Eur Radiol (2014) 24:1403–1409 DOI 10.1007/s00330-014-3123-z
HEAD AND NECK
Core needle biopsy can minimise the non-diagnostic results and need for diagnostic surgery in patients with calcified thyroid nodules Eun Ju Ha & Jung Hwan Baek & Jeong Hyun Lee & Jin Kyoung Kim & Jae Kyun Kim & Hyun Kyung Lim & Dong Eun Song & Tae Yon Sung & Tae Yong Kim & Won Bae Kim & Young Kee Shong
Received: 14 October 2013 / Revised: 31 January 2014 / Accepted: 11 February 2014 / Published online: 7 March 2014 # European Society of Radiology 2014
Abstract Purpose To evaluate the role of core needle biopsy (CNB) for calcified thyroid nodules. Methods Between October 2008 and July 2011, 264 patients underwent ultrasound-guided CNB for 272 calcified thyroid nodules at our institution. We retrospectively evaluated the incidence of technical failure, non-diagnostic readings, and the diagnostic performance of CNB, and analysed the E. J. Ha : J. H. Baek (*) : J. H. Lee : J. K. Kim : H. K. Lim Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea e-mail: [email protected] E. J. Ha Department of Radiology, Ajou University School of Medicine, Wonchon-Dong, Yeongtong-Gu, Suwon 443-380, Korea J. K. Kim Department of Radiology, Chung-Ang University College of Medicine, 224-1 Heukseokdong, Dongjak-gu, Seoul 156-755, Korea H. K. Lim Department of Radiology, Soonchunhyang University Hospital, 59, Daesagwan-Ro, Yongsan-Gu, Seoul 140-887, Korea D. E. Song Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea T. Y. Sung Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Republic of Korea T. Y. Kim : W. B. Kim : Y. K. Shong Department of Endocrinology and Metabolism, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Republic of Korea
relationship between the types of calcification and the CNB results. Finally, the incidence of diagnostic surgery was calculated. Results The incidence of technical failure was 1.1 % (3/275) and that of non-diagnostic results was 0.7 % (2/272). The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CNB were 94.7 %, 89.5 %, 100 %, 100 %, and 90.2 %, respectively. There were no significant differences according to the calcification subtype for either the non-diagnostic results or the incidence of technical failure (P>0.99 and P>0.99). CNB could prevent diagnostic surgery for 92.9 % (13/14) of the patients who showed more than two non-diagnostic results in previous FNA. Conclusions CNB can minimise the non-diagnostic results as well as diagnostic surgery in patients with calcified thyroid nodules. Therefore, CNB may be used as a first-line diagnostic tool for calcified thyroid nodules rather than FNA. Key points • CNB results show the low incidence of technical failure (1.1 %, 3/275). • CNB results show the low non-diagnostic rate (0.7 %, 2/272). • There were no significant differences according to the calcification subtype. • CNB can prevent unnecessary diagnostic surgery in 92.9 % (13/14).
Keywords Core needle biopsy . Calcification . Non-diagnostic results . Fine-needle aspiration
Abbreviations US ultrasound FNA fine-needle aspiration CNB core-needle biopsy
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Introduction Ultrasound (US)-guided fine-needle aspiration (FNA) is a safe and accurate method for diagnosing thyroid nodules, although approximately 10–33.6 % of FNA procedures produce nondiagnostic results [5, 6]. Several factors are related to the nondiagnostic FNA results, and calcification is one of the wellknown factors related to a non-diagnostic FNA result [2]. The current guidelines recommend repeat FNA for thyroid nodules with previous, non-diagnostic FNA results [5, 6, 15]. However, after an initial non-diagnostic result, repeat FNA still has 9.9 % to 47.8 % non-diagnostic results [17, 26]. For patients with repeated, non-diagnostic FNA results, diagnostic surgery is recommended according to the current guidelines [5, 6]. Recently, the use of core-needle biopsy (CNB) has been suggested in order to reduce the need for diagnostic surgery in patients with non-diagnostic FNA results [26]. CNB has also been suggested to be more useful than repeat FNA for thyroid nodules with previously non-diagnostic results [17, 22]. Ha et al. also suggested that calcified thyroid nodules should be re-biopsied because of the high incidence of cancer detected by CNB, regardless of the initial, benign FNA results [7]. Although CNB was recommended for patients with insufficient FNA results, to our knowledge, there has been no report that verified the role of CNB for calcified thyroid nodules. Therefore, the purpose of this study is to evaluate the use of CNB for calcified thyroid nodules, focussing on reducing the non-diagnostic results as well as the need for diagnostic surgery.
