- Open Access
Ultrasound features of medullary thyroid carcinoma correlate with cancer aggressiveness: a retrospective multicenter study
- Pierpaolo Trimboli1, 2, 15Email author,
- Luca Giovanella2,
- Stefano Valabrega3,
- Massimiliano Andrioli4,
- Roberto Baldelli5,
- Nadia Cremonini6,
- Fabio Rossi1,
- Leo Guidobaldi7,
- Agnese Barnabei5,
- Francesca Rota5,
- Antonella Paoloni5,
- Laura Rizza5,
- Giorgio Fattorini1, 8,
- Maurizio Latini1,
- Claudio Ventura1,
- Paolo Falasca9,
- Fabio Orlandi10,
- Anna Crescenzi11,
- Ferdinando D’Ambrosio12,
- Vito Cantisani12,
- Francesco Romanelli8,
- Roberto Negro13,
- Enrico Saggiorato10, 14 and
- Marialuisa Appetecchia5
© Trimboli et al.; licensee BioMed Central Ltd. 2014
Received: 19 August 2014
Accepted: 2 October 2014
Published: 25 October 2014
Poor prognosis of medullary thyroid cancer (MTC) with suspicious ultrasound (US) features has been reported. The aim of the study was to investigate the association between preoperative US presentation and aggressiveness features of MTC. Also, US features of MTC were compared with those previously reported.
Study group comprised 134 MTC from nine different centers. Based on US presentation the nodules were stratified in “at risk for malignancy” (m-MTC) or “probably benign” (b-MTC) lesions.
Eighty nine (66.4%) m-MTC and 45 (33.6%) b-MTC were found. Metastatic lymph nodes (p = 0.0001) and extrathyroid invasiveness (p < 0.0001) were more frequent in m-MTC. There was statistically significant correlation (p = 0.0002) between advanced TNM stage and m-MTC with an Odds Ratio 5.5 (95% CI 2.1–14.4). Mean postsurgical calcitonin values were 224 – 64 pg/ml in m-MTC and 51 – 21 in b-MTC (p = 0.003).
This study showed that sonographically suspicious MTC is frequently associated with features of aggressiveness, suggesting that careful preoperative US of MTC patients may better plan their surgical approach.
Medullary thyroid cancer (MTC) originates from thyroid C cells and accounts for about 5% of thyroid malignancy . MTC may occur as sporadic tumor (about 80% of cases) or be part of a familial disorder . The diagnosis of MTC represents a diagnostic challenge in clinical practice. Fine needle aspiration (FNA) of thyroid nodules has several pitfalls for this histologic type. The cytologic examination can diagnose MTC with classical presentation, and the detection rate was reported of 56% in a recent meta-analysis . The routine measurement of serum calcitonin is still a matter of debate and ultrasonography (US) does not achieve high reliability rates . Due to these limitations, many MTC are still incidentally discovered after thyroid excision, leading to the risk of an incomplete therapeutic approach and thus of a poorer prognosis . To diagnose MTC prior to surgery is of high importance. This allows to examine other disorders potentially associated with hereditary forms of MTC and increases the possibility to achieve a complete surgical cure. Therefore, a carefully planned initial surgical treatment of patients with the preoperative diagnosis of MTC is strongly required .
Ultrasound examination is the pivotal imaging tool in the risk stratification of thyroid nodules. It allows the identification of non palpable nodules and the assessment of their characteristics. Several papers have reported the presence of specific US features as highly suggestive of malignancy ,. Moreover, preoperative neck US evaluation is the gold standard in the surgical planning of patients undergoing thyroidectomy . However, most studies have focused on the US features of differentiated papillary thyroid carcinoma (PTC), and only limited data are available regarding the US criteria for possibly malignant MTCs, and the possible association between US features of MTCs and cancer aggressiveness –.
The aim of this study was investigate the aggressiveness features of MTC in association with their preoperative US presentation. The US features of MTC in comparison to those reported in the literature are also described.
