Accuracy of Fine-Needle Aspiration of Thyroid A Review of 6226 Cases and Correlation With Surgical or Clinical Outcome Mojghan Amrikachi, MD; Ibrahim Ramzy, MD; Sheldon Rubenfeld, MD; Thomas M. Wheeler, MD ● Context.—Fine-needle aspiration has become an accepted and cost-effective procedure for rapid diagnosis of thyroid lesions. The routine use of fine-needle aspiration has reduced the rate of unnecessary surgery for thyroid nodules. Objectives.—To determine the accuracy of fine-needle aspiration biopsy diagnosis and to discuss the possible pitfalls. Design, Setting, and Participants.—Reports of 6226 fineneedle aspiration biopsies of the thyroid performed during a period of 16 years (1982–1998) were reviewed. Computerized reports of the fine-needle aspiration biopsies were sent to the physicians who performed the procedures, and clinical follow-up information regarding the patients was requested. Twenty-four clinicians participated in the study. Histologic diagnoses were available for 354 cases. The cytopathologic diagnoses were correlated with the histologic findings or clinical outcomes. Results.—The cytologic diagnoses were as follows: 210 (3.4%) malignant, 450 (7.2%) suspicious, 3731 (60%) benign, and 1845 (29.5%) unsatisfactory. Most of the cases with negative or unsatisfactory aspirates were followed clinically or by repeat fine-needle aspiration. We identified 11 false-negative and 7 false-positive diagnoses. For aspirates considered sufficient for diagnosis, the sensitivity and specificity levels were 93% and 96%, respectively. Conclusions.—Fine-needle aspiration of the thyroid gland is highly accurate and has a low rate of false-negative and false-positive diagnoses. The major diagnostic problems are caused by diagnosis using a marginally adequate specimen, diagnosis of malignancy based on just 1 or 2 atypical cytologic features, or overlapping cytologic features of follicular neoplasm with those of follicular variant of papillary carcinoma. (Arch Pathol Lab Med. 2001;125:484–488) T Fine-needle aspiration has made the surgical procedures much more selective, assisting in the treatment of many patients. The routine use of FNA has reduced the rate of unnecessary surgery for thyroid nodules and has doubled the percentage of cancers found in the surgical materials.4,5,10 Due to its simplicity, low cost, and absence of major complications, this procedure is being performed on an increasing number of patients, which has led to the detection of thyroid cancers at earlier stages, resulting in better outcomes for patients. Nevertheless, like any other test, FNA has its limitations. The reported pitfalls are those related to specimen adequacy, sampling techniques, the skill of the physician performing the aspiration, the experience of the pathologist interpreting the aspirate, and overlapping cytologic features between benign and malignant follicular neoplasms.7,11,12 In this study, we reviewed the cytologic diagnoses of more than 6000 consecutive FNA biopsies of the thyroid, focusing on the correlation with surgical or clinical outcomes and possible pitfalls. hyroid nodules are common clinical findings and have a reported prevalence of 4% to 7% in the general population.1–3 Thyroid nodules are more common in women, and the incidence increases with age, a history of radiation exposure, and a diet containing goitrogenic material.3 The vast majority of these nodules are nonneoplastic lesions or benign neoplasms. However, the distinction of these benign lesions from a malignancy cannot be based reliably on the clinical presentation only. Several diagnostic tests, such as radionuclide scanning, high-resolution ultrasonography, and fine-needle aspiration (FNA) biopsy have been used to select the patient population requiring surgical intervention. Recent studies have demonstrated that among all these diagnostic modalities, FNA is the most accurate, cost-effective, and simplest screening test for rapid diagnosis of thyroid nodules.4–6 Fine-needle aspiration has also been shown to have similar or higher sensitivity and accuracy levels than frozen section examination.7–9 Accepted for publication November 7, 2000. From the Departments of Pathology (Drs Amrikachi, Ramzy, and Wheeler), Obstetrics-Gynecology (Dr Ramzy), Medicine (Dr Rubenfeld), and Urology (Dr Wheeler), Baylor College of Medicine, Houston, Tex; and The Methodist Hospital, Houston, Tex (Drs Ramzy and Wheeler). Dr Amrikachi is now with the Department of Pathology, M. D. Anderson Cancer Center, Houston, Tex. Presented at the 88th Annual Meeting of the United States and Canadian Academy of Pathology, San Francisco, Calif, March 1999. Reprints: Thomas M. Wheeler, MD, Department of Pathology, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030 (e-mail: twheeler@bcm.tmc.edu). 