Materials and methods Study population This retrospective study was approved by the institutional review board of Asan Medical Centre and required neither patient permission nor informed consent for review of the images and/or medical records. However, informed consent for CNB was obtained from all patients prior to biopsy. Between October 2008 and July 2011, US-guided CNB was performed at our institution for 600 thyroid nodules from 587 patients. Among these patients, 264 (mean age, 51.6 years; range, 18–79 years, male:female=64:200) with 272 calcified thyroid nodules were enrolled in this study. However, three patients were excluded from the study because of technical failures that did not allow tissue to be obtained. Final diagnoses were obtained for 206 nodules (105 malignant and 101 benign nodules). All of the malignant nodules (n=105) were diagnosed based on the histopathological results obtained after surgical resection. For the benign nodules (n=101), the final diagnosis was based on the histopathological results obtained following surgical resection (n=13,
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12.9 %), on the repeated benign cytology results of FNA and/or CNB procedures that had been performed at least twice (n=46, 45.5 %) or on the benign results of CNB or FNAwith a stable size seen on US after a 1-year follow-up period (n=42, 41.6 %). Final diagnosis of benign nodules with repeated benign cytopathology (n=46) was based on repeated FNA (n=20), repeated CNB (n=21) or both (n=5). Ultrasound-guided CNB procedures US examinations were performed using one of three US systems: an iU22 or HDI-5000 unit (Philips Healthcare, Bothell, WA) or an EUB-7500 unit (Hitachi Medical Systems, Tokyo, Japan). Each system was equipped with a linear, high-frequency probe (5–14 MHz). All US examinations and US-guided biopsy procedures were performed by one of four radiologists (JHB, JHL, HKL and EJH) with 16, 11 and 7 years of clinical experience, respectively, performing and evaluating thyroid US images. US-guided CNBs were performed using a disposable 1.1or 1.6-cm excursion, 18-gauge double-action spring-activated needle (TSK Ace-cut; Create Medic, Yokohama, Japan) and using the trans-isthmic approach method [7, 17, 18, 25, 26]. Before inserting the core needle, the power Doppler US was applied to evaluate the vessels in order to minimise haemorrhage. Using a freehand technique, the core needle was advanced from the isthmus toward the calcified nodules. After the tip of the core needle had been advanced into the calcified nodule, the firing distance (1.1 or 1.6 cm) was measured before sequential firing of the stylet and cutting cannula [7, 26] (Fig. 1 a-c). The procedure was continuously monitored using real-time US, and the adequacy of the obtained tissue was assessed using visual inspection [17, 25, 26] (Fig. 1d). Additional CNB was performed when the lesion targeting was considered to have been inaccurate. Each patient was observed after firm, local compression of the biopsy site for 10–20 min following the biopsy. If a patient complained of pain or neck swelling, a repeat US examination was performed to evaluate possible complications [7, 26]. Analysis of the US findings The US images were reviewed independently by two radiologists (EJH and JHB). Neither had any information regarding a patient’s clinical history, previous imaging results or histological results. Discrepancies in the US findings between the two investigators were resolved by consensus. The following US features were evaluated: the largest diameter, internal contents (solid, predominantly solid, predominantly cystic or cystic), shape (oval to round, irregular or taller than wide), margins (smooth, ill-defined or spiculated), echogenicity (hyperechoic, isoechoic, hypoechoic or marked
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Fig. 1 Core needle biopsy procedure performed for a calcified thyroid nodule. After insertion of the core needle into the thyroid gland, the distance of the firing (1.1 cm) from the tip of the needle (arrow) to the thyroid nodule was measured (a). We then sequentially fired the stylet (b) and the cutting cannula (c). Visual assessment of the biopsied material showed a sufficient amount of specimen (d). The red portion is true nodule tissue, and the white area is a mixture of calcification and fibrosis
