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Acta Radiol OnlineFirst, published on September 17, 2014 as doi:10.1177/0284185114549225
Original Article
The ultrasonography features of hyalinizing trabecular tumor of the thyroid gland and the role of fine needle aspiration cytology and core needle biopsy in its diagnosis
Acta Radiologica 0(0) 1–6 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185114549225 acr.sagepub.com
Woo Jung Choi1, Jung Hwan Baek1, Eun Ju Ha1,2, Young Jun Choi1, Min Ji Hong1, Dong Eun Song3, Jin Yong Sung4, Hyunju Yoo5, So Lyung Jung6, Ha Young Lee7 and Jeong Hyun Lee1
Abstract Background: Hyalinizing trabecular tumor (HTT) of the thyroid gland is a rare, benign neoplasm of follicular cell origin. Misdiagnosis of HTT as either papillary or medullary thyroid carcinoma after fine-needle aspiration (FNA) may lead to unnecessary surgery. Purpose: To evaluate the ultrasonography (US) findings of HTT of the thyroid gland and the role of FNA cytology and core needle biopsy (CNB) in its diagnosis. Material and Methods: Data from 24 patients with a histopathological diagnosis of HTT between January 2000 and May 2013 were retrospectively analyzed. US findings were categorized according to shape, margin, orientation, echogenicity, composition, calcification, and vascularity. Cytologic and histologic results of FNA, CNB, and surgery were reviewed. Results: US revealed the following tumor features: oval-to-round (24/24), solid (22/24), smooth margin (21/24), hypoechoic or marked hypoechogenicity (18/24), and peri- and/or intranodular vascularity (17/17). Malignant US features such as marked hypoechogenicity (n ¼ 7) and a spiculated margin (n ¼ 3) were also observed. Final confirmation was by surgery in 22 patients and by CNB in two patients. All 19 patients who underwent FNA were initially misdiagnosed, including 12 with malignancies and five with atypia of undetermined significance. All four patients who underwent CNB were correctly diagnosed with HTT. The histology of CNB specimens suggested HTT, which was confirmed by immunostaining of MIB-1. Conclusion: HTT should be suspected when the cytological diagnosis of papillary thyroid carcinoma is made after FNA without malignant US findings. CNB could prevent unnecessary surgery for HTT.
Keywords Hyalinizing trabecular tumor, thyroid, ultrasonography, core-needle biopsy, fine-needle aspiration Date received: 10 May 2014; accepted: 13 July 2014
1
Department of Radiology and the Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 2 Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea 3 Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 4 Department of Radiology, Thyroid Center, Daerim St. Mary’s Hospital, Seoul, Republic of Korea 5 Department of Pathology, Thyroid Center, Daerim St. Mary’s Hospital, Seoul, Republic of Korea
6 Department of Radiology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea 7 Department of Radiology, Inha University Hospital, Incheon, Republic of Korea
Corresponding author: Jung Hwan Baek, 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, Republic of Korea. Email: [email protected]
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Introduction Hyalinizing trabecular tumor (HTT) of the thyroid gland is a rare, benign neoplasm of follicular cell origin (1). This benign neoplasm shows histologic characteristics of a circumscribed or encapsulated, trabecular and alveolar architecture, consisting of polygonal spindle cells, intratrabecular hyaline, and colloid, and frequently shows vesicular nuclei with grooves, cytoplasmic inclusions, small nucleoli, occasional psammoma bodies, and infrequent mitoses (1). HTT is a rare and controversial lesion of the thyroid because of the disagreement regarding the nature of the tumor and the probability of misinterpreting the fine-needle aspiration (FNA) cytologic findings as papillary thyroid carcinoma (PTC) or medullary thyroid carcinoma (2,3). To date, only about 140 cases have been reported in the literature. The entity remains controversial as HTT may be regarded a variant of PTC as some similarities are noted in nuclear features (4,5). This misinterpretation may lead to unnecessary surgery (6). MIB-1 immunostaining and core-needle biopsy (CNB) have been proposed as alternatives for achieving a correct diagnosis (7–9). If FNA cytology suggests HTT, MIB-1 immunostaining can confirm a diagnosis of HTT; however, the majority of FNA cytology results do not suggest HTT (3,10). Previous studies have described the ultrasonography (US) findings of HTT (11,12). These studies attempted to validate an accurate diagnostic method for HTT, but only 10 cases were enrolled and the diagnosis remains unclear. The purpose of this study was to evaluate the ultrasonography (US) findings of HTT of the thyroid gland and the role of FNA cytology and CNB in its diagnosis.
