Annals of Diagnostic Pathology 18 (2014) 297–300
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Cytologic-Pathologic Correlation
Do repeatedly nondiagnostic fine needle aspirations of thyroid nodules predict malignancy risk? Dilek Arpaci, MD a,⁎, Didem Ozdemir, MD b, Neslihan Cuhaci, MD b, Gulten Kiyak, MD c, Abdussamet Yalcin, MD d, Soner Akbaba, MD c, Aylin Kilicyazgan, MD e, Reyhan Ersoy, MD b, Bekir Cakir, MD b a
Department of Endocrinology, Sakarya Training and Research Hospital, Sakarya, Turkey Department of Endocrinology and Metabolism Diseases, Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital, Ankara, Turkey c Department of General Surgery, Ankara Ataturk Training and Research Hospital, Ankara, Turkey d Department of General Surgery, Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital, Ankara, Turkey e Department of Pathology, Ankara Ataturk Training and Research Hospital, Ankara, Turkey b
a r t i c l e
i n f o
Keywords: Nondiagnostic Biopsy Malignancy Surgery
a b s t r a c t Fine needle aspiration biopsy (FNAB) is a common, minimally invasive, cost-effective, and rapid method to manage thyroid nodules, but nondiagnostic FNAB (ND-FNAB) is still a common problem due to high prevalence (2%-20%). Our purpose in this study is to investigate risk of malignancy of repeating ND-FNABs and correlation between clinical and ultrasound findings. Our cohort study included 75 patients who had 2 or more times ND-FNABs and, finally, undergone surgical resection. We evaluated demographic, clinical, ultasonographic, and pathologic features. Fifty-seven patients were female, and 22 patients were male. Seventy-five patients' histopathologic results were 76% (n = 57) benign and 24% (n = 18) malignant. Of malignant nodules, 94.4% (n = 17) were papillary carcinoma, whereas 5.6% (n = 1) were follicular carcinoma. We did not find any predictive factor for malignancy and any differences associated with clinical and ultrasonographic features between benign and malignant nodules. Reaspiration followed by surgery for appropriate patients is recommended. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Fine needle aspiration biopsy (FNAB) is the most accurate, costeffective, minimally invasive, and rapid diagnostic technique to evaluate risk of malignancy in thyroid nodules [1,2]. A successful fine needle aspiration requires a specimen with adequate cellularity, high-quality preparation, an experienced aspirator, and cytopathologist [3,4]. Bethesda system for reporting thyroid cytopathology states that the rate of nondiagnostic fine needle aspiration biopsy (ND-FNAB) should ideally not exceed 10% [1]. Although most biopsies are adequate for a cytological diagnosis, 2% to 20% of FNABs are qualitatively and quantitavely inadequate to diagnose [1]. Because the risk of malignancy in thyroid nodules is 1% to 10%, the American Thyroid Association (ATA) and Bethesda system for reporting thyroid cytopathology suggest performing a repeat FNAB under ultrasound (US) guidance for ND-FNAB. The suggested waiting time for repeat FNAB to avoid reparative cellular atypia is at least 3 months [2,5,6].
⁎ Corresponding author. Korucuk 1683 Isl. A/10, Adapazari, Sakarya, Turkey. Tel.: +90 5072476698. E-mail addresses: [email protected] (D. Arpaci), [email protected] (D. Ozdemir), [email protected] (N. Cuhaci), [email protected] (R. Ersoy), [email protected] (B. Cakir). http://dx.doi.org/10.1016/j.anndiagpath.2014.08.005 1092-9134/© 2014 Elsevier Inc. All rights reserved.
