, The Netherlands. This study was presented as a poster at the fall meeting of the Netherlands Society of ORL and Cervicofacial Surgery in 2001, Amsterdam, The Netherlands. B 2004 Wiley Periodicals, Inc. malignant. A non-neoplastic lesion at cytology proved to be correctly classified in 53 (68%) of 80 patients. Conclusions. Our data show that cytology is a reliable and accurate technique to assess lesions of the salivary glands. The cytologic diagnosis of cysts and non-neoplastic lesions should be interpreted with caution. A 2004 Wiley Periodicals, Inc. Head Neck 26: , 2004 Keywords: fine-needle aspiration; salivary gland lesions; cytologic diagnosis There is widespread acceptance of the importance of fine-needle aspiration cytology (FNAC) in the diagnosis of salivary gland lesions Nevertheless, the relative value of FNAC in distinguishing among the various types of malignancies and the assumed minor influence of FNAC on treatment planning are sometimes used as arguments against cytology. 11,12 In the literature, the diagnostic accuracy of FNAC ranges from 84% to 99%. 418 Fine-Needle Aspiration Cytology of Salivary Gland Lesions

2 Table 1. All patients (n = 388) included in the study.* No. patients by cytology Histologic diagnosis Benign Malignant Non-neoplastic Too few cells, uncertain Total Benign tumor Malignant tumor Non-neoplastic Uncertain diagnosis 1 1 Total *The eight patients with uncertain cytologic diagnoses were left out of the analysis. Preoperatively taken core biopsies or frozen sections for treatment planning carry serious risks of tumor spill, bleeding, or inflammation and damage to the facial nerve (branches), whereas complications of FNAC are almost negligible. 7,19 21 Preoperative information about the malignant nature of a parotid lesion can also be helpful in assessing and establishing a policy toward the neck lymph nodes, achieving wide tumor-free excision margins, preventing treatment delay, and informing the patient more appropriately on the treatment plan and on the possible risk of facial nerve injury. Thus in case of a benign tumor, surgery can be postponed or the patient can be followed if the general health or other medical conditions pose a major surgical risk. Therefore, in our institute, FNAC is routinely performed in all salivary gland lesions. In the ongoing process of quality control of our diagnostic procedures and to learn from previous faults, we investigated the sensitivity, specificity, and accuracy of FNAC in salivary gland lesions of the last decade ( ). PATIENTS AND METHODS All 1023 patients diagnosed with salivary gland lesions in The Netherlands Cancer Institute from 1991 to July 2001 were retrieved from a database (PALGA: Dutch Automated Pathology Database). A cytohistologic correlation study was performed. Five parameters were studied to evaluate FNAC results: positive predictive value, sensitivity, specificity, accuracy, and rate of concordance with histologic typing. In this analysis, the cytologic diagnosis of a malignant salivary gland tumor or a metastasis was classified as a positive result, whereas diagnosis of a benign tumor or a nonneoplastic lesion was classified as a negative result. Aspirates with too few cells that were scored as uncertain diagnosis were left out of the analysis. Histology Monomorphic Adenoma Table 2. Cytohistologic correlation of 223 benign tumors. Pleomorphic adenoma No. tumors by cytology Warthin s tumor Lipoma Myoepithelioma Oncocytoma Total Cyst 1 1 Benign lymphoepithelial 1 1 lesion Monomorphic adenoma Pleomorphic adenoma Warthin s tumor Lipoma 2 2 Myoepithelioma 2 2 Oncocytoma Leiomyoma 1 1 Oncocytic cystadenoma 1 1 Adeno 1 1 Malignant lymphoma 1 1 Total Fine-Needle Aspiration Cytology of Salivary Gland Lesions 419

3 Table 3. Cytohistologic correlation of 77 cytologically malignant tumors. No. tumors by cytology Histology Acinic cell Adenoid cystic Adeno Carcinosarcoma Mucoepidermoid Myoepithelial Large cell Lymphoma Metastasis Total Acinic cell Adenoid cystic Adeno Carcinosarcoma Mucoepidermoid (Myo)epithelial Undifferentiated large cell Lymphoma 6 6 Metastasis Monomorphic adenoma Pleomorphic adenoma Lipoma 1 1 Total Fine-Needle Aspiration Cytology of Salivary Gland Lesions