21 women; age range, 23–58 years; mean age,SD, 52 15 years) were included in the study.
US examinations, US-guided FNA, CNB, and image analysis
This retrospective study was approved by the Institutional Review Boards for Human Investigation of all five participating institutions (Asan Medical Center, Seoul; St. Mary’s Hospital, Daerim; St. Mary’s Hospital, Inha University Hospital; and Ajou University Hospital). Informed consent was waived for the review of patients’ information, but was obtained from all patients prior to US or US-guided procedures.
US examinations were obtained using one of four US systems: an iU22 or HDI-5000 unit (Philips Healthcare, Bothell, WA, USA), or EUB-75 unit (Hitachi Medical Systems, Tokyo, Japan), or Aplio SSA-770A (Toshiba Medical Systems, Otawara-shi, Japan). Each was equipped with a linear highfrequency probe (5–14 MHz). US examinations were performed by radiologists and were supervised by one of five experienced thyroid radiologists with more than 7 years of experience. In all cases, the scanning protocol included both transverse and longitudinal real-time imaging of the thyroid nodules. Two radiologists (JHB and WJC) with 18 and 6 years of thyroid clinical expertise, respectively, reviewed the US images and all the images were adequate for review. Images were analyzed using criteria established by the Korean Society of Radiology (13). Information obtained from US included tumor shape (oval-to-round or irregular), margin (smooth, ill-defined, or spiculated/microlobulated), orientation (parallel or non-parallel), echogenicity (hyperechoic, isoechoic, hypoechoic, or markedly hypoechoic), composition (solid, predominantly solid, predominantly cystic, or cystic), calcification (presence or absence), and vascularity (grade 0, no vascularity; grade 1, perinodular vascularity only; grade 2, intranodular vascularity 50%). FNA or CNB were performed in all cases according to the recommendations of the Korean Society of Radiology (13). For FNA, a 21–25-gauge (G) needle was routinely used with a combination of capillary and aspiration techniques according to the nodule characteristics. CNB was performed using a disposable, 18-G, single- or double-action, spring-activated needle (1.1- or 1.6-cm excursion; TSK Ace-cut: Create Medic, Yokohama, Japan). Using a free-hand technique, the core needle was advanced from the isthmus of the thyroid, the biopsy needle tip was manually advanced to the margin or into the nodule, and the stylet and cutting cannula of the needle were fired sequentially (14).
Study population
Cytology, histology, and histopathological analysis
The electronic medical records at five hospitals were searched for patients with a final diagnosis of HTT of the thyroid gland between January 2000 and May 2013. During this period, 28 patients were diagnosed with HTT. Of these, four were excluded because US results were unavailable. Therefore, 24 patients (3 men,
Direct smears were made in all cases and were immediately fixed in 95% alcohol and stained with hematoxylin and eosin. The Papanicolaou stain was also applied. All biopsy specimens were fixed with 10% neutral buffered formalin and then routinely stained prior to histological examination. If HTT was suggested,
Material and Methods
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MIB-1 immunostaining was also performed after FNA or CNB. Formalin-fixed, paraffin-embedded tissue sections obtained after surgery were immunostained for MIB-1 using specific antibodies (DAKO, Glostrup, Denmark).
Results US imaging results The US results are summarized in Table 1. All nodules were oval-to-round, 87.5% (21/24) had a smooth margin, 75% (18/24) were hypoechoic or markedly hypoechoic, and 91.7% (22/24) were solid. Color Doppler US results were available for 17 patients, and all showed peri- and/or intranodular vascularity (Fig. 1). Seven patients had malignant US tumor features, such as marked hypoechogenicity (n ¼ 7) or a spiculated margin (n ¼ 3) (Fig. 2). None of the patients had a tumor with a taller-than-wide shape or calcification.
The mean nodule size was 19.9 12.3 mm (range, 5–52 mm).