hypoechoic) and the presence of micro-, rim or macrocalcifications. Thyroid nodules with more than one of these US features were used to diagnose malignancy, as described in previous studies [12, 15], i.e., a taller than wide shape, spiculated margin, marked hypoechogenicity, and macro- or micro-calcification [16]. The calcification patterns were classified into four categories (Fig. 2): microcalcification, incomplete macrocalcification, complete macrocalcification and rim calcification. Microcalcifications are defined as punctuate echogenic foci less than 1 mm [16]. Macrocalcifications were defined as punctuate echogenic foci larger than 1 mm in size. Incomplete macrocalcifications were defined as thick and peripheral calcifications as less than 50 % of the nodule margin. Complete macrocalcification involved more than 50 % of the nodule margin. Rim calcifications were defined as thickening less than 0.5 mm over more than 50 % of the circumference of the nodule or visibility of a large calcification only without the ability to interpret the tumour according to its acoustic shadowing [11, 15, 16]. Analysis of the CNB results All CNB specimens were reviewed by experienced pathologists. Given that the diagnostic criteria for CNB of thyroid nodules have not been standardised [17, 26], CNB readings were classified into the six categories of the Bethesda System according to the histologic results obtained in our study [1, 4,
26]. A non-diagnostic CNB reading included the absence of any identifiable follicular thyroid tissue, the presence of only a normal thyroid gland, and tissue containing only a few follicular cells and therefore insufficient for diagnosis [17]. Benign CNB readings included colloid nodules, nodular hyperplasia and lymphocytic thyroiditis. Atypia (or a follicular lesion) of undetermined significance in the CNB reading included nodules in which some atypical cells and/or a microfollicular pattern was present but was not diagnostic of follicular neoplasm, suspicious malignancy or malignancy. Nodules with histological features favouring follicular neoplasm were categorised as “suspicious for follicular neoplasm or follicular neoplasm”. The “suspicious for malignancy” CNB readings were assigned when the specimen exhibited atypia but there was insufficient evidence for malignancy. The “malignancy” CNB reading was assigned when a specimen exhibited unequivocal features of cancer [4, 17, 25]. Statistical analysis Statistical analysis was performed using the SPSS version 19.0 software package for Windows (SPSS, Chicago, IL, USA). The incidence of any technical failure of the CNB was evaluated. Technical failure was defined as failure to puncture a calcified nodule due to its hardness caused by calcification. The incidence of non-diagnostic results was also evaluated. The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of
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Fig. 2 Four types of calcifications: (a) microcalcification, (b) macroincomplete, (c) macro-complete and (d) rim calcification
CNB for the diagnosis of thyroid malignancy were then calculated. Positive CNB results for detecting malignancy were defined as such when they were categorised as suspicious for malignancy or malignancy, and negative CNB results for detecting malignancy were defined as being categorised as the others. The CNB results were compared with the surgical results. The percentage of diagnostic surgeries was calculated in order to evaluate whether CNB could prevent the need for diagnostic surgery for patients whose nodules showed more than twice the non-diagnostic results seen on FNA. The relationship between the types of calcification and the CNB results, i.e. non-diagnostic result and technical failure, were analysed using Fisher's exact test.
CNB specimens. These results suggested mis-targeted biopsies. The largest diameters of these two nodules were 0.5 and 0.6 cm.
Diagnostic value of US-guided CNB The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of CNB for the detection of malignancy in calcified thyroid nodules were 94.7 % (195/206), 89.5 % (94/105), 100 % (101/101), 100 % (94/94) and 90.2 % (101/112), respectively.
Table 1 CNB results and the final diagnoses in thyroid nodules with calcifications
Results In all patients, the targeting of thyroid nodules was available, except for three patients with technical failure (1.1 %, 3/275). All three technical failures were caused by complete macrocalcification. The biopsy procedures were well tolerated in all patients, and the mean number of tissue cores obtained by CNB during one session was 1.3 (range, 1–3). Sample adequacy The CNB results (n=272) and final diagnosis (n=206) are summarised in Table 1. The incidence of non-diagnostic results was 0.7 % (2/272). Two non-diagnostic patients showed the presence of muscle tissue and normal thyroid tissue in
CNB resultsa
Total CNB Final diagnosis (n=206) (n=272) Benign Malignant (n=101) (n=105)
Nondiagnostic 2 (0.7) 1 (1) Benign 117 (43) 81 (80.2) Atypia of undetermined 25 (9.2) 14 (13.9) significance Follicular neoplasm or 12 (4.4) 5 (4.9) suspicious follicular neoplasm Suspicious for malignancy 9 (3.3) 0 (0) Malignancy 107 (39.3) 0 (0)