484 Arch Pathol Lab Med—Vol 125, April 2001 METHODS The cytologic diagnoses of 6226 consecutive FNA biopsies of thyroid performed on 4819 patients during a period of 16 years (1982–1998) were reviewed. The data were obtained from the personal series of one of the authors (T.M.W.), at Baylor College of Medicine, Houston, Tex. The procedures were performed by endocrinologists or surgeons, using 25-gauge needles. More than 20 clinicians contributed slides to the series; however, approxiFine-Needle Aspiration of Thyroid—Amrikachi et al Figure 1. Cytologic diagnoses of 6226 fine-needle aspiration biopsies of thyroid. Figure 2. Histologic diagnoses of 81 cases with a cytologic diagnosis of positive for papillary carcinoma. Figure 3. Histologic diagnoses of 44 cases with a cytologic diagnosis of suspicious for papillary carcinoma. Figure 4. Histologic diagnoses of 59 cases with a cytologic diagnosis of follicular neoplasm. mately 50% of the procedures were performed by one of the authors (S.R.). The nodules were palpable and no ultrasound was employed in the biopsy procedures. An average of 6 to 10 spray-fixed smears were prepared and sent to the cytology laboratory, where they were stained by the Papanicolaou technique. Approximately 99% of the smears were evaluated by the same pathologist (T.M.W.). The criteria used for adequacy of specimens were those suggested by Kini et al13 and included at least 6 to 8 tissue fragments of well-preserved follicular epithelium on each of 2 slides. The cytology results were categorized into 4 groups: benign, suspicious, malignant, and unsatisfactory. Aspirates classified as ‘‘benign’’ included adenomatous (colloid) nodule, Hashimoto thyroiditis, and subacute thyroiditis. The ‘‘suspicious’’ category included follicular neoplasm, Hürthle cell tumor, and aspirates with atypical features suggestive of, but not diagnostic for, malignancy. The aspirates with unequivocal cytologic findings of primary or secondary malignancy were classified in the ‘‘malignant’’ category. Aspirates with insufficient cellularity or poorquality smears due to delayed or inadequate fixation were considered ‘‘unsatisfactory.’’ This group also included the aspirates consisting only of cyst fluid. Computerized reports of the FNA biopsies were sent to the clinicians who performed the procedures, and clinical follow-up information regarding their patients was requested. Histologic diagnoses were available for 354 (5.7%) cases. We only had access to the pathology reports of the patients in whom thyroidectomies were performed at outside institutions. For statistical analysis, the cases with cytologic diagnoses of positive or suspicious for malignancy, which on final histologic examination were diagnosed as malignant, were considered true Arch Pathol Lab Med—Vol 125, April 2001 positives. The cases with negative cytologic diagnoses that either had a surgical specimen with benign diagnosis or a benign clinical course were considered to be true negatives. The false-positive category comprised the cases with a benign histology that had a suspicious or positive cytologic diagnosis. A false-negative diagnosis encompassed the cases with a malignant histology that had been diagnosed as benign on cytology. We did not consider papillary microcarcinomas as false negative when the much larger adjacent lesion was sampled and diagnosed appropriately. Since unsatisfactory aspirates yielded no information, they were excluded from calculations. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of FNA relative to final histologic or clinical outcome were calculated. RESULTS The cytologic diagnoses were as follows: 210 (3.4%) malignant, 450 (7.2%) suspicious, 3731 (60%) benign, and 1845 (29.5%) unsatisfactory (Figure 1). The clinical follow-up interval ranged from 1 to 16 years. Approximately 13% of the cases with a negative diagnosis and 29% of the cases with unsatisfactory aspirates were followed by repeat FNA. Repeat FNA biopsies in 539 cases with initial diagnoses of unsatisfactory provided diagnostic smears in 333 (62%) cases. Of 495 patients with initial negative cytology who had repeat FNAs, 4 (0.8%) were found to have malignant aspirates. Histologic diagnoses were available for 85 (40%) cases Fine-Needle Aspiration of Thyroid—Amrikachi et al 485 Table 1. Number and Percentage of Cases With Surgical Follow-up in Each Category Cytologic Diagnosis No. of Cases With Surgical Follow-up, % No. of Cases, % Malignant Suspicious Negative Unsatisfactory 210 450 3731 1835 (3.4) (7.2) (60) (29.5) 85 166 64 39 (40) (36) (1.7) (2.2) Table 2. Correlation of Cytologic and Histologic Diagnoses Surgical Diagnosis Cytology Diagnosis Positive Negative Total Positive Suspicious Negative Unsatisfactory Total 78 68 11 8 165 7 98 53 31 189 85 166 64 39 354 Table 3. Cytologic Diagnosis of 132 Cases With Histologic Diagnosis of Papillary Carcinoma Cytologic Diagnosis No. (%) of Cases Papillary carcinoma Suspicious for papillary carcinoma Suspicious NOS* Suspicious for follicular carcinoma Adenomatous nodule Hashimoto thyroiditis Unsatisfactory Total * NOS indicates not otherwise specified. 75 30 13 2 1 1 6 132 (57) (23) (10) (2) (1) (1) (5) Table 4. Histologic Diagnoses of 28 Cases With Cytologic Diagnosis of Hürthle Cell Neoplasm Histologic Diagnosis No. (%) of Cases Hürthle cell adenoma Follicular carcinoma Hürthle cell carcinoma Follicular adenoma Adenomatous nodule Total 13 7 2 3 3 28 (46) (25) (7) (11) (11) with a cytologic diagnosis of positive for malignancy and 166 (36%) cases with a cytologic diagnosis of suspicious for malignancy. Owing to referral to several other institutions, the results of surgical intervention were not available for the remaining cases. However, although this group is relatively large (60%), no discrepancies between cytologic and histologic diagnoses have been reported by any of the treating physicians and no medicolegal consequences have emerged. Approximately 2% of the cases with benign or unsatisfactory diagnoses were referred to surgery (Table 1). Table 2 demonstrates the correlation of cytologic and histologic diagnoses. For aspirates considered sufficient for diagnosis, the sensitivity and specificity values were 93% and 96%, respectively. Positive predictive values of cases with positive and suspicious cytologies were 92% and 42%, respectively. Negative predictive value of the cases with benign cytologic diagnoses was 99%, with an accuracy of 96%. The histologic findings for 81 patients with a cytologic diagnosis of positive for papillary carcinoma and 44 cases diagnosed as suspicious for papillary carcinoma are illustrated in Figures 2 and 3, respectively. Papillary carcinoma was found in 93% of the cases diagnosed as positive for papillary carcinoma and 69% of the patients with a cytologic diagnosis of suspicious for papillary carcinoma. One patient in each group had follicular carcinoma. Conversely, on retrospective review of 132 cases with a histologic diagnosis of papillary carcinoma, 57% had a cytologic interpretation of positive for papillary carcinoma, and 35% were suspicious for malignancy. In 6% of the cases, the aspirates were nondiagnostic (Table 3). Of 59 cases with the cytologic diagnosis of follicular neoplasm, 11% had malignant histologic diagnoses. The malignancies found in this group, in decreasing order of frequency, were follicular carcinoma, medullary carcinoma, and papillary carcinoma. Eighty-one percent of the cases were found to have follicular adenoma in the surgical specimen (Figure 4). Histologic diagnoses of 28 patients with a cytologic diagnosis of Hürthle cell tumor are demonstrated in Table 4. Approximately 32% of these cases had malignancy on subsequent surgical material. We identified 7 cases with positive cytology diagnoses who had benign lesions at surgery (Table 5). The most common false-positive diagnosis was papillary carcinoma. The cytology slides for 4 of these false-positive cases were available for retrospective review. The smears of 3 cases showed many cells with intranuclear inclusions and grooves and occasional psammoma bodies, but they lacked the other features of papillary carcinoma. The aspirates of the fourth case showed marked atypia; however, due to scant cellularity, the smears were marginally adequate for optimal evaluation. We had 11 false-negative diagnoses (Table 6). Retrospective review of the cytology slides for 7 of these cases showed abundant colloid with benign follicular cells in 4 cases. In 3 cases, the specimens were marginally adequate for appropriate evaluation. Table 5. Histologic Diagnoses of 7 Cases With False-Positive Cytology Cytology Diagnosis Papillary carcinoma Positive for malignancy, NOS* * NOS indicates not otherwise specified. 