FNA, CNB, and diagnostic accuracy Of the 24 study patients, 19 underwent FNA, and four underwent CNB. One patient underwent CNB after atypia of undetermined significance were identified upon previous FNA. Two patients were diagnosed via surgery without FNA or CNB. The initial cytopathological results from the 24 patients subsequently
Table 1. Ultrasonographic features of 24 patients with HTT of the thyroid. Characteristics Shape Oval-to-round Irregular Margin Smooth Ill-defined Spiculated or microlobulated Orientation Non-parallel Parallel Echogenicity Hyperechoic Isoechoic Hypoechoic Marked hypoechoic Composition Solid Predominantly solid Predominantly cystic or cystic Calcification Vascularity (n ¼ 17)* Grade 0 Grade 1 Grade 2 Grade 3 *Vascularity was evaluated in 17 nodules.
n
%
24 0
100 0
21 0 3 0 24
87.5 0 12.5 0 100
0 6 11 7
0 25 45.8 29.2
22 2 0 0
91.7 8.3 0 0
0 3 9 5
0 17.7 52.9 29.4
Fig. 1. HTT in a 54-year-old woman. Transverse (a) and longitudinal (b) ultrasonography images show a 2.2 cm, solid, oval, smooth, and hypoechoic mass without calcification. The nodule shows intranodular vascularity (c).
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Acta Radiologica 0(0) and subsequent MIB-1 immunostaining confirmed the diagnosis. Of the four patients who underwent CNB, two underwent diagnostic surgery but two avoided surgery.
Histopathologic results Histological analysis of the CNB biopsy specimens showed a thin capsule without capsular or vascular invasion, and trabecular architecture separated by minimal fibrous stroma. Intratrabecular hyalinization was prominent. Nuclei were round or oval with inconspicuous small nucleoli, frequent nuclear grooves, and less frequent intranuclear pseudo-inclusions. The membranes of tumor cells from CNB and surgical specimens were immunoreactive for MIB-1 (Fig. 3).
Discussion
Fig. 2. HTT in a 52-year-old woman. Transverse ultrasonography (a) image shows a 1.1 cm, solid, oval, spiculated, and marked hypoechoic mass with intranodular vascularity (b). US-guided CNB (c) correctly diagnosed it as a HTT.
diagnosed with HTT are summarized in Table 2. All 19 patients who underwent FNA were misdiagnosed, including 12 who were initially diagnosed with malignancies and five with atypia of undetermined significance. Four cases of HTT were correctly diagnosed via CNB. In these four cases, CNB suggested HTT
This study demonstrates that all 19 patients who underwent FNA had been incorrectly diagnosed. Of these, 58% (11/19) were initially classified as having PTC. However, only 29% (7/24) of the patients showed malignant US findings. A careful clinical approach may therefore be needed when the cytological diagnosis is PTC by FNA without malignant US findings. All four patients who underwent CNB were correctly diagnosed with HTT. CNB has been suggested as an alternative to FNA to reduce non-diagnostic and inconclusive results for suspected thyroid malignancies (8,14,15). Histological results from CNB specimens may suggest HTT, which is then confirmed by immunostaining for MIB-1. CNB can possibly reduce the risk of incorrect diagnosis of HTT and unnecessary surgery. In a previous study, HTT showed no malignant features in US images (11). Here, 70.8% (17/24) of HTT patients showed no malignancy, but seven tumors exhibited malignant US features such as marked hypoechogenicity and spiculated margins. However, no cases of HTT contained calcifications. Many cases of HTT are often misdiagnosed as PTC on FNA. Lee et al. (11) reported that all 10 of their FNA cases were reported as either suspicious for PTC or as PTC. In the current study, 58% (11/19) of cases were also misdiagnosed as either suspicious PTC (n ¼ 9) or PTC (n ¼ 2) by FNA. Misdiagnosis can occur because of the difficulty in distinguishing the nuclear features of PTC from those of HTT (16). HTT can, therefore, be considered if the cytological results suggest PTC in the absence of malignant US findings. Carney et al. reported one case of HTT correctly diagnosed by CNB (17). The current study reports four cases, suggesting that CNB is a reliable approach to the proper diagnosis of all cases of HTT; however,
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Table 2. Initial FNA and CNB results along with the final diagnosis in 24 patients. Initial FNA results (n ¼ 19)* ND 1
AUS 5
FLUS 1
Suspicious for PTC 9
PTC 2
MTC 1
CNB results (n ¼ 4)
Incidental OP finding (n ¼ 2)
HTT 4
HTT 2
*One patient underwent CNB after previous FNA for AUS. AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance; HTT, hyalinizing trabecular tumor; MTC, medullary thyroid carcinoma; ND, non-diagnostic; PTC, papillary thyroid carcinoma.
Fig. 3. Histological features of HTTs of the thyroid gland. A thin capsule surrounded the tumor, which showed a characteristic trabecular growth pattern (a). Intratrabecular hyalinization was prominent (b). A high-power view of cells showed round or oval nuclei with frequent nuclear grooves (c). The membranes of tumor cells were immunoreactive for MIB-1 (d).