The Bethesda system reports 1% to 4% risk of malignancy associated with ND-FNAB, but other series reported a range of 2% to 51% [6-9]. If second FNAB is nondiagnostic, the ATA, European Thyroid Association, American Association of Clinical Endocrinologist, and Associazione Medici Endocrologi recommend consideration for surgical resection [2,10]. Some factors, such as experiences of performers, operators, or pathologist; method and needle gauge used in FNAB; and intrinsic characteristics of the thyroid nodules, such as size, cystic component, and margin, may cause ND-FNAB [11,7,12,13]. The aim of this study was to evaluate risk of malignancy in patients with repeat ND-FNABs who are referred to surgery and to identify clinical and ultrasonographic characteristics of these nodules. 2. Materials and methods Our study was a retrospective study. Seventy-five patients with nodular thyroid disease who were operated on because of twice or more repeated ND-FNABs were included in the study. Medical reports were obtained from records of council of endocrinologists, general surgeons, and pathologists between 2007 and 2012. The study was conducted at Yildirim Beyazit University Ankara Ataturk Education and Research Hospital. Informed consent was received from all
298
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patients before each biopsy. All patients signed for having their information used in this study. The study was received approval from the local ethical committee. Esaote color Doppler US (model: 796FDII; MAG Technology Co, Ltd, Yung-ho City, Taipei, Taiwan) and a superficial probe (model no: LA523 13-4, 5.5-12.5 MHz) were used for standard US. Localization, diameters (millimeters), halo, echogenicity, marginal regularity, type of calcification, and peripheral vascularization of the nodules were evaluated by using standard US. Repeat FNABs were performed under US guidance using a General Electric Logiq pro 200 (model no.: 2270968; GE Healthcare Korea, Seongnam-si, Gyeonggi-do, Korea) and a 5.5- to 7.5-MHz probe by an endocrinologist using a 25-gauge needle attached to a 10-mL plastic syringe. Total thyroidectomy or lobectomy was performed depending on the size of nodule and surgeon's discretion. All of the statistical analyses were performed with SPSS 18.0 (SPSS, Inc, Chicago, IL) statistical software. Descriptive statistics were shown as frequency tables or the mean ± SD notation for qualitative and quantitative data, respectively. Relations between the qualitative data were examined with χ 2 test. Independent-samples t test was used to compare the continuous variables.
Fig. 1. Papillary thyroid microcarcinoma (original magnification ×400).
3. Results In the cohort of 75 cases presented in this study, 53 patients (70.7%) were female, and 22 (29.3%) were male. The mean age was 47.9 ± 10.9 years. Histopathologically, 76% of nodules (n = 57) were benign, and 24% (n = 18) were malignant. Of malignant nodules, 94.4% (n = 17) were papillary carcinoma, whereas 5.6% (n = 1) were follicular carcinoma (Table 1). Demographical and clinical factors, ultrasonographic characteristics, and histopathologic findings were investigated (Figs. 1-6). In addition, the relation of these features with benign and malignant histology was analyzed. We found no significant differences between benign and malignant histologies with respect to age, sex, nodule size, thyroid-stimulating hormone levels, and thyroid status. Ultrasound findings such as presence of solitary or multiple nodules, macrocalcification/microcalcification, halo marginal regularity, localization, cystic component, and echogenicity did not differ between malignant and benign nodules (Table 2). There was no difference in size of nodule between benign and malign histologies (P = .15). Besides, nodule size greater than 3 cm was not associated with malignancy (P = .18) (Table 3).
Fig. 2. Rare follicular epithelial cells (original magnification ×200, May-Grünwald-Giemsa).
4. Discussion In the last 2 decades, FNAB has gained widespread acceptance as a diagnostic tool in the management of thyroid nodules [3,6,14]. Several authors have shown its remarkable sensitivity and specificity compared with other tools (radiology and laboratory tests) used in the diagnosis of thyroid nodules [3,14]. In general, thyroid nodules that are diagnosed as benign are managed clinically, and neoplastic and malignant ones undergo surgical excision [14]. However, there is no consensus about the management of thyroid nodules, which are Table 1 Histopathologic findings Histopathologic (postsurgical) findings
N = 75 (%)
Benign Malignant Papillary carcinoma Follicular carcinoma Lenfovascular invasion Capsular invasion Extracapsular invasion Multicentricity
57 (76.0%) 18 (24%) 17 (94.4%) 1 (5.6%) 1 (5.6%) 5 (27.8%) 1 (5.6%) 6 (33.3)
Fig. 3. Degenerated cells and macrophages (original magnification ×200, MayGrünwald-Giemsa).
D. Arpaci et al. / Annals of Diagnostic Pathology 18 (2014) 297–300
299
Table 2 Demographics and ultrasonographic features in patients with repeated ND-FNAB and comparison of benign and malignant nodules All, N = 75 (%) Age Sex
Fig. 4. Papillary thyroid microcarcinoma (original magnification ×400).