4 In general, the pathologist performs FNA of palpable salivary gland lesions. FNA material was routinely processed in smears, air dried, and stained with Giemsa stain. A Quick Diff stain (Dade-Behring, Düdingen, Switzerland) was performed in cases for immediate diagnosis or, if repeated FNA was considered, in case of doubtful adequacy of puncture material. RESULTS FNAC was performed for 360 cases but not followed by surgery in our hospital; in another 275 cases, only histologic slides were available. This last group consisted of patients who underwent surgery elsewhere and who were only referred for radiotherapy in our institute. In the remaining 388 cases, both cytology and histology of the same salivary gland lesions were available. In the fine-needle aspirate of eight of these patients, too few cells were found, leading to uncertain diagnoses (Table 1). As a consequence, the study population consisted of 380 patients, of whom 242 proved by histology to have a benign tumor, 55 a non-neoplastic lesion, and 83 a malignancy (Table 1). The most common cytologic benign diagnosis was adenoma (pleomorphic/monomorphic) (154 cases), followed by Warthin s tumor (63 cases). Two hundred twenty of 223 cytologically benign cases were confirmed to be benign at histology. Two patients had a malignant tumor. Both were cytologically diagnosed as Warthin s tumors: one proved to be a metastasis and the other a non- Hodgkin s lymphoma (NHL). One patient had a salivary gland cyst. Exact type-specific correlation of the diagnosis was achieved in 211 out of 223 cases (95%). One hundred fifty-two (99%) of 154 cytologically diagnosed adenomas (pleomorphic and monomorphic) were correctly classified, as proven by histology. Neither of the two misclassified lesions was a malignant tumor: one proved to be a Warthin s tumor and one a leiomyoma. Fifty-seven (90%) of 63 cytologically diagnosed Warthin s tumors were correctly assessed. Of the other six cases, two involved a malignant tumor (mentioned above); one a cyst and one a benign lymphoepithelial lesion. The other two had benign neoplastic lesions: one oncocytoma and one oncocytic cystadenoma. The cytologic diagnoses in the cases with lipomas and oncocytomas were correct. Two of three cases cytologically diagnosed as myoepitheliomas matched with histology, and the other had a pleomorphic adenoma and was therefore correctly classified as a benign tumor. The cytohistologic correlations of 223 cytologic benign tumors are summarized in Table 2. A cytologic diagnosis of a malignancy was confirmed by histology in 73 of 77 cases. Four had a benign tumor, resulting in a positive predictive value of 95%. The most common cytologic diagnoses were adenoid cystic (15 cases), metastatic (15 cases), acinic cell (14 cases), and adeno not Histology Table 4. Cytohistologic correlation of 80 cytologically non-neoplastic lesions. Inflammation No. lesions by cytology No tumor cells Cyst Reactive lymphoid Total Normal tissue 7 7 Inflammation Cyst Monomorphic adenoma 1 1 Pleomorphic adenoma 4 4 Warthin s tumor Benign lymphoepithelial lesion 1 1 Lipoma 4 4 Hemangioma 1 1 Acinic cell tumor Mucoepidermoid 2 2 Adeno 1 1 Metastasis 1 1 Total Fine-Needle Aspiration Cytology of Salivary Gland Lesions 421

5 Table 5. Sensitivity, specificity, and accuracy of salivary gland cytology as reported by several authors. First author No. of cases Sensitivity Specificity Accuracy Positive predictive value Orell Stewart Al-Khafaji Schröder Zbären Atula van Heerde Zurrida Cajulis Mean This study otherwise specified (13 cases). Three of the four false-positive cases were from the group of 15 cytologically diagnosed adenoid cystic s. They proved to be a monomorphic or pleomorphic adenoma at histology. In the fourth case, FNAC from the salivary gland was consistent with an acinic cell, whereas histology revealed a lipoma between the superficial and deep lobe of the parotid gland. Table 3 shows the correlations between 77 cytologically malignant tumors and the respective histologies. Exact type-specific concordance of the malignant diagnosis was achieved in 63 (81%) of 77 cases. Ten of 14 acinic cell tumors diagnosed by cytology matched histology. The other four cases were two adenos, one epithelial myoepithelial, and one lipoma. Twelve of 15 cytologic adenoid cystic s were correctly classified, whereas the three remaining cases had an adenoma at histology (see above). Twelve of 13 cases with an adeno at cytology matched histology, whereas one had a carcinosarcoma. Three of five cytologically diagnosed mucoepidermoid s matched histology. The other two cases concerned an acinic cell and an (myo)epithelial. All six cases cytologically diagnosed as malignant lymphomas and 15 cases cytologically diagnosed as metastasis matched. For the diagnosis of metastasis, the clinical context was, however, indispensable. Histology matched the FNA diagnosis in 53 (68%) of 80 cytologically diagnosed non-neoplastic lesions. In 18 of these 80 cases, a benign tumor was diagnosed; in eight cases, a malignancy was diagnosed. Of the 19 cases with a cyst at cytology, this diagnosis was confirmed histologically in 11 cases. In the other eight cases, three patients had a Warthin s tumor, two an acinic cell, two a mucoepidermoid, and one an inflammation of the gland. Table 4 shows the cytohistologic correlations of 80 non-neoplastic lesions. The cytologic diagnosis no evidence of tumor cells was confirmed histologically in 24 of 39 cases: inflammation (14 cases), a cyst (three cases), or no lesion at all (seven cases). Twelve of these 39 cases had a benign tumor: a lipoma (four cases), a pleomorphic adenoma (four cases), a Warthin s tumor (three cases), or a hemangioma (one case). Three of these 39 cases turned out to be malignant: two acinic cell s and one adeno. Seventeen (89%) of 19 cytologically diagnosed cases with inflammation were histologically confirmed. The other two cases had a Warthin s tumor or a metastatic. Of the three cases with aspiration of reactive lymphoid tissue, histology showed a cyst, a monomorphic adenoma, and a benign lymphoepithelial lesion, respectively. For the calculations of overall quality assurance measures, the cytologic confirmation of a malignancy is used as a starting point, which leads to the following values: sensitivity, 88%; specificity, 99%; positive predicting value, 95%; negative predicting value, 97%; and accuracy, 96%. DISCUSSION FNAC may be performed for salivary gland lesions to guide operation planning and to provide patient information. To evaluate the reliability of FNAC and to examine the sources of false-positive and false-negative results, we analyzed the results of 422 Fine-Needle Aspiration Cytology of Salivary Gland Lesions