486 Arch Pathol Lab Med—Vol 125, April 2001 Histologic Diagnosis No. of Cases Follicular adenoma 1 Hashimoto thyroiditis Follicular adenoma Multinodular goiter Subacute granulomatous thyroiditis Benign cystic nodule Atypical adenoma Hürthle cell adenoma 1 1 1 1 1 1 1 Fine-Needle Aspiration of Thyroid—Amrikachi et al Table 6. Histologic Diagnoses of 11 Cases With False-Negative Cytology Cytologic Diagnosis Negative: Negative: Negative: Negative: Histologic Diagnosis NOS* follicular adenoma Hashimoto thyroiditis adenomatous nodule No. of Cases Papillary carcinoma Well-differentiated follicular carcinoma Follicular variant of papillary carcinoma Follicular variant of papillary carcinoma Hürthle cell carcinoma Follicular carcinoma 5 1 1 2 1 1 * NOS indicates not otherwise specified. Table 7. Comparing Our Data to Other Studies in the Literature Series, y Total No. of Aspirates Cytologic Diagnosis, % Positive Negative Suspicious Unsatisfactory Sensitivity, % Specificity, % Gardiner et al, 1986 1465 1 74 10 Altavilla et al,16 1990 2433 1 78 5 Caraway et al,12 1993 394 17 60 14 Gharib et al,17 1993 10 971 4 64 11 Gharib,2 1993* 18 183 3.5 69 10 18 Burch et al, 1996 504 3 57 9 Baloch et al,7 1998 662 16 69 4 Current study 6226 3.4 60 7.2 * Review of 7 series. † After repeat fine-needle aspiration biopsy, number of unsatisfactory diagnoses decreased to 22%. 15 COMMENT In the last 20 years, FNA biopsy has evolved as the most accurate and sensitive diagnostic tool for the initial screening of patients with thyroid nodules in the United States.8,13,14 The ideal goal is to identify and surgically remove malignant nodules, while avoiding surgical intervention in benign lesions. In published series, the sensitivity and specificity values of thyroid FNA vary from 65% to 98% and from 73% to 100%, respectively (Table 7).2,7,12,15–18 The main reason for such a wide range of sensitivity and specificity is how cytopathologists handle the category of ‘‘suspicious’’ and how they define the false-positive and false-negative results. Some authors include follicular lesion in the malignant/neoplastic category. Others categorize them in the negative group, whereas some exclude them from the calculations altogether.2,7,12,15–18 In some series, the prevalence of malignancy in cases with a cytologic diagnosis of suspicious for malignancy approaches 60%.8 In our study, 41% of the cases with cytology classified as suspicious were found to have malignancy at surgery. The high percentage of malignancy in cases with suspicious cytology justifies the need for surgical exploration of all cases in this category. However, in cases with a cytologic diagnosis of malignancy, a more extensive surgical intervention, such as total or near total thyroidectomy, is the treatment of choice.8,9 Therefore, to avoid a more aggressive surgical intervention with an increased risk of morbidity and mortality, definitive criteria for the diagnosis of malignancy should be present before a cytologic diagnosis of malignancy is considered. In our review of 6226 thyroid FNAs, we identified 7 cases with false-positive cytology diagnoses. Of these cases, 3 underwent total thyroidectomy. The remaining 4 cases were treated more conservatively with thyroid lobectomy. The most common false-positive diagnosis was papillary carcinoma. The cytology slides for 4 of these falsepositive cases were available. These smears showed 1 or more of the following characteristics: intranuclear incluArch Pathol Lab Med—Vol 125, April 2001 15 16 9 21 17 31 11 29† 65 71 93 98 83 80 92 93 91 100 91 99 92 73 84 96 sions, grooves, and occasional psammoma bodies. However, retrospectively, the other features of papillary carcinoma, such as finely granular chromatin, nucleoli, and papillary or syncytial-type tissue fragments were absent. One case showed marked atypia, but because of low cellularity, the smears were marginally adequate for optimal evaluation. Retrospectively, these cases should have been diagnosed as suspicious rather than positive for malignancy. The cytology