47.9 ± 10.9 Male 22 (29.3%) Female 53 (70.7%) No. of nodule Solitary 11 (14.6%) Multiple 64 (85.4%) TSH 1.45 ± 1.47 TFT status Euthyroid 45 (60%) Hypothyroid 5 (6.7%) Hyperthyroid 25 (33.3%) Microcalcification Present 20 (26.7%) Absent 55 (76.3%) Macrocalcification Present 30 (40%) Absent 45 (60%) Echogenicity Isoechoic Hypoechoic Nodule size (cm) 2.13 ± 1.28 Component Cystic 1 (1.4%) Solid 40 (53.3%) Mixed 34 (45.3%) Peripheral calcification Present 1 (1.4%) Absent 74 (98.6%) Margin Irregular 45 (60%) Regular 30 (40%) Halo Present 32 (42.7%) Absent 43 (57.3%) Localization Right 41 (54.7%) Left 34 (45.3%)
Benign (n = 57)
Malignant (n = 18)
P
47.1 ± 11 18 (31.5%) 39 (68.5) 7 (12.2%) 50 (87.8%) 1.53 ± 1.63 31 (54.4%) 4 (7%) 22 (38.6%) 24 (42.1%) 33 (57.9) 16 (28%) 41 (72%) 36 (63.2%) 21 (36.8%) 2.28 ± 1.35 1 (1.8%) 28 (49.1%) 28 (49.1%) 1 (1.8%) 56 (98.2) 23 (40.4%) 34 (59.6%) 22 (38.6%) 35 (61.4%) 34 (59.6%) 23 (40.4%)
50.3 ± 10.5 4 (22.2%) 14 (77.8%) 4 (22.2%) 14 (77.8%) 1.21 ± 0.74 14 (77.8%) 1 (5.5) 3 (16.7%) 6 (33.3%) 12 (66.7%) 4 (22.2%) 14 (77.8%) 7 (38.9%) 11 (61.1%) 1.66 ± 0.75 0 (0%) 12 (66.7%) 6 (33.3%) 0 (0%) 18 (100%) 7 (38.9%) 11 (61.1%) 6 (33.3%) 12 (66.7%) 7 (38.9%) 11 (61.1%)
.28 .44 .29 .42 .19
.50 .62 .07 .07 .39
.57 .91 .68 .12
Abbreviations: TSH, thyroid-stimulating hormone; TFT, thyroid function test.
Fig. 5. Papillary thyroid microcarcinoma (original magnification ×400).
nondiagnostic due to lack of adequate cellular component and are indeterminate for neoplasm due to overlapping cytologic features between benign and neoplastic thyroid lesions [6,7].
At our institution, it is recommended that all nondiagnostic thyroid FNAB should undergo repeat FNAB under US guidance at least 3 months after initial FNAB. In the present study, 75 patients who were diagnosed on initial FNAB as nondiagnostic were rebiopsied under US guidance 2 or more times for each patient. Then all patients undergone surgery; malignancy was identified in 18 patients (24%). Several studies have shown varying rates of malignancy among nondiagnostic thyroid biopsies [8,9,15]. MacDonald and Yazdi [15] analyzed 114 patients with ND-FNAB, with histologic follow-up data available in 91 patients, and identified a malignancy rate of 2% [15]. Richards et al [16] have reported in their study that ND-FNABs rate was 21% with a higher rate of malignancy among these nodules as 14%. In another study by Baloch et al [6], malignancy risk of ND-FNAB was 26%, similar to our study. In a recent study from Mayo Clinic by Chow et al [9], malignancy of ND-FNAB was 37%, which is considerably higher than our study. McHenry et al [8] reported a malignancy rate of 9% in a cohort of 92 patients with ND-FNABs. Moreover, among clinical factors such as age, sex, nodule size, and history of irradiation, only male sex was identified as significant predictive factor for malignancy [8]. We did not identify any potential predictive factor for malignancy concerning ND-FNAB in our study. In a report of Alexander et al [7], ND-FNABs rate was 13%. They did not point out any differences between diagnostic and nondiagnostic nodules with regard to age, sex, thyroid function status, presence of solitary and multiple nodules, nodule size, or location. The only predictive factor for malignancy in ND-FNABs was determined as
Table 3 Nodule size and histopathologic findings
Fig. 6. Degenerated cells (original magnification ×200, May-Grünwald-Giemsa).