FNA resulted in misdiagnosis in all cases. The usefulness of CNB for the diagnosis of HTT may result from histological rather than cytological assessment. In the current study, there were no differences in the pathology results between CNB and the surgical specimens. Diagnostic surgery was avoided in two patients. Several investigators have used different approaches to correctly diagnose HTT. Akin et al. (2) reported that HTT can be diagnosed with FNA if the cytoplasm of the aspirated tumor cells is ill-defined and filamentous; however, diagnosis by FNA is frequently incorrect in clinical practice. Salvatore et al. (18) showed that HTT has a high prevalence of RET/PTC rearrangements and
an absence of BRAF or NRAS point mutations. RET/ PTC rearrangements are also common in PTC, and cytological findings from HTT after FNA may mimic the nuclear characteristics of PTC. Hirokawa et al. (9) demonstrated that the membrane and cytoplasm of HTT cells are immunoreactive for MIB-1 (Ki-67). In the current study, MIB-1 immunostaining was not performed on FNA specimens because FNA cytology did not suggest HTT. However, when CNB did suggest HTT, additional MIB-1 immunostaining was applied to confirm the diagnosis. There are some limitations of our study. First, as it was a retrospective study, the US findings were not
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evaluated in real time. Furthermore, color Doppler US was not performed in all patients and four different US machines were used by multiple radiologists. Finally, only four patients underwent CNB. Further study on a larger scale will be necessary. In conclusion, HTT should be suspected when the cytological diagnosis of PTC is made after FNA without malignant US findings. CNB could prevent unnecessary surgery for HTT. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
References 1. Carney JA, Ryan J, Goellner JR. Hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol 1987;11: 583–591. 2. Akin MR, Nguyen GK. Fine-needle aspiration biopsy cytology of hyalinizing trabecular adenomas of the thyroid. Diagn Cytopathol 1999;20:90–94. 3. Bondeson L, Bondeson AG. Clue helping to distinguish hyalinizing trabecular adenoma from carcinoma of the thyroid in fine-needle aspirates. Diagn Cytopathol 1994; 10:25–29. 4. Papotti M, Volante M, Giuliano A, et al. RET/PTC activation in hyalinizing trabecular tumors of the thyroid. Am J Surg Pathol 2000;24:1615–1621. 5. Cheung CC, Boerner SL, MacMillan CM, et al. Hyalinizing trabecular tumor of the thyroid: a variant of papillary carcinoma proved by molecular genetics. Am J Surg Pathol 2000;24:1622–1626. 6. Gaffney RL, Carney JA, Sebo TJ, et al. Galectin-3 expression in hyalinizing trabecular tumors of the thyroid gland. Am J Surg Pathol 2003;27:494–498. 7. Park KT, Ahn SH, Mo JH, et al. Role of core needle biopsy and ultrasonographic finding in management of indeterminate thyroid nodules. Head Neck 2011;33: 160–165.
8. Screaton NJ, Berman LH, Grant JW. US-guided coreneedle biopsy of the thyroid gland. Radiology 2003;226: 827–832. 9. Hirokawa M, Carney JA. Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol 2000;24:575–578. 10. Goellner JR, Carney JA. Cytologic features of fine-needle aspirates of hyalinizing trabecular adenoma of the thyroid. Am J Clin Pathol 1989;91:115–119. 11. Lee S, Han BK, Ko EY, et al. The ultrasonography features of hyalinizing trabecular tumor of the thyroid are more consistent with its benign behavior than cytology or frozen section readings. Thyroid 2011;21:253–259. 12. Kobayashi K, Hirokawa M, Jikuzono T, et al. Hyalinizing trabecular tumor of the thyroid gland: characteristic features on ultrasonography. J Med Ultrason 2007;34:43–47. 13. Moon WJ, Baek JH, Jung SL, et al. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean J Radiol 2011;12:1–14. 14. Yeon JS, Baek JH, Lim HK, et al. Thyroid nodules with initially nondiagnostic cytologic results: the role of coreneedle biopsy. Radiology 2013;268:274–280. 15. Ha EJ, Baek JH, Lee JH, et al. Core needle biopsy can minimise the non-diagnostic results and need for diagnostic surgery in patients with calcified thyroid nodules. Eur Radiol 2014;24:1403–1409. 16. Baloch ZW, LiVolsi VA. Cytologic and architectural mimics of papillary thyroid carcinoma. Diagnostic challenges in fine-needle aspiration and surgical pathology specimens. Am J Clin Pathol 2006;125(Suppl.): S135–S144. 17. Carney JA, Hirokawa M, Lloyd RV, et al. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol 2008;32:1877–1889. 18. Salvatore G, Chiappetta G, Nikiforov YE, et al. Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer 2005;41:816–821.