and histology slides were not available in 3 of the false-positive cases. It is possible that the surgical material were misinterpreted as benign in these cases. Other investigators have reported a similar rate of false-positive diagnosis. Kini13 reported a 3% rate of falsepositive diagnosis in a series of 316 patients with a cytodiagnosis of papillary carcinoma. In that study, most often the errors were due to interpretation based on insufficient criteria, especially in a very cellular aspirate with degeneration and papillary formation. Since FNA is considered as a screening tool for patients with a thyroid nodule, a 2% false-positive rate is not of major concern. However, the goal is to decrease the rate of false-negative diagnosis. In our study, we identified 11 false-negative diagnoses. The cytology slides were available for 7 cases in this group. Retrospective review of the smears for 4 of these cases showed abundant colloid with benign follicular cells and no evidence of neoplastic changes. Since no ultrasound guidance was used during these procedures, some of these false-negative results could be due to sampling errors. The interval between the initial negative diagnosis and the surgery was several years in some cases. Therefore, the possibility of development of new malignancy in a previously benign lesion should also be considered. In the other 3 cases, the specimens were marginally adequate for appropriate evaluation and probably should have been classified as unsatisfactory rather than negative. The reported rates of false-negative cytology diagnoses range from 1% to 16% in different series.2,7,12,15–18 The high Fine-Needle Aspiration of Thyroid—Amrikachi et al 487 false-negative rate in some of these reports is because these studies were often conducted as retrospective investigations of patients with thyroidectomy with only subsequent review of the cytologic material. Thus, the large number of patients with a negative cytologic diagnosis who did not undergo surgery because of the negative FNA results was not included in their statistical analyses. Indeed, in our series, had we used such criteria, our falsenegative rate would have been 17% (11/64). Very few investigators have addressed the clinical follow-up data. Grant et al14 studied the accuracy of thyroid FNA-based diagnosis, particularly with respect to falsenegative errors, in a group of 680 patients with a mean follow-up period of 6.1 years. They reported less than 1% false-negative diagnoses for 439 patients with a negative cytodiagnosis and no false-positive diagnoses for 24 cases with positive cytology.14 In our study, we correlated the cytology results with the surgical pathology diagnosis, repeat FNA, or clinical follow-up information. Of 3731 aspirates with negative cytologic diagnoses, 64 patients (2%) with clinically suspicious nodules underwent surgical exploration. Of these, 11 patients were found to have malignant lesions at surgery. Repeat FNA in 495 cases with an initial negative cytology showed malignancy in only 4 (0.8%). The remaining cases had close follow-up, ranging from 1 to 16 years, and no discrepancies were reported by the treating physicians. Therefore, the overall false-negative rate in our study was less than 1%. Some cases in our study may have been lost to follow-up, or low-grade malignancies may have been clinically stable. However, due to the large number of negative cases with clinically benign follow-up, we believe that our true-negative rate is very close to the actual figure. One of the major limitations of FNA of the thyroid is the large number of insufficient aspirates. Insufficiency rates ranging between 7% and 31% have been reported (Table 7).12,15–18 The most important factors in the rate of insufficient aspirates are the experience of the aspirator and the criteria used to define a satisfactory specimen.7,18 In our study, the insufficiency rate was 29%, and that was reduced to 22% after repeat FNAs were performed. Although this insufficiency rate seems to be on the high side of the previous reports, all procedures in this study were performed by clinicians, without adequacy checks at the time of the aspiration. In addition, some of palpable nodules were due to cystic lesions that yielded fluid with mostly histiocytes and few if any follicular cells, which did not meet the criteria proposed for an adequate sample. Recently, the