6 10-year salivary gland FNAC at our institute, comparing FNAC diagnosis with histologic findings in 388 cases. The overall accuracy of FNAC in this study was 96%, which is comparable to our previous results 22 and to the results described by others 23,24 (see Table 5). We believe that these good results can be obtained only in a setting with close collaboration of head and neck surgeons, radiologists, and cytopathologists. A negative FNA from salivary gland lesions will always be followed by a second puncture. In these cases, the multidisciplinary team makes the decision whether this can be done under ultrasound guidance or under palpation. Sensitivity of FNAC in diagnosing malignancy was 88%, as 73 of the 83 malignant tumors were diagnosed by this procedure. Eight of the 10 falsenegative cases had been cytologically diagnosed as non-neoplastic lesions owing to the absence of representative material in the FNA smears. Poor cell yield or aspiration of nonrepresentative material is a major source of misdiagnosis. This is further illustrated by the fact that a non-neoplastic lesion at cytology proved to be correctly classified in only 53 (66%) of 80 patients. In 27 of these 80 patients, an underlying salivary gland tumor was missed at the FNA procedure. However, because in this study only surgically treated patients were included, there might be a selection bias because nonsurgically treated patients probably did not have tumors clinically. Another cause of misdiagnosis is aspiration of cystic lesions. Seven of 19 cases diagnosed as cyst proved to be a Warthin s tumor, acinic cell tumor, or mucoepidermoid. A negative FNA diagnosis in case of a clinically obvious lump, and especially cystic lesions, should always be regarded with suspicion, as many have reported before. 25,26 In these cases, repeated, preferably ultrasound-guided FNA, is advocated. 27 This series contained four false-positive cases, of which three monomorphic or pleomorphic adenomas had cytologically been mistaken for adenoid cystic. This is a well-known pitfall due to the similarity of cellular and stromal components of these lesions, 28,29 which can only be avoided when the clinical and radiologic contexts are taken into account. The fourth falsepositive case was a lipoma. In this case, because of nonrepresentative sampling, normal acinic cells were mistaken for an acinic cell tumor. The specificity of the diagnosis of malignancy was 99%, as 293 of 297 nonmalignant lesions were correctly classified as nonmalignant. This high specificity warrants that, in case of the FNA diagnosis malignancy, a complete work-up is performed. In our institute, this consists of preoperative ultrasound-guided FNAC staging of the neck, an MRI of the primary tumor, a chest x-ray, and intraoperative frozen section of the subdigastric lymph nodes. Exact type-specific concordance of a malignant diagnosis could only be achieved in 66 (88%) of 75 cases. In benign tumors, this percentage was significantly higher (95%; 211 of 223). The most frequent cytologic diagnosis in our series, pleomorphic adenoma (149 cases), was highly accurate (145 cases histologically confirmed). This high specificity warrants a wait-and-see policy in selected elderly patients with a high surgical risk and a cytologic diagnosis of a benign tumor. In conclusion, we believe that cytology is a reliable technique to assess the nature of salivary gland lesions. 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