1 (1) 3 (2.8) 1 (1) 6 (5.7) 7 (6.7) 87 (82.8)
Data indicate the number of nodules, with the percentage indicated in parentheses. CNB core needle biopsy a
CNB results classified according to the Bethesda system
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Correlation of CNB results with surgery A comparison of the CNB results with those of surgery is summarised in Table 2. Surgery was performed for 118 nodules and determined that 105 nodules were malignant and 13 benign. All 94 nodules with Bethesda classification 5 and 6 (suspicious for malignancy or malignant) after CNB were confirmed as malignancies at surgery. Therefore, the positive predictive rate for malignancy was 100 % (94/94). Among the 12 nodules with Bethesda classification 4 (follicular neoplasm or suspicious follicular neoplasm) after CNB, surgery was carried out on 11. The histological results of these 11 nodules indicated one adenomatous hyperplasia, one Hurthle cell adenoma, three follicular adenomas and six follicular carcinomas. Surgery was performed for 11 patients with non-diagnostic (n=1) and benign (n=10) CNB results. One patient with a non-diagnostic CNB result had a pathologically confirmed metastatic lymph node and therefore, underwent surgery, which revealed papillary carcinomas with lymph node metastasis. Among the 117 nodules with benign CNB results, surgery was performed for 10. The decision to perform surgery was based on the fact that there were thyroid cancers in the other anatomical areas (n=3), for associated cosmetic reasons (n=3) or because of suspicious US findings (n=3) or lymph node metastasis (n=1). Of the ten surgically removed nodules, three were papillary carcinomas. All of them were related to the last two reasons for a surgical confirmation
Table 2 Comparison of the results of CNB and surgery in 118 thyroid nodules CNB
Surgical diagnosis
Diagnosis
No. of nodules
Nondiagnostic Benign
1 10
Atypia of undetermined significance Follicular neoplasm
Suspicious for malignancy Malignancy
2 11
7 87
1: Papillary microcarcinoma 3: Papillary microcarcinoma 1: Focal thyroiditis 6: Adenomatous hyperplasia 1: Papillary carcinoma 1: Adenomatous hyperplasia 1: Adenomatous hyperplasia 1: Hurthle cell adenoma 3: Follicular adenoma 6: Follicular carcinoma 7: Papillary carcinoma 1: Metastatic squamous cell carcinoma 1: Medullary carcinoma 2: Anaplastic carcinoma 83: Papillary carcinoma
[suspicious US findings (n=2) or lymph node metastasis (n=1)]. Diagnostic surgery Table 3 shows the final diagnoses of the 15 candidates for diagnostic surgery (more than twice the non-diagnostic results seen on previous FNA), and of the 15 nodules, surgery was performed on 2. In one patient, the purpose of the surgery was therapeutic because of the malignant CNB results, whereas in another case, we performed diagnostic surgery because of the malignant US findings. Therefore, CNB was able to prevent unnecessary diagnostic surgery for 92.9 % (13/14, except one patient with malignancy in CNB) of the patients. Sonographic findings The largest diameter of the thyroid nodules ranged from 3 to 70 mm (median, 15.1 mm). There were 263 (96.7 %) solid nodules, 8 (2.9 %) predominantly solid nodules and 1 (0.4 %) predominantly cystic nodule. Regarding the types of calcification, 84 nodules had microcalcification and 188 had macrocalcification (148 had incomplete macrocalcification, 31 had complete macrocalcification and 9 had rim calcification). Two nodules with nondiagnostic CNB results showed one (0.5 cm) with microcalcification and the other (0.6 cm) with macro-incomplete calcification. There were three nodules in which we experienced technical failure. There were no significant statistical differences according to the subtype of the calcification for either the non-diagnostic results or the technical failure (P>0.99 and P>0.99, respectively). Complications There were no complications associated with intervention or hospitalisation in our patient cohort. Three patients showed minor complications, i.e. one patient had thyroid parenchymal oedema, one had perithyroidal haematoma, and one had both Table 3 Final diagnosis of the 15 candidates for diagnostic surgery CNB Diagnosis
No. of nodules
Non-diagnostica Malignant Benign FLUS
1 1 12 1
Papillary carcinoma Papillary carcinoma -
CNB core needle biopsy, FLUS follicular lesion of undetermined significance a
CNB core needle biopsy
Final diagnosis
CNB results showed normal thyroid tissue due to mis-targeted biopsy; however, the patient underwent surgery because of malignant US features
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thyroid parenchymal oedema and perithyroidal haematoma. Their symptoms were relieved after neck compression for 1 h.