Papanicolaou Society of Cytopathology published guidelines for the examination of FNA specimens from thyroid nodules. They suggest reporting such cases as ‘‘consistent with benign thyroid cyst,’’ with a qualifier indicating that the interpretation is limited by paucity or lack of follicular cells, rather than reporting them as insufficient for diagnosis.19 Most of the cases with insufficient aspirates in our series were followed clinically or by repeat FNA. Of 539 cases with initial insufficient aspirate classifications, 62% had a diagnostic aspirate after repeat FNA. Some series have reported on the accuracy of thyroid FNA biopsy over time. Our study did not address this point. In summary, FNA of thyroid is highly accurate and has 488 Arch Pathol Lab Med—Vol 125, April 2001 a low rate of false-negative and false-positive diagnoses. If the suspicious diagnoses are considered positive (because these patients were also sent to surgery), the sensitivity and specificity values of thyroid FNA are 93% and 96%, respectively. Fine-needle aspiration of the thyroid is highly specific in the diagnosis of most of the benign lesions, such as adenomatous nodules and lymphocytic thyroiditis, and in several malignant conditions as well, such as papillary carcinoma and anaplastic carcinoma. Although the cytologic diagnosis of papillary carcinoma has the highest specificity of thyroid malignancies, the most common false-positive diagnosis is also papillary carcinoma. Cytopathologists should be aware of these potential limitations of FNA interpretation. The major diagnostic problems arise when a marginally adequate specimen is interpreted in a definitive fashion or when the diagnosis of malignancy is made based on just 1 or 2 atypical cytologic features. Overlapping cytologic features of follicular neoplasm with those of follicular variant of papillary carcinoma is another diagnostic challenge. Patients with benign cytologic findings should have close clinical follow-up. There is a possibility of false-negative diagnosis in a small percentage of patients. Therefore, despite a benign cytology, clinically suspicious lesions probably should be excised if the patient is a surgical candidate. References 1. Vander JB, Gaston EA, Dawber TR. The significance of nontoxic thyroid nodules: final report of a 15-year study of the incidence of thyroid malignancy. Ann Int Med. 1968;69:537–540. 2. Gharib H. Fine needle aspiration biopsy of thyroid: an appraisal. Ann Int Med. 1993;118:282–289. 3. Rojeski MT, Gharib H. 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Bouvet M, Feldman JI, Dillman WH, Nahun AM, Russack V, Robbins KT. Surgical management of the thyroid nodules: patient selection based on the results of fine needle aspiration cytology. Laryngoscope. 1992;102:1353–1356. 11. Gharib H. Fine needle aspiration of thyroid nodules: advantages, limitations, and effects. Mayo Clin Proc. 1994;69:44–49. 12. Caraway NP, Sniege N, Samaan NA. Diagnostic pitfalls in thyroid fineneedle aspiration: a review of 394 cases. Diagn Cytopathol. 1993;9:345–350. 13. Kini SR. Thyroid. In: Kline TS, ed. Guides to Clinical Aspiration Biopsy. 2nd ed. New York, NY: Igaku-Shoin Medical Publishers; 1996:176–188. 14. Grant CS, Hay ID, Gough IR, McCarthy PM, Goellner JR. Long term followup of patients with benign thyroid fine-needle aspiration cytology diagnosis. Surgery. 1989;106:980–986. 15. Gardiner GW, de Souza FM, Carydis B, Seemann C. Fine needle aspiration biopsy of the thyroid gland: results of a 5-year experience and discussion of its clinical limitations. J Otolaryngol. 1986;15:161–165. 16. Altavilla G, Pascale M, Nenci I. Fine needle aspiration cytology of thyroid gland disease. Acta Cytol. 1990;34:251–256. 17. Gharib H, Goellner JR, Johnson DA. Fine needle aspiration cytology of the thyroid: a 12 year experience with 11 000 biopsies. Clin Lab Med. 1993;13:699– 709. 18. Burch HB, Burman KD, Reed HL, Buckner L, Raber T, Ownbey JL. Fine needle aspiration biopsy of thyroid nodules: determinants of insufficiency rate and malignancy yield at thyroidectomy. Acta Cytol. 1996;40:1176–1183. 19. The Papanicolaou Society of Cytopathology Task Force on Standards of Practice. Guidelines of Papanicolaou Society of Cytopathology for the examination of fine-needle aspiration specimens from thyroid nodules. Mod Pathol. 1996; 9:710–715. Fine-Needle Aspiration of Thyroid—Amrikachi et al