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Acta Radiol OnlineFirst, published on September 17, 2014 as doi:10.1177/0284185114549225
Original Article
The ultrasonography features of hyalinizing trabecular tumor of the thyroid gland and the role of fine needle aspiration cytology and core needle biopsy in its diagnosis
Acta Radiologica 0(0) 1–6 ! The Foundation Acta Radiologica 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0284185114549225 acr.sagepub.com
Woo Jung Choi1, Jung Hwan Baek1, Eun Ju Ha1,2, Young Jun Choi1, Min Ji Hong1, Dong Eun Song3, Jin Yong Sung4, Hyunju Yoo5, So Lyung Jung6, Ha Young Lee7 and Jeong Hyun Lee1
Abstract Background: Hyalinizing trabecular tumor (HTT) of the thyroid gland is a rare, benign neoplasm of follicular cell origin. Misdiagnosis of HTT as either papillary or medullary thyroid carcinoma after fine-needle aspiration (FNA) may lead to unnecessary surgery. Purpose: To evaluate the ultrasonography (US) findings of HTT of the thyroid gland and the role of FNA cytology and core needle biopsy (CNB) in its diagnosis. Material and Methods: Data from 24 patients with a histopathological diagnosis of HTT between January 2000 and May 2013 were retrospectively analyzed. US findings were categorized according to shape, margin, orientation, echogenicity, composition, calcification, and vascularity. Cytologic and histologic results of FNA, CNB, and surgery were reviewed. Results: US revealed the following tumor features: oval-to-round (24/24), solid (22/24), smooth margin (21/24), hypoechoic or marked hypoechogenicity (18/24), and peri- and/or intranodular vascularity (17/17). Malignant US features such as marked hypoechogenicity (n ¼ 7) and a spiculated margin (n ¼ 3) were also observed. Final confirmation was by surgery in 22 patients and by CNB in two patients. All 19 patients who underwent FNA were initially misdiagnosed, including 12 with malignancies and five with atypia of undetermined significance. All four patients who underwent CNB were correctly diagnosed with HTT. The histology of CNB specimens suggested HTT, which was confirmed by immunostaining of MIB-1. Conclusion: HTT should be suspected when the cytological diagnosis of papillary thyroid carcinoma is made after FNA without malignant US findings. CNB could prevent unnecessary surgery for HTT.
Keywords Hyalinizing trabecular tumor, thyroid, ultrasonography, core-needle biopsy, fine-needle aspiration Date received: 10 May 2014; accepted: 13 July 2014
1
Department of Radiology and the Research Institute of Radiology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 2 Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea 3 Department of Pathology, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Republic of Korea 4 Department of Radiology, Thyroid Center, Daerim St. Mary’s Hospital, Seoul, Republic of Korea 5 Department of Pathology, Thyroid Center, Daerim St. Mary’s Hospital, Seoul, Republic of Korea
6 Department of Radiology, Seoul St. Mary’s Hospital, The Catholic University of Korea, Seoul, Republic of Korea 7 Department of Radiology, Inha University Hospital, Incheon, Republic of Korea
Corresponding author: Jung Hwan Baek, 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, Republic of Korea. Email: [email protected]
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Introduction Hyalinizing trabecular tumor (HTT) of the thyroid gland is a rare, benign neoplasm of follicular cell origin (1). This benign neoplasm shows histologic characteristics of a circumscribed or encapsulated, trabecular and alveolar architecture, consisting of polygonal spindle cells, intratrabecular hyaline, and colloid, and frequently shows vesicular nuclei with grooves, cytoplasmic inclusions, small nucleoli, occasional psammoma bodies, and infrequent mitoses (1). HTT is a rare and controversial lesion of the thyroid because of the disagreement regarding the nature of the tumor and the probability of misinterpreting the fine-needle aspiration (FNA) cytologic findings as papillary thyroid carcinoma (PTC) or medullary thyroid carcinoma (2,3). To date, only about 140 cases have been reported in the literature. The entity remains controversial as HTT may be regarded a variant of PTC as some similarities are noted in nuclear features (4,5). This misinterpretation may lead to unnecessary surgery (6). MIB-1 immunostaining and core-needle biopsy (CNB) have been proposed as alternatives for achieving a correct diagnosis (7–9). If FNA cytology suggests HTT, MIB-1 immunostaining can confirm a diagnosis of HTT; however, the majority of FNA cytology results do not suggest HTT (3,10). Previous studies have described the ultrasonography (US) findings of HTT (11,12). These studies attempted to validate an accurate diagnostic method for HTT, but only 10 cases were enrolled and the diagnosis remains unclear. The purpose of this study was to evaluate the ultrasonography (US) findings of HTT of the thyroid gland and the role of FNA cytology and CNB in its diagnosis.