Materials and methods
This multicenter retrospective study included patients who had been diagnosed and operated for MTC over the period from March 2007 to March 2013 at nine different centers. The preoperative diagnosis had been based on high serum calcitonin levels with a suggestive cytology and/or detection of calcitonin in fine needle aspiration washout –. All patients had undergone total thyroidectomy with central nodal neck dissection in all cases. Patients with suspicious neck lymph nodes on preoperative imaging had undergone lateral neck dissection. In all patients the diagnosis of MTC was confirmed by histology according to the WHO classification criteria . Tumour staging was based on the TNM classification . Postoperative parameters that could be associated with aggressiveness including the presence of lymph node involvement (pN1), extrathyroid tumor extension, RET mutation, multifocality of lesions, concomitant C cell hyperplasia and MEN 2 were recorded by reviewing the patients files.
The US appearance of the lesions was assessed by retrieving and reviewing the preoperative thyroid and neck US images in the institution PACS systems. In order to assess the risk of malignancy by US, all nodules were assessed by four reviewers with more than ten years experience in thyroid US (PT, ES, VC, LuGi) according to a previously described validated classification system. This classification system stratifies nodules in classes 1 to 5 with intermediate steps of 0.5 for classes 2 to 5 and nodules with category 3.5 or greater are regarded as probably malignant with a positive predictive value of 97% ,. Briefly, class 1 includes round or oval anechoic lesion, in class 2 there are regular-shaped nodules with cystic change, class 3 contains solid and regular-shaped nodule, class 4 comprises solid and regular-shaped nodule, while solid and irregular-shaped nodules with extrathyroid extension are in class 5. Based on this system nodules with class ≥3.5 were categorized as “malignant” (m-MTC) and nodules with class <3.5 as “indeterminate or benign” (b-MTC). Discordant cases of the present study were categorized by the examiners in consensus. In case of multifocal MTC, only the most prominent focus was analyzed in the study.
Statistical analysis was performed using standard statistical software using Graph Pad Prism (Graph Pad Software Inc, La Jolla, CA, USA). Differences in frequencies were analyzed by chi-square test or Fisher exact test and differences in mean values were evaluated using t-test. Statistical significance was set at p < 0.05. Means and standard errors were compared using Mann-Whitney test. The association of suspicious US features of MTC with TNM stages was analyzed using Odds Ratio (OR).
Clinical characteristics of the study group
Age of patients (years)*
56.7 – 1.2
Preoperative calcitonin (pg/ml)*
558 – 62
Postoperative calcitonin (pg/ml)*
167 – 44
Nodule’s size (mm)*
19.8 – 1.0
C cell hyperplasia (number of patients/total)
MEN 2 (number of patients/total)
Hereditary cancer (number of patients/total)
Single nodule (number of patients/total)
Based on the US criteria for risk evaluation, 89/134 (66.4%) were classified as m-MTC and 45/134 (33.6%) as b-MTC. There was no statistically significant difference between the two groups regarding the lesion size (m-MTC, 19.7 – 1.3 mm; b-MTC, 20.1 – 1.7, t-test p = 0.13) and patients’ age (m-MTC, 56.9 – 1.5 years; b-MTC, 56.6 – 2.4 years, t-test p = 0.37).
Comparison of predictors of tumor aggressiveness
m-MTC (n = 89)
b-MTC (n = 45)
Extrathyroid tumor extension
C cell hyperplasia
Presence of >1 of the above parameters
Detectable postoperative serum CT
Preoperative serum calcitonin levels were available in 117 cases. Significant difference in mean preoperative calcitonin levels was found (595 – 76 pg/ml in m-MTC, 484 – 106 pg/ml in b-MTC p = 0.0001). Mean postoperative calcitonin value was available in 106 patients, 30/71 (42.2%) m-MTC and 7/35 (20%) b-MTC cases had detectable calcitonin. Mean postoperative calcitonin value was significantly (p = 0.003) higher in the m-MTC group (224 – 64 pg/ml) compared to b-MTC group (51 – 21 pg/ml).
In the last decade, high resolution US has been widely available and this contributed to an increase in the diagnosis of thyroid malignancy ,. The presence of specific US features has been closely associated with higher risk for malignancy . Most of the US data in the literature concern the papillary thyroid cancers, because of its higher frequency among thyroid malignancies (about 80%) ,, whereas limited and discordant data are available about the US characteristics of medullary carcinomas –.