Discussion This study demonstrated that CNB procedures were tolerated by all of our study patients. Our results show a low incidence of technical failure (1.1 %, 3/275) and a non-diagnostic rate (0.7 %, 2/272). There were also no significant differences according to the calcification subtype for either nondiagnostic results or technical failure. These results indicate that CNB can effectively obtain tissue from calcified thyroid nodules and can thus prevent unnecessary diagnostic surgery in 92.9 % (13/14) of patients whose FNA results showed repeated non-diagnostic results after two separate FNAs. The diagnostic accuracy of CNB for the detection of malignancy was 94.7 %, and there were no major complications. Regarding the FNA results for calcified thyroid nodules, the non-diagnostic results ranged from 6.4 % to 17.2 %; however, thyroid nodules with macrocalcification (including rim calcification) showed a slightly higher non-diagnostic rate up to 21.3 % [2, 3, 13, 27, 28]. Choi et al. [2] reported a large population FNA study with 1,122 calcified thyroid nodules. Their results showed calcification to be a significant factor related to non-diagnostic FNA results. Thyroid nodules with macrocalcification also showed a significantly higher nondiagnostic rate than those with microcalcification (21.3 % versus 11.9 %, P
HEAD AND NECK
Core needle biopsy can minimise the non-diagnostic results and need for diagnostic surgery in patients with calcified thyroid nodules Eun Ju Ha & Jung Hwan Baek & Jeong Hyun Lee & Jin Kyoung Kim & Jae Kyun Kim & Hyun Kyung Lim & Dong Eun Song & Tae Yon Sung & Tae Yong Kim & Won Bae Kim & Young Kee Shong
Received: 14 October 2013 / Revised: 31 January 2014 / Accepted: 11 February 2014 / Published online: 7 March 2014 # European Society of Radiology 2014
Abstract Purpose To evaluate the role of core needle biopsy (CNB) for calcified thyroid nodules. Methods Between October 2008 and July 2011, 264 patients underwent ultrasound-guided CNB for 272 calcified thyroid nodules at our institution. We retrospectively evaluated the incidence of technical failure, non-diagnostic readings, and the diagnostic performance of CNB, and analysed the E. J. Ha : J. H. Baek (*) : J. H. Lee : J. K. Kim : H. K. Lim Department of Radiology and Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea e-mail: [email protected] E. J. Ha Department of Radiology, Ajou University School of Medicine, Wonchon-Dong, Yeongtong-Gu, Suwon 443-380, Korea J. K. Kim Department of Radiology, Chung-Ang University College of Medicine, 224-1 Heukseokdong, Dongjak-gu, Seoul 156-755, Korea H. K. Lim Department of Radiology, Soonchunhyang University Hospital, 59, Daesagwan-Ro, Yongsan-Gu, Seoul 140-887, Korea D. E. Song Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Korea T. Y. Sung Department of Surgery, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Republic of Korea T. Y. Kim : W. B. Kim : Y. K. Shong Department of Endocrinology and Metabolism, University of Ulsan College of Medicine, Asan Medical Center, 86 Asanbyeongwon-Gil, Songpa-Gu, Seoul 138-736, Republic of Korea
relationship between the types of calcification and the CNB results. Finally, the incidence of diagnostic surgery was calculated. Results The incidence of technical failure was 1.1 % (3/275) and that of non-diagnostic results was 0.7 % (2/272). The diagnostic accuracy, sensitivity, specificity, positive predictive value, and negative predictive value of CNB were 94.7 %, 89.5 %, 100 %, 100 %, and 90.2 %, respectively. There were no significant differences according to the calcification subtype for either the non-diagnostic results or the incidence of technical failure (P>0.99 and P>0.99). CNB could prevent diagnostic surgery for 92.9 % (13/14) of the patients who showed more than two non-diagnostic results in previous FNA. Conclusions CNB can minimise the non-diagnostic results as well as diagnostic surgery in patients with calcified thyroid nodules. Therefore, CNB may be used as a first-line diagnostic tool for calcified thyroid nodules rather than FNA. Key points • CNB results show the low incidence of technical failure (1.1 %, 3/275). • CNB results show the low non-diagnostic rate (0.7 %, 2/272). • There were no significant differences according to the calcification subtype. • CNB can prevent unnecessary diagnostic surgery in 92.9 % (13/14).
Keywords Core needle biopsy . Calcification . Non-diagnostic results . Fine-needle aspiration
Abbreviations US ultrasound FNA fine-needle aspiration CNB core-needle biopsy
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Introduction Ultrasound (US)-guided fine-needle aspiration (FNA) is a safe and accurate method for diagnosing thyroid nodules, although approximately 10–33.6 % of FNA procedures produce nondiagnostic results [5, 6]. Several factors are related to the nondiagnostic FNA results, and calcification is one of the wellknown factors related to a non-diagnostic FNA result [2]. The current guidelines recommend repeat FNA for thyroid nodules with previous, non-diagnostic FNA results [5, 6, 15]. However, after an initial non-diagnostic result, repeat FNA still has 9.9 % to 47.8 % non-diagnostic results [17, 26]. For patients with repeated, non-diagnostic FNA results, diagnostic surgery is recommended according to the current guidelines [5, 6]. Recently, the use of core-needle biopsy (CNB) has been suggested in order to reduce the need for diagnostic surgery in patients with non-diagnostic FNA results [26]. CNB has also been suggested to be more useful than repeat FNA for thyroid nodules with previously non-diagnostic results [17, 22]. Ha et al. also suggested that calcified thyroid nodules should be re-biopsied because of the high incidence of cancer detected by CNB, regardless of the initial, benign FNA results [7]. Although CNB was recommended for patients with insufficient FNA results, to our knowledge, there has been no report that verified the role of CNB for calcified thyroid nodules. Therefore, the purpose of this study is to evaluate the use of CNB for calcified thyroid nodules, focussing on reducing the non-diagnostic results as well as the need for diagnostic surgery.