Nodule size
ND-FNABs, N = 75
Benign, n = 57
Malignant, n = 18
P
b1 cm 1-1.9 cm 2-2.9 cm ≥3 cm
10 33 15 17
5 (6.6%) 26 (34.7%) 11 (14.7%) 15 (%20)
5 7 4 2
.15
(6.6%) (9.4%) (5.3%) (2.7%)
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D. Arpaci et al. / Annals of Diagnostic Pathology 18 (2014) 297–300
presence of cystic component [7]. In our study, only 1 nodule had pure cystic structure. As known, peripheral macrocalcification is the cause of ND-FNAB. However, in our study, only 1 nodule had peripheral calcification. Richard et al [16] found that thyroid nodule size is predictive of ND-FNAB and ND-FNAB rate is higher for nodules greater than or equal to 3 cm in size; possible mechanism for this finding was supposed to be higher rate of cystic component and degeneration associated with such nodules [16]. A study from our country revealed 12% rate of malignancy among ND-FNABs [17]. Choi et al [18] reported that malignancy risk of initial ND-FNAB was 11.3% and 3.2% in ND-FNABs performed twice. Factors associated with second ND-FNAB were cystic component more than 50%, nodule size more than 5 mm, hypoechoic nodules, and macrocalcification in nodules [18]. Thus, persistent evaluation of initially nondiagnostic thyroid nodules is mandated and should be pursued promptly. 5. Conclusion Nondiagnostic cytology in repeated FNABs remains a significant problem in the evaluation of thyroid nodules for both physicians and patients. Despite US guidance, there is a 2% to 20% risk of initial nondiagnostic specimens. Patient with initial ND-FNAB should be assessed with repeated sampling or direct surgery. Decision of surgery is often compelling. The decision is affected by multiple factors such as nodule size; clinical and ultrasonographic features; clinical suspicion; and, finally, patient preferences. If the initial and second FNABs are nondiagnostic, we should consider surgery following the ATA/ European Thyroid Association/Associazione Medici Endocrologi/ American Association of Clinical Endocrinologist guidelines [2,10]. Nondiagnostic FNAB should not be considered benign. Reaspiration followed by surgery for appropriate patients is recommended. Competing interests The authors declare that they have no competing interests. Authors' contributions DO participated in the design of the study and performed the statistical analysis. RE conceived the study and participated in its design and coordination and helped draft the manuscript. All authors read and approved the manuscript.
References [1] Cibas ES, Ali SZ. The Bethesda system for reporting thyroid cytopathology. Thyroid 2009;19:1159–65. [2] Cooper DS, Doherty GM, Haugen BR, Kloos RT, Lee SL, et al. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009; 19:1167–214. [3] Silverman JF, West RL, Larkin EW, Park HK, Finley JL, Swanson MS, et al. The role of fine-needle aspiration biopsy in the rapid diagnosis and management of thyroid neoplasms. Cancer 1986;57:1164–70. [4] Kini SR. Guides to clinical aspiration biopsy thyroid. 2nd ed. New York: IgakuShoin; 1996. [5] Layfield LJ, Abrams J, Cochand-Priollet B, Evans D, Gharib H, Greenspan F, et al. Post-thyroid FNA testing and treatment options: a synopsis of the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:442–8. [6] Baloch Z, LiVolsi VA, Jain P, Jain R, Aljada I, Mandel S, et al. Role of repeat fineneedle aspiration biopsy (FNAB) in the management of thyroid nodules. Diagn Cytopathol 2003;29:203–6. [7] Alexander EK, Heering JP, Benson CB, Frates MC, Doubilet PM, Cibas ES, et al. Assessment of nondiagnostic ultrasound-guided fine needle aspirations of thyroid nodules. J Clin Endocrinol Metab 2002;87:4924–7. [8] McHenry CR, Walfish PG, Rosen IB. Non-diagnostic fine needle aspiration biopsy: a dilemma in management of nodular thyroid disease. Am Surg 1993;59:415–9. [9] Chow LS, Gharib H, Goellner JR, van Heerden JA. Nondiagnostic thyroid fineneedle aspiration cytology: management dilemmas. Thyroid 