21 women; age range, 23–58 years; mean age,SD, 52 15 years) were included in the study.
US examinations, US-guided FNA, CNB, and image analysis
This retrospective study was approved by the Institutional Review Boards for Human Investigation of all five participating institutions (Asan Medical Center, Seoul; St. Mary’s Hospital, Daerim; St. Mary’s Hospital, Inha University Hospital; and Ajou University Hospital). Informed consent was waived for the review of patients’ information, but was obtained from all patients prior to US or US-guided procedures.
US examinations were obtained using one of four US systems: an iU22 or HDI-5000 unit (Philips Healthcare, Bothell, WA, USA), or EUB-75 unit (Hitachi Medical Systems, Tokyo, Japan), or Aplio SSA-770A (Toshiba Medical Systems, Otawara-shi, Japan). Each was equipped with a linear highfrequency probe (5–14 MHz). US examinations were performed by radiologists and were supervised by one of five experienced thyroid radiologists with more than 7 years of experience. In all cases, the scanning protocol included both transverse and longitudinal real-time imaging of the thyroid nodules. Two radiologists (JHB and WJC) with 18 and 6 years of thyroid clinical expertise, respectively, reviewed the US images and all the images were adequate for review. Images were analyzed using criteria established by the Korean Society of Radiology (13). Information obtained from US included tumor shape (oval-to-round or irregular), margin (smooth, ill-defined, or spiculated/microlobulated), orientation (parallel or non-parallel), echogenicity (hyperechoic, isoechoic, hypoechoic, or markedly hypoechoic), composition (solid, predominantly solid, predominantly cystic, or cystic), calcification (presence or absence), and vascularity (grade 0, no vascularity; grade 1, perinodular vascularity only; grade 2, intranodular vascularity 50%). FNA or CNB were performed in all cases according to the recommendations of the Korean Society of Radiology (13). For FNA, a 21–25-gauge (G) needle was routinely used with a combination of capillary and aspiration techniques according to the nodule characteristics. CNB was performed using a disposable, 18-G, single- or double-action, spring-activated needle (1.1- or 1.6-cm excursion; TSK Ace-cut: Create Medic, Yokohama, Japan). Using a free-hand technique, the core needle was advanced from the isthmus of the thyroid, the biopsy needle tip was manually advanced to the margin or into the nodule, and the stylet and cutting cannula of the needle were fired sequentially (14).
Study population
Cytology, histology, and histopathological analysis
The electronic medical records at five hospitals were searched for patients with a final diagnosis of HTT of the thyroid gland between January 2000 and May 2013. During this period, 28 patients were diagnosed with HTT. Of these, four were excluded because US results were unavailable. Therefore, 24 patients (3 men,
Direct smears were made in all cases and were immediately fixed in 95% alcohol and stained with hematoxylin and eosin. The Papanicolaou stain was also applied. All biopsy specimens were fixed with 10% neutral buffered formalin and then routinely stained prior to histological examination. If HTT was suggested,
Material and Methods
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MIB-1 immunostaining was also performed after FNA or CNB. Formalin-fixed, paraffin-embedded tissue sections obtained after surgery were immunostained for MIB-1 using specific antibodies (DAKO, Glostrup, Denmark).
Results US imaging results The US results are summarized in Table 1. All nodules were oval-to-round, 87.5% (21/24) had a smooth margin, 75% (18/24) were hypoechoic or markedly hypoechoic, and 91.7% (22/24) were solid. Color Doppler US results were available for 17 patients, and all showed peri- and/or intranodular vascularity (Fig. 1). Seven patients had malignant US tumor features, such as marked hypoechogenicity (n ¼ 7) or a spiculated margin (n ¼ 3) (Fig. 2). None of the patients had a tumor with a taller-than-wide shape or calcification.
The mean nodule size was 19.9 12.3 mm (range, 5–52 mm).