Materials and methods Study population This retrospective study was approved by the institutional review board of Asan Medical Centre and required neither patient permission nor informed consent for review of the images and/or medical records. However, informed consent for CNB was obtained from all patients prior to biopsy. Between October 2008 and July 2011, US-guided CNB was performed at our institution for 600 thyroid nodules from 587 patients. Among these patients, 264 (mean age, 51.6 years; range, 18–79 years, male:female=64:200) with 272 calcified thyroid nodules were enrolled in this study. However, three patients were excluded from the study because of technical failures that did not allow tissue to be obtained. Final diagnoses were obtained for 206 nodules (105 malignant and 101 benign nodules). All of the malignant nodules (n=105) were diagnosed based on the histopathological results obtained after surgical resection. For the benign nodules (n=101), the final diagnosis was based on the histopathological results obtained following surgical resection (n=13,
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12.9 %), on the repeated benign cytology results of FNA and/or CNB procedures that had been performed at least twice (n=46, 45.5 %) or on the benign results of CNB or FNAwith a stable size seen on US after a 1-year follow-up period (n=42, 41.6 %). Final diagnosis of benign nodules with repeated benign cytopathology (n=46) was based on repeated FNA (n=20), repeated CNB (n=21) or both (n=5). Ultrasound-guided CNB procedures US examinations were performed using one of three US systems: an iU22 or HDI-5000 unit (Philips Healthcare, Bothell, WA) or an EUB-7500 unit (Hitachi Medical Systems, Tokyo, Japan). Each system was equipped with a linear, high-frequency probe (5–14 MHz). All US examinations and US-guided biopsy procedures were performed by one of four radiologists (JHB, JHL, HKL and EJH) with 16, 11 and 7 years of clinical experience, respectively, performing and evaluating thyroid US images. US-guided CNBs were performed using a disposable 1.1or 1.6-cm excursion, 18-gauge double-action spring-activated needle (TSK Ace-cut; Create Medic, Yokohama, Japan) and using the trans-isthmic approach method [7, 17, 18, 25, 26]. Before inserting the core needle, the power Doppler US was applied to evaluate the vessels in order to minimise haemorrhage. Using a freehand technique, the core needle was advanced from the isthmus toward the calcified nodules. After the tip of the core needle had been advanced into the calcified nodule, the firing distance (1.1 or 1.6 cm) was measured before sequential firing of the stylet and cutting cannula [7, 26] (Fig. 1 a-c). The procedure was continuously monitored using real-time US, and the adequacy of the obtained tissue was assessed using visual inspection [17, 25, 26] (Fig. 1d). Additional CNB was performed when the lesion targeting was considered to have been inaccurate. Each patient was observed after firm, local compression of the biopsy site for 10–20 min following the biopsy. If a patient complained of pain or neck swelling, a repeat US examination was performed to evaluate possible complications [7, 26]. Analysis of the US findings The US images were reviewed independently by two radiologists (EJH and JHB). Neither had any information regarding a patient’s clinical history, previous imaging results or histological results. Discrepancies in the US findings between the two investigators were resolved by consensus. The following US features were evaluated: the largest diameter, internal contents (solid, predominantly solid, predominantly cystic or cystic), shape (oval to round, irregular or taller than wide), margins (smooth, ill-defined or spiculated), echogenicity (hyperechoic, isoechoic, hypoechoic or marked
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Fig. 1 Core needle biopsy procedure performed for a calcified thyroid nodule. After insertion of the core needle into the thyroid gland, the distance of the firing (1.1 cm) from the tip of the needle (arrow) to the thyroid nodule was measured (a). We then sequentially fired the stylet (b) and the cutting cannula (c). Visual assessment of the biopsied material showed a sufficient amount of specimen (d). The red portion is true nodule tissue, and the white area is a mixture of calcification and fibrosis
hypoechoic) and the presence of micro-, rim or macrocalcifications. Thyroid nodules with more than one of these US features were used to diagnose malignancy, as described in previous studies [12, 15], i.e., a taller than wide shape, spiculated margin, marked hypoechogenicity, and macro- or micro-calcification [16]. The calcification patterns were classified into four categories (Fig. 2): microcalcification, incomplete macrocalcification, complete macrocalcification and rim calcification. Microcalcifications are defined as punctuate echogenic foci less than 1 mm [16]. Macrocalcifications were defined as punctuate echogenic foci larger than 1 mm in size. Incomplete macrocalcifications were defined as thick and peripheral calcifications as less than 50 % of the nodule margin. Complete macrocalcification involved more than 50 % of the nodule margin. Rim calcifications were defined as thickening less than 0.5 mm over more than 50 % of the circumference of the nodule or visibility of a large calcification only without the ability to interpret the tumour according to its acoustic shadowing [11, 15, 16]. Analysis of the CNB results All CNB specimens were reviewed by experienced pathologists. Given that the diagnostic criteria for CNB of thyroid nodules have not been standardised [17, 26], CNB readings were classified into the six categories of the Bethesda System according to the histologic results obtained in our study [1, 4,