As a second objective, here we analyzed the US reliability in diagnosing MTC lesions and our data might be discussed in comparison to the previous reports –. In all, these papers reported that a not negligible percentage of MTC may be found with no ultrasound risk features. In particular, characteristics of benignancy, such as round shape, cystic changes, homogeneous echostructure, and circumscribed margins, were often recorded in MTC. More recently, these data confirm the previous experience of one center of those participant to the present multicenter study; there, MTC and PTC were compared with a large benign control group, and MTC showed poor discrepancy with respect to the controls . Also, a heterogeneous elastographic presentation was recently described . Here we recorded that about one in three MTC nodules manifests at ultrasonography as benign, being this finding quite similar to that reported by Fukushima et al . This finding extends the conclusions of all the above studies – and indirectly prompts to use calcitonin measurement in the initial evaluation of thyroid nodules ,. In general, the possibility to submit to FNA all nodules with a significant size (i.e. 1 cm) should be taken into account, even if they have a “benign” US presentation.
The strength of this paper is the large sample size of MTC and the multicenter design. Also, it has to be underlined that the series was collected in a recent period using high resolution ultrasound systems which improved both diagnosis and follow-up of several conditions ,–. To date, the knowledge on US presentation of MTC is poor, and the present data strongly improve the literature on this matter.
In conclusion, this study showed that MTC with preoperative “at-risk” US presentation is more frequently associated with features of tumor aggressiveness than those with no suspicious ultrasonography. In clinical practice, these data suggest a preoperative thyroid ultrasound assessment of MTC patients to better plan their surgical approach. Further prospective studies on this topic are necessary.
Drafting of manuscript: PT, RB, MA. Acquisition of data: FR, SV, AB, FR, AP, LR, GF, ML, CV, PF, FO, FD, VC. Study design and conception: PT, RB, MA, RN, ES, MA, NC. Analysis and interpretation of cytology and histology: LG, AC. Critical revision and supervision: LG, FR. All authors read and approved the final manuscript.
- Kloos RT, Eng C, Evans DB, Francis GL, Gagel RF, Gharib H, Moley JF, Pacini F, Ringel MD, Schlumberger M, Wells SA: Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009, 19: 565-612. 10.1089/thy.2008.0403.View ArticlePubMedGoogle Scholar
- Trimboli P, Treglia G, Guidobaldi L, Romanelli F, Nigri G, Valabrega S, Sadeghi R, Crescenzi A, Faquin WC, Bongiovanni M, Giovanella L. Detection rate of FNA cytology in medullary thyroid carcinoma: a meta-analysis.Clin Endocrinol (Oxf) 2014. doi:10.1111/cen.12563.,Google Scholar
- Trimboli P, Giovanella L, Crescenzi A, Romanelli F, Valabrega S, Spriano G, Cremonini N, Guglielmi R, Papini E: Medullary thyroid cancer diagnosis: an appraisal. Head Neck. 2014, 36: 1216-1223. 10.1002/hed.23449.View ArticlePubMedGoogle Scholar
- Pacini F, Castagna MG, Cipri C, Schlumberger M: Medullary thyroid carcinoma. Clin Oncol (R Coll Radiol). 2010, 22: 475-485. 10.1016/j.clon.2010.05.002.View ArticleGoogle Scholar
- Gharib H, Papini E, Paschke R, Duick DS, Valcavi R, Heged’s L, Vitti P: 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: 468-475. 10.4158/EP.16.3.468.View ArticlePubMedGoogle Scholar
- Gorman B, Charboneau JW, James EM, Reading CC, Wold LE, Grant CS, Gharib H, Hay ID: Medullary thyroid carcinoma: role of high-resolution US. Radiology. 1987, 162: 147-150. 10.1148/radiology.162.1.3538147.View ArticlePubMedGoogle Scholar
- Saller B, Moeller L, Gorges R, Janssen OE, Mann K: Role of conventional ultrasound and color Doppler sonography in the diagnosis of medullary thyroid carcinoma. Exp Clin Endocrinol Diabetes. 2002, 110: 403-407. 10.1055/s-2002-36546.View ArticlePubMedGoogle Scholar