2001;11:1147–51. [10] Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Hegedüs L, et al. American Association of Clinical Endocrinologists, Associazione Medici Endocrinologi, and European Thyroid Association medical guidelines for clinical practice for the diagnosis and management of thyroid nodules. Endocr Pract 2010;16:468–75. [11] Yokozawa T, Miyauchi A, Kuma K, Sugawara M. Accurate and simple method of diagnosing thyroid nodules the modified technique of ultrasound-guided fine needle aspiration biopsy. Thyroid 1995;5:141–5. [12] Baier ND, Hahn PF, Gervais DA, Samir A, Halpern EF, Mueller PR, et al. Fine-needle aspiration biopsy of thyroid nodules: experience in a cohort of 944 patients. AJR Am J Roentgenol 2009;193:1175–9. [13] Degirmenci B, Haktanir A, Albayrak R, Acar M, Sahin DA, Sahin O, et al. Sonographically guided fine-needle biopsy of thyroid nodules: the effects of nodule characteristics, sampling technique, and needle size on the adequacy of cytological material. Clin Radiol 2007;62:798–803. [14] Ashcraft MW, Van Herle AJ. Management of thyroid nodules. II: scanning techniques, thyroid suppressive therapy and fine-needle aspiration. Head Neck Surg 1981;3:297–322. [15] MacDonald L, Yazdi HM. Nondiagnostic fine needle aspiration biopsy of the thyroid gland: a diagnostic dilemma. Acta Cytol 1996;40:423–8. [16] Richards ML, Bohnenblust E, Sirinik K, Bingener J. Nondiagnostic thyroid fine needle aspiration biopsies are no longer a dilemma. Am J Surg 2008;196:398–402. [17] Akgul O, Ocak S, Keskek L, Koc M, Tez M. Risk of malignancy in non-diagnostic thyroid fine-needle aspiration biopsy in multinodular goitre patients. Endocr Regul 2011;45:9–12. [18] Choi YS, Hong SW, Kwak JY, Moon HJ, Kim EK. Clinical and ultrasonographic findings affecting nondiagnostic results upon the second fine needle aspiration for thyroid nodules. Ann Surg Oncol 2012;19:2304–9.
Contents lists available at ScienceDirect
Annals of Diagnostic Pathology
Cytologic-Pathologic Correlation
Do repeatedly nondiagnostic fine needle aspirations of thyroid nodules predict malignancy risk? Dilek Arpaci, MD a,⁎, Didem Ozdemir, MD b, Neslihan Cuhaci, MD b, Gulten Kiyak, MD c, Abdussamet Yalcin, MD d, Soner Akbaba, MD c, Aylin Kilicyazgan, MD e, Reyhan Ersoy, MD b, Bekir Cakir, MD b a
Department of Endocrinology, Sakarya Training and Research Hospital, Sakarya, Turkey Department of Endocrinology and Metabolism Diseases, Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital, Ankara, Turkey c Department of General Surgery, Ankara Ataturk Training and Research Hospital, Ankara, Turkey d Department of General Surgery, Yildirim Beyazit University, Ankara Ataturk Training and Research Hospital, Ankara, Turkey e Department of Pathology, Ankara Ataturk Training and Research Hospital, Ankara, Turkey b
a r t i c l e
i n f o
Keywords: Nondiagnostic Biopsy Malignancy Surgery
a b s t r a c t Fine needle aspiration biopsy (FNAB) is a common, minimally invasive, cost-effective, and rapid method to manage thyroid nodules, but nondiagnostic FNAB (ND-FNAB) is still a common problem due to high prevalence (2%-20%). Our purpose in this study is to investigate risk of malignancy of repeating ND-FNABs and correlation between clinical and ultrasound findings. Our cohort study included 75 patients who had 2 or more times ND-FNABs and, finally, undergone surgical resection. We evaluated demographic, clinical, ultasonographic, and pathologic features. Fifty-seven patients were female, and 22 patients were male. Seventy-five patients' histopathologic results were 76% (n = 57) benign and 24% (n = 18) malignant. Of malignant nodules, 94.4% (n = 17) were papillary carcinoma, whereas 5.6% (n = 1) were follicular carcinoma. We did not find any predictive factor for malignancy and any differences associated with clinical and ultrasonographic features between benign and malignant nodules. Reaspiration followed by surgery for appropriate patients is recommended. © 2014 Elsevier Inc. All rights reserved.