FNA, CNB, and diagnostic accuracy Of the 24 study patients, 19 underwent FNA, and four underwent CNB. One patient underwent CNB after atypia of undetermined significance were identified upon previous FNA. Two patients were diagnosed via surgery without FNA or CNB. The initial cytopathological results from the 24 patients subsequently
Table 1. Ultrasonographic features of 24 patients with HTT of the thyroid. Characteristics Shape Oval-to-round Irregular Margin Smooth Ill-defined Spiculated or microlobulated Orientation Non-parallel Parallel Echogenicity Hyperechoic Isoechoic Hypoechoic Marked hypoechoic Composition Solid Predominantly solid Predominantly cystic or cystic Calcification Vascularity (n ¼ 17)* Grade 0 Grade 1 Grade 2 Grade 3 *Vascularity was evaluated in 17 nodules.
n
%
24 0
100 0
21 0 3 0 24
87.5 0 12.5 0 100
0 6 11 7
0 25 45.8 29.2
22 2 0 0
91.7 8.3 0 0
0 3 9 5
0 17.7 52.9 29.4
Fig. 1. HTT in a 54-year-old woman. Transverse (a) and longitudinal (b) ultrasonography images show a 2.2 cm, solid, oval, smooth, and hypoechoic mass without calcification. The nodule shows intranodular vascularity (c).
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Histopathologic results Histological analysis of the CNB biopsy specimens showed a thin capsule without capsular or vascular invasion, and trabecular architecture separated by minimal fibrous stroma. Intratrabecular hyalinization was prominent. Nuclei were round or oval with inconspicuous small nucleoli, frequent nuclear grooves, and less frequent intranuclear pseudo-inclusions. The membranes of tumor cells from CNB and surgical specimens were immunoreactive for MIB-1 (Fig. 3).
Discussion
Fig. 2. HTT in a 52-year-old woman. Transverse ultrasonography (a) image shows a 1.1 cm, solid, oval, spiculated, and marked hypoechoic mass with intranodular vascularity (b). US-guided CNB (c) correctly diagnosed it as a HTT.
diagnosed with HTT are summarized in Table 2. All 19 patients who underwent FNA were misdiagnosed, including 12 who were initially diagnosed with malignancies and five with atypia of undetermined significance. Four cases of HTT were correctly diagnosed via CNB. In these four cases, CNB suggested HTT
This study demonstrates that all 19 patients who underwent FNA had been incorrectly diagnosed. Of these, 58% (11/19) were initially classified as having PTC. However, only 29% (7/24) of the patients showed malignant US findings. A careful clinical approach may therefore be needed when the cytological diagnosis is PTC by FNA without malignant US findings. All four patients who underwent CNB were correctly diagnosed with HTT. CNB has been suggested as an alternative to FNA to reduce non-diagnostic and inconclusive results for suspected thyroid malignancies (8,14,15). Histological results from CNB specimens may suggest HTT, which is then confirmed by immunostaining for MIB-1. CNB can possibly reduce the risk of incorrect diagnosis of HTT and unnecessary surgery. In a previous study, HTT showed no malignant features in US images (11). Here, 70.8% (17/24) of HTT patients showed no malignancy, but seven tumors exhibited malignant US features such as marked hypoechogenicity and spiculated margins. However, no cases of HTT contained calcifications. Many cases of HTT are often misdiagnosed as PTC on FNA. Lee et al. (11) reported that all 10 of their FNA cases were reported as either suspicious for PTC or as PTC. In the current study, 58% (11/19) of cases were also misdiagnosed as either suspicious PTC (n ¼ 9) or PTC (n ¼ 2) by FNA. Misdiagnosis can occur because of the difficulty in distinguishing the nuclear features of PTC from those of HTT (16). HTT can, therefore, be considered if the cytological results suggest PTC in the absence of malignant US findings. Carney et al. reported one case of HTT correctly diagnosed by CNB (17). The current study reports four cases, suggesting that CNB is a reliable approach to the proper diagnosis of all cases of HTT; however,
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Table 2. Initial FNA and CNB results along with the final diagnosis in 24 patients. Initial FNA results (n ¼ 19)* ND 1
AUS 5
FLUS 1
Suspicious for PTC 9
PTC 2
MTC 1
CNB results (n ¼ 4)
Incidental OP finding (n ¼ 2)
HTT 4
HTT 2
*One patient underwent CNB after previous FNA for AUS. AUS, atypia of undetermined significance; FLUS, follicular lesion of undetermined significance; HTT, hyalinizing trabecular tumor; MTC, medullary thyroid carcinoma; ND, non-diagnostic; PTC, papillary thyroid carcinoma.