26]. A non-diagnostic CNB reading included the absence of any identifiable follicular thyroid tissue, the presence of only a normal thyroid gland, and tissue containing only a few follicular cells and therefore insufficient for diagnosis [17]. Benign CNB readings included colloid nodules, nodular hyperplasia and lymphocytic thyroiditis. Atypia (or a follicular lesion) of undetermined significance in the CNB reading included nodules in which some atypical cells and/or a microfollicular pattern was present but was not diagnostic of follicular neoplasm, suspicious malignancy or malignancy. Nodules with histological features favouring follicular neoplasm were categorised as “suspicious for follicular neoplasm or follicular neoplasm”. The “suspicious for malignancy” CNB readings were assigned when the specimen exhibited atypia but there was insufficient evidence for malignancy. The “malignancy” CNB reading was assigned when a specimen exhibited unequivocal features of cancer [4, 17, 25]. Statistical analysis Statistical analysis was performed using the SPSS version 19.0 software package for Windows (SPSS, Chicago, IL, USA). The incidence of any technical failure of the CNB was evaluated. Technical failure was defined as failure to puncture a calcified nodule due to its hardness caused by calcification. The incidence of non-diagnostic results was also evaluated. The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of
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Fig. 2 Four types of calcifications: (a) microcalcification, (b) macroincomplete, (c) macro-complete and (d) rim calcification
CNB for the diagnosis of thyroid malignancy were then calculated. Positive CNB results for detecting malignancy were defined as such when they were categorised as suspicious for malignancy or malignancy, and negative CNB results for detecting malignancy were defined as being categorised as the others. The CNB results were compared with the surgical results. The percentage of diagnostic surgeries was calculated in order to evaluate whether CNB could prevent the need for diagnostic surgery for patients whose nodules showed more than twice the non-diagnostic results seen on FNA. The relationship between the types of calcification and the CNB results, i.e. non-diagnostic result and technical failure, were analysed using Fisher's exact test.
CNB specimens. These results suggested mis-targeted biopsies. The largest diameters of these two nodules were 0.5 and 0.6 cm.
Diagnostic value of US-guided CNB The diagnostic accuracy, sensitivity, specificity, positive predictive value and negative predictive value of CNB for the detection of malignancy in calcified thyroid nodules were 94.7 % (195/206), 89.5 % (94/105), 100 % (101/101), 100 % (94/94) and 90.2 % (101/112), respectively.
Table 1 CNB results and the final diagnoses in thyroid nodules with calcifications
Results In all patients, the targeting of thyroid nodules was available, except for three patients with technical failure (1.1 %, 3/275). All three technical failures were caused by complete macrocalcification. The biopsy procedures were well tolerated in all patients, and the mean number of tissue cores obtained by CNB during one session was 1.3 (range, 1–3). Sample adequacy The CNB results (n=272) and final diagnosis (n=206) are summarised in Table 1. The incidence of non-diagnostic results was 0.7 % (2/272). Two non-diagnostic patients showed the presence of muscle tissue and normal thyroid tissue in
CNB resultsa
Total CNB Final diagnosis (n=206) (n=272) Benign Malignant (n=101) (n=105)
Nondiagnostic 2 (0.7) 1 (1) Benign 117 (43) 81 (80.2) Atypia of undetermined 25 (9.2) 14 (13.9) significance Follicular neoplasm or 12 (4.4) 5 (4.9) suspicious follicular neoplasm Suspicious for malignancy 9 (3.3) 0 (0) Malignancy 107 (39.3) 0 (0)
1 (1) 3 (2.8) 1 (1) 6 (5.7) 7 (6.7) 87 (82.8)
Data indicate the number of nodules, with the percentage indicated in parentheses. CNB core needle biopsy a
CNB results classified according to the Bethesda system
Eur Radiol (2014) 24:1403–1409