1. Introduction Fine needle aspiration biopsy (FNAB) is the most accurate, costeffective, minimally invasive, and rapid diagnostic technique to evaluate risk of malignancy in thyroid nodules [1,2]. A successful fine needle aspiration requires a specimen with adequate cellularity, high-quality preparation, an experienced aspirator, and cytopathologist [3,4]. Bethesda system for reporting thyroid cytopathology states that the rate of nondiagnostic fine needle aspiration biopsy (ND-FNAB) should ideally not exceed 10% [1]. Although most biopsies are adequate for a cytological diagnosis, 2% to 20% of FNABs are qualitatively and quantitavely inadequate to diagnose [1]. Because the risk of malignancy in thyroid nodules is 1% to 10%, the American Thyroid Association (ATA) and Bethesda system for reporting thyroid cytopathology suggest performing a repeat FNAB under ultrasound (US) guidance for ND-FNAB. The suggested waiting time for repeat FNAB to avoid reparative cellular atypia is at least 3 months [2,5,6].
⁎ Corresponding author. Korucuk 1683 Isl. A/10, Adapazari, Sakarya, Turkey. Tel.: +90 5072476698. E-mail addresses: [email protected] (D. Arpaci), [email protected] (D. Ozdemir), [email protected] (N. Cuhaci), [email protected] (R. Ersoy), [email protected] (B. Cakir). http://dx.doi.org/10.1016/j.anndiagpath.2014.08.005 1092-9134/© 2014 Elsevier Inc. All rights reserved.
The Bethesda system reports 1% to 4% risk of malignancy associated with ND-FNAB, but other series reported a range of 2% to 51% [6-9]. If second FNAB is nondiagnostic, the ATA, European Thyroid Association, American Association of Clinical Endocrinologist, and Associazione Medici Endocrologi recommend consideration for surgical resection [2,10]. Some factors, such as experiences of performers, operators, or pathologist; method and needle gauge used in FNAB; and intrinsic characteristics of the thyroid nodules, such as size, cystic component, and margin, may cause ND-FNAB [11,7,12,13]. The aim of this study was to evaluate risk of malignancy in patients with repeat ND-FNABs who are referred to surgery and to identify clinical and ultrasonographic characteristics of these nodules. 2. Materials and methods Our study was a retrospective study. Seventy-five patients with nodular thyroid disease who were operated on because of twice or more repeated ND-FNABs were included in the study. Medical reports were obtained from records of council of endocrinologists, general surgeons, and pathologists between 2007 and 2012. The study was conducted at Yildirim Beyazit University Ankara Ataturk Education and Research Hospital. Informed consent was received from all
298
D. Arpaci et al. / Annals of Diagnostic Pathology 18 (2014) 297–300
patients before each biopsy. All patients signed for having their information used in this study. The study was received approval from the local ethical committee. Esaote color Doppler US (model: 796FDII; MAG Technology Co, Ltd, Yung-ho City, Taipei, Taiwan) and a superficial probe (model no: LA523 13-4, 5.5-12.5 MHz) were used for standard US. Localization, diameters (millimeters), halo, echogenicity, marginal regularity, type of calcification, and peripheral vascularization of the nodules were evaluated by using standard US. Repeat FNABs were performed under US guidance using a General Electric Logiq pro 200 (model no.: 2270968; GE Healthcare Korea, Seongnam-si, Gyeonggi-do, Korea) and a 5.5- to 7.5-MHz probe by an endocrinologist using a 25-gauge needle attached to a 10-mL plastic syringe. Total thyroidectomy or lobectomy was performed depending on the size of nodule and surgeon's discretion. All of the statistical analyses were performed with SPSS 18.0 (SPSS, Inc, Chicago, IL) statistical software. Descriptive statistics were shown as frequency tables or the mean ± SD notation for qualitative and quantitative data, respectively. Relations between the qualitative data were examined with χ 2 test. Independent-samples t test was used to compare the continuous variables.
Fig. 1. Papillary thyroid microcarcinoma (original magnification ×400).
3. Results In the cohort of 75 cases presented in this study, 53 patients (70.7%) were female, and 22 (29.3%) were male. The mean age was 47.9 ± 10.9 years. Histopathologically, 76% of nodules (n = 57) were benign, and 24% (n = 18) were malignant. Of malignant nodules, 94.4% (n = 17) were papillary carcinoma, whereas 5.6% (n = 1) were follicular carcinoma (Table 1). Demographical and clinical factors, ultrasonographic characteristics, and histopathologic findings were investigated (Figs. 1-6). In addition, the relation of these features with benign and malignant histology was analyzed. We found no significant differences between benign and malignant histologies with respect to age, sex, nodule size, thyroid-stimulating hormone levels, and thyroid status. Ultrasound findings such as presence of solitary or multiple nodules, macrocalcification/microcalcification, halo marginal regularity, localization, cystic component, and echogenicity did not differ between malignant and benign nodules (Table 2). There was no difference in size of nodule between benign and malign histologies (P = .15). Besides, nodule size greater than 3 cm was not associated with malignancy (P = .18) (Table 3).