Fig. 3. Histological features of HTTs of the thyroid gland. A thin capsule surrounded the tumor, which showed a characteristic trabecular growth pattern (a). Intratrabecular hyalinization was prominent (b). A high-power view of cells showed round or oval nuclei with frequent nuclear grooves (c). The membranes of tumor cells were immunoreactive for MIB-1 (d).
FNA resulted in misdiagnosis in all cases. The usefulness of CNB for the diagnosis of HTT may result from histological rather than cytological assessment. In the current study, there were no differences in the pathology results between CNB and the surgical specimens. Diagnostic surgery was avoided in two patients. Several investigators have used different approaches to correctly diagnose HTT. Akin et al. (2) reported that HTT can be diagnosed with FNA if the cytoplasm of the aspirated tumor cells is ill-defined and filamentous; however, diagnosis by FNA is frequently incorrect in clinical practice. Salvatore et al. (18) showed that HTT has a high prevalence of RET/PTC rearrangements and
an absence of BRAF or NRAS point mutations. RET/ PTC rearrangements are also common in PTC, and cytological findings from HTT after FNA may mimic the nuclear characteristics of PTC. Hirokawa et al. (9) demonstrated that the membrane and cytoplasm of HTT cells are immunoreactive for MIB-1 (Ki-67). In the current study, MIB-1 immunostaining was not performed on FNA specimens because FNA cytology did not suggest HTT. However, when CNB did suggest HTT, additional MIB-1 immunostaining was applied to confirm the diagnosis. There are some limitations of our study. First, as it was a retrospective study, the US findings were not
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evaluated in real time. Furthermore, color Doppler US was not performed in all patients and four different US machines were used by multiple radiologists. Finally, only four patients underwent CNB. Further study on a larger scale will be necessary. In conclusion, HTT should be suspected when the cytological diagnosis of PTC is made after FNA without malignant US findings. CNB could prevent unnecessary surgery for HTT. Conflict of interest None declared.
Funding This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.
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8. Screaton NJ, Berman LH, Grant JW. US-guided coreneedle biopsy of the thyroid gland. Radiology 2003;226: 827–832. 9. Hirokawa M, Carney JA. Cell membrane and cytoplasmic staining for MIB-1 in hyalinizing trabecular adenoma of the thyroid gland. Am J Surg Pathol 2000;24:575–578. 10. Goellner JR, Carney JA. Cytologic features of fine-needle aspirates of hyalinizing trabecular adenoma of the thyroid. Am J Clin Pathol 1989;91:115–119. 11. Lee S, Han BK, Ko EY, et al. The ultrasonography features of hyalinizing trabecular tumor of the thyroid are more consistent with its benign behavior than cytology or frozen section readings. Thyroid 2011;21:253–259. 12. Kobayashi K, Hirokawa M, Jikuzono T, et al. Hyalinizing trabecular tumor of the thyroid gland: characteristic features on ultrasonography. J Med Ultrason 2007;34:43–47. 13. Moon WJ, Baek JH, Jung SL, et al. Ultrasonography and the ultrasound-based management of thyroid nodules: consensus statement and recommendations. Korean J Radiol 2011;12:1–14. 14. Yeon JS, Baek JH, Lim HK, et al. Thyroid nodules with initially nondiagnostic cytologic results: the role of coreneedle biopsy. Radiology 2013;268:274–280. 15. Ha EJ, Baek JH, Lee JH, et al. Core needle biopsy can minimise the non-diagnostic results and need for diagnostic surgery in patients with calcified thyroid nodules. Eur Radiol 2014;24:1403–1409. 16. Baloch ZW, LiVolsi VA. Cytologic and architectural mimics of papillary thyroid carcinoma. Diagnostic challenges in fine-needle aspiration and surgical pathology specimens. Am J Clin Pathol 2006;125(Suppl.): S135–S144. 17. Carney JA, Hirokawa M, Lloyd RV, et al. Hyalinizing trabecular tumors of the thyroid gland are almost all benign. Am J Surg Pathol 2008;32:1877–1889. 18. Salvatore G, Chiappetta G, Nikiforov YE, et al. Molecular profile of hyalinizing trabecular tumours of the thyroid: high prevalence of RET/PTC rearrangements and absence of B-raf and N-ras point mutations. Eur J Cancer 2005;41:816–821.
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