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Correlation of CNB results with surgery A comparison of the CNB results with those of surgery is summarised in Table 2. Surgery was performed for 118 nodules and determined that 105 nodules were malignant and 13 benign. All 94 nodules with Bethesda classification 5 and 6 (suspicious for malignancy or malignant) after CNB were confirmed as malignancies at surgery. Therefore, the positive predictive rate for malignancy was 100 % (94/94). Among the 12 nodules with Bethesda classification 4 (follicular neoplasm or suspicious follicular neoplasm) after CNB, surgery was carried out on 11. The histological results of these 11 nodules indicated one adenomatous hyperplasia, one Hurthle cell adenoma, three follicular adenomas and six follicular carcinomas. Surgery was performed for 11 patients with non-diagnostic (n=1) and benign (n=10) CNB results. One patient with a non-diagnostic CNB result had a pathologically confirmed metastatic lymph node and therefore, underwent surgery, which revealed papillary carcinomas with lymph node metastasis. Among the 117 nodules with benign CNB results, surgery was performed for 10. The decision to perform surgery was based on the fact that there were thyroid cancers in the other anatomical areas (n=3), for associated cosmetic reasons (n=3) or because of suspicious US findings (n=3) or lymph node metastasis (n=1). Of the ten surgically removed nodules, three were papillary carcinomas. All of them were related to the last two reasons for a surgical confirmation
Table 2 Comparison of the results of CNB and surgery in 118 thyroid nodules CNB
Surgical diagnosis
Diagnosis
No. of nodules
Nondiagnostic Benign
1 10
Atypia of undetermined significance Follicular neoplasm
Suspicious for malignancy Malignancy
2 11
7 87
1: Papillary microcarcinoma 3: Papillary microcarcinoma 1: Focal thyroiditis 6: Adenomatous hyperplasia 1: Papillary carcinoma 1: Adenomatous hyperplasia 1: Adenomatous hyperplasia 1: Hurthle cell adenoma 3: Follicular adenoma 6: Follicular carcinoma 7: Papillary carcinoma 1: Metastatic squamous cell carcinoma 1: Medullary carcinoma 2: Anaplastic carcinoma 83: Papillary carcinoma
[suspicious US findings (n=2) or lymph node metastasis (n=1)]. Diagnostic surgery Table 3 shows the final diagnoses of the 15 candidates for diagnostic surgery (more than twice the non-diagnostic results seen on previous FNA), and of the 15 nodules, surgery was performed on 2. In one patient, the purpose of the surgery was therapeutic because of the malignant CNB results, whereas in another case, we performed diagnostic surgery because of the malignant US findings. Therefore, CNB was able to prevent unnecessary diagnostic surgery for 92.9 % (13/14, except one patient with malignancy in CNB) of the patients. Sonographic findings The largest diameter of the thyroid nodules ranged from 3 to 70 mm (median, 15.1 mm). There were 263 (96.7 %) solid nodules, 8 (2.9 %) predominantly solid nodules and 1 (0.4 %) predominantly cystic nodule. Regarding the types of calcification, 84 nodules had microcalcification and 188 had macrocalcification (148 had incomplete macrocalcification, 31 had complete macrocalcification and 9 had rim calcification). Two nodules with nondiagnostic CNB results showed one (0.5 cm) with microcalcification and the other (0.6 cm) with macro-incomplete calcification. There were three nodules in which we experienced technical failure. There were no significant statistical differences according to the subtype of the calcification for either the non-diagnostic results or the technical failure (P>0.99 and P>0.99, respectively). Complications There were no complications associated with intervention or hospitalisation in our patient cohort. Three patients showed minor complications, i.e. one patient had thyroid parenchymal oedema, one had perithyroidal haematoma, and one had both Table 3 Final diagnosis of the 15 candidates for diagnostic surgery CNB Diagnosis
No. of nodules
Non-diagnostica Malignant Benign FLUS
1 1 12 1
Papillary carcinoma Papillary carcinoma -
CNB core needle biopsy, FLUS follicular lesion of undetermined significance a
CNB core needle biopsy
Final diagnosis
CNB results showed normal thyroid tissue due to mis-targeted biopsy; however, the patient underwent surgery because of malignant US features
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thyroid parenchymal oedema and perithyroidal haematoma. Their symptoms were relieved after neck compression for 1 h.
Discussion This study demonstrated that CNB procedures were tolerated by all of our study patients. Our results show a low incidence of technical failure (1.1 %, 3/275) and a non-diagnostic rate (0.7 %, 2/272). There were also no significant differences according to the calcification subtype for either nondiagnostic results or technical failure. These results indicate that CNB can effectively obtain tissue from calcified thyroid nodules and can thus prevent unnecessary diagnostic surgery in 92.9 % (13/14) of patients whose FNA results showed repeated non-diagnostic results after two separate FNAs. The diagnostic accuracy of CNB for the detection of malignancy was 94.7 %, and there were no major complications. Regarding the FNA results for calcified thyroid nodules, the non-diagnostic results ranged from 6.4 % to 17.2 %; however, thyroid nodules with macrocalcification (including rim calcification) showed a slightly higher non-diagnostic rate up to 21.3 % [2, 3, 13, 27, 28]. Choi et al. [2] reported a large population FNA study with 1,122 calcified thyroid nodules. Their results showed calcification to be a significant factor related to non-diagnostic FNA results. Thyroid nodules with macrocalcification also showed a significantly higher nondiagnostic rate than those with microcalcification (21.3 % versus 11.9 %, P