Fig. 2. Rare follicular epithelial cells (original magnification ×200, May-Grünwald-Giemsa).
4. Discussion In the last 2 decades, FNAB has gained widespread acceptance as a diagnostic tool in the management of thyroid nodules [3,6,14]. Several authors have shown its remarkable sensitivity and specificity compared with other tools (radiology and laboratory tests) used in the diagnosis of thyroid nodules [3,14]. In general, thyroid nodules that are diagnosed as benign are managed clinically, and neoplastic and malignant ones undergo surgical excision [14]. However, there is no consensus about the management of thyroid nodules, which are Table 1 Histopathologic findings Histopathologic (postsurgical) findings
N = 75 (%)
Benign Malignant Papillary carcinoma Follicular carcinoma Lenfovascular invasion Capsular invasion Extracapsular invasion Multicentricity
57 (76.0%) 18 (24%) 17 (94.4%) 1 (5.6%) 1 (5.6%) 5 (27.8%) 1 (5.6%) 6 (33.3)
Fig. 3. Degenerated cells and macrophages (original magnification ×200, MayGrünwald-Giemsa).
D. Arpaci et al. / Annals of Diagnostic Pathology 18 (2014) 297–300
299
Table 2 Demographics and ultrasonographic features in patients with repeated ND-FNAB and comparison of benign and malignant nodules All, N = 75 (%) Age Sex
Fig. 4. Papillary thyroid microcarcinoma (original magnification ×400).
47.9 ± 10.9 Male 22 (29.3%) Female 53 (70.7%) No. of nodule Solitary 11 (14.6%) Multiple 64 (85.4%) TSH 1.45 ± 1.47 TFT status Euthyroid 45 (60%) Hypothyroid 5 (6.7%) Hyperthyroid 25 (33.3%) Microcalcification Present 20 (26.7%) Absent 55 (76.3%) Macrocalcification Present 30 (40%) Absent 45 (60%) Echogenicity Isoechoic Hypoechoic Nodule size (cm) 2.13 ± 1.28 Component Cystic 1 (1.4%) Solid 40 (53.3%) Mixed 34 (45.3%) Peripheral calcification Present 1 (1.4%) Absent 74 (98.6%) Margin Irregular 45 (60%) Regular 30 (40%) Halo Present 32 (42.7%) Absent 43 (57.3%) Localization Right 41 (54.7%) Left 34 (45.3%)
Benign (n = 57)
Malignant (n = 18)
P
47.1 ± 11 18 (31.5%) 39 (68.5) 7 (12.2%) 50 (87.8%) 1.53 ± 1.63 31 (54.4%) 4 (7%) 22 (38.6%) 24 (42.1%) 33 (57.9) 16 (28%) 41 (72%) 36 (63.2%) 21 (36.8%) 2.28 ± 1.35 1 (1.8%) 28 (49.1%) 28 (49.1%) 1 (1.8%) 56 (98.2) 23 (40.4%) 34 (59.6%) 22 (38.6%) 35 (61.4%) 34 (59.6%) 23 (40.4%)
50.3 ± 10.5 4 (22.2%) 14 (77.8%) 4 (22.2%) 14 (77.8%) 1.21 ± 0.74 14 (77.8%) 1 (5.5) 3 (16.7%) 6 (33.3%) 12 (66.7%) 4 (22.2%) 14 (77.8%) 7 (38.9%) 11 (61.1%) 1.66 ± 0.75 0 (0%) 12 (66.7%) 6 (33.3%) 0 (0%) 18 (100%) 7 (38.9%) 11 (61.1%) 6 (33.3%) 12 (66.7%) 7 (38.9%) 11 (61.1%)
.28 .44 .29 .42 .19
.50 .62 .07 .07 .39
.57 .91 .68 .12
Abbreviations: TSH, thyroid-stimulating hormone; TFT, thyroid function test.
Fig. 5. Papillary thyroid microcarcinoma (original magnification ×400).
nondiagnostic due to lack of adequate cellular component and are indeterminate for neoplasm due to overlapping cytologic features between benign and neoplastic thyroid lesions [6,7].
At our institution, it is recommended that all nondiagnostic thyroid FNAB should undergo repeat FNAB under US guidance at least 3 months after initial FNAB. In the present study, 75 patients who were diagnosed on initial FNAB as nondiagnostic were rebiopsied under US guidance 2 or more times for each patient. Then all patients undergone surgery; malignancy was identified in 18 patients (24%). Several studies have shown varying rates of malignancy among nondiagnostic thyroid biopsies [8,9,15]. MacDonald and Yazdi [15] analyzed 114 patients with ND-FNAB, with histologic follow-up data available in 91 patients, and identified a malignancy rate of 2% [15]. Richards et al [16] have reported in their study that ND-FNABs rate was 21% with a higher rate of malignancy among these nodules as 14%. In another study by Baloch et al [6], malignancy risk of ND-FNAB was 26%, similar to our study. In a recent study from Mayo Clinic by Chow et al [9], malignancy of ND-FNAB was 37%, which is considerably higher than our study. McHenry et al [8] reported a malignancy rate of 9% in a cohort of 92 patients with ND-FNABs. Moreover, among clinical factors such as age, sex, nodule size, and history of irradiation, only male sex was identified as significant predictive factor for malignancy [8]. We did not identify any potential predictive factor for malignancy concerning ND-FNAB in our study. In a report of Alexander et al [7], ND-FNABs rate was 13%. They did not point out any differences between diagnostic and nondiagnostic nodules with regard to age, sex, thyroid function status, presence of solitary and multiple nodules, nodule size, or location. The only predictive factor for malignancy in ND-FNABs was determined as
Table 3 Nodule size and histopathologic findings
Fig. 6. Degenerated cells (original magnification ×200, May-Grünwald-Giemsa).
Nodule size
ND-FNABs, N = 75
Benign, n = 57
Malignant, n = 18
P
b1 cm 1-1.9 cm 2-2.9 cm ≥3 cm
10 33 15 17
5 (6.6%) 26 (34.7%) 11 (14.7%) 15 (%20)
5 7 4 2
.15
(6.6%) (9.4%) (5.3%) (2.7%)
300
D. Arpaci et al. / Annals of Diagnostic Pathology 18 (2014) 297–300
presence of cystic component [7]. In our study, only 1 nodule had pure cystic structure. As known, peripheral macrocalcification is the cause of ND-FNAB. However, in our study, only 1 nodule had peripheral calcification. Richard et al [16] found that thyroid nodule size is predictive of ND-FNAB and ND-FNAB rate is higher for nodules greater than or equal to 3 cm in size; possible mechanism for this finding was supposed to be higher rate of cystic component and degeneration associated with such nodules [16]. A study from our country revealed 12% rate of malignancy among ND-FNABs [17]. Choi et al [18] reported that malignancy risk of initial ND-FNAB was 11.3% and 3.2% in ND-FNABs performed twice. Factors associated with second ND-FNAB were cystic component more than 50%, nodule size more than 5 mm, hypoechoic nodules, and macrocalcification in nodules [18]. Thus, persistent evaluation of initially nondiagnostic thyroid nodules is mandated and should be pursued promptly. 5. Conclusion Nondiagnostic cytology in repeated FNABs remains a significant problem in the evaluation of thyroid nodules for both physicians and patients. Despite US guidance, there is a 2% to 20% risk of initial nondiagnostic specimens. Patient with initial ND-FNAB should be assessed with repeated sampling or direct surgery. Decision of surgery is often compelling. The decision is affected by multiple factors such as nodule size; clinical and ultrasonographic features; clinical suspicion; and, finally, patient preferences. If the initial and second FNABs are nondiagnostic, we should consider surgery following the ATA/ European Thyroid Association/Associazione Medici Endocrologi/ American Association of Clinical Endocrinologist guidelines [2,10]. Nondiagnostic FNAB should not be considered benign. Reaspiration followed by surgery for appropriate patients is recommended. Competing interests The authors declare that they have no competing interests. Authors' contributions DO participated in the design of the study and performed the statistical analysis. RE conceived the study and participated in its design and coordination and helped draft the manuscript. All authors read and approved the manuscript.
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