- Kim SH, Kim BS, Jung SL, Lee JW, Yang PS, Kang BJ, Lim HW, Kim JY, Whang IY, Kwon HS, Jung CK: Ultrasonographic findings of medullary thyroid carcinoma: a comparison with papillary thyroid carcinoma. Korean J Radiol. 2009, 10: 101-105. 10.3348/kjr.2009.10.2.101.PubMed CentralView ArticlePubMedGoogle Scholar
- Lee S, Shin JH, Han BK, Ko EY: Medullary thyroid carcinoma: comparison with papillary thyroid carcinoma and application of current sonographic criteria. Am J Roentgenol. 2010, 194: 1090-1094. 10.2214/AJR.09.3276.View ArticleGoogle Scholar
- Choi N, Moon WJ, Lee JH, Baek JH, Kim DW, Park SW: Ultrasonographic findings of medullary thyroid cancer: differences according to tumor size and correlation with fine needle aspiration results. Acta Radiol. 2011, 52: 312-316. 10.1258/ar.2010.100247.View ArticlePubMedGoogle Scholar
- Trimboli P, Nasrollah N, Amendola S, Rossi F, Ramacciato G, Romanelli F, Aurello P, Crescenzi A, Laurenti O, Condorelli E, Ventura C, Valabrega S: Should we use ultrasound features associated with papillary thyroid cancer in diagnosing medullary thyroid cancer?. Endocr J. 2012, 59: 503-508. 10.1507/endocrj.EJ12-0050.View ArticlePubMedGoogle Scholar
- Fukushima M, Ito Y, Hirokawa M, Miya A, Kobayashi K, Akasu H, Shimizu K, Miyauchi A: Excellent prognosis of patients with nonhereditary medullary thyroid carcinoma with ultrasonographic findings of follicular tumor or benign nodule. World J Surg. 2009, 33: 963-968. 10.1007/s00268-009-9939-z.View ArticlePubMedGoogle Scholar
- Trimboli P, Cremonini N, Ceriani L, Saggiorato E, Guidobaldi L, Romanelli F, Ventura C, Laurenti O, Messuti I, Solaroli E, Madaio R, Bongiovanni M, Orlandi F, Crescenzi A, Valabrega S, Giovanella L: Calcitonin measurement in aspiration needle washout fluids has higher sensitivity than cytology in detecting medullary thyroid cancer: a retrospective multicentre study. Clin Endocrinol (Oxf). 2014, 80: 135-140. 10.1111/cen.12234.View ArticleGoogle Scholar
- Trimboli P, Rossi F, Baldelli R, Laurenti O, Nigri G, Ventura C, Appetecchia M, Attanasio D, Romanelli F, Guidobaldi L, Guarino M, Crescenzi A, Valabrega S: Measuring calcitonin in washout of the needle in patients undergoing fine needle aspiration with suspicious medullary thyroid cancer. Diagn Cytopathol. 2012, 40: 394-398. 10.1002/dc.21731.View ArticlePubMedGoogle Scholar
- Trimboli P, Nigri G, Romanelli F, Cicciarella Modica DD, Crescenzi A, Valabrega S, Giovanella L: Medullary thyroid nodules by measurement of calcitonin (Ct) in aspiration needle washout in patients with multinodular goiter and moderately elevated serum Ct. Exp Clin Endocrinol Diabetes. 2012, 120: 234-237. 10.1055/s-0031-1291344.View ArticlePubMedGoogle Scholar
- Hedinger C, Williams ED, Sobin LH: The WHO histological classification of thyroid tumors: a commentary on the second edition. Cancer. 1989, 63: 908-911. 10.1002/1097-0142(19890301)63:5<908::AID-CNCR2820630520>3.0.CO;2-I.View ArticlePubMedGoogle Scholar
- Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A: Thyroid. AJCC Cancer Staging Manual. 2010, Springer, New York, NY, 87-96. 7Google Scholar
- Ito Y, Amino N, Yokozawa T, Ota H, Ohshita M, Murata N, Morita S, Kobayashi K, Miyauchi A: Ultrasonographic evaluation of thyroid nodules in 900 patients: comparison among ultrasonographic, cytological, and histological findings. Thyroid. 2007, 17: 1269-1276. 10.1089/thy.2007.0014.View ArticlePubMedGoogle Scholar
- Yokozawa T, Fukata S, Kuma K, Matsuzuka F, Kobayashi A, Hirai K, Miyauchi A, Sugawara M: Thyroid cancer detected by ultrasound-guided fine-needle aspiration biopsy. World J Surg. 1996, 20: 848-853. 10.1007/s002689900129.View ArticlePubMedGoogle Scholar
- Davies L, Welch HG: Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA. 2006, 295: 2164-2167. 10.1001/jama.295.18.2164.View ArticlePubMedGoogle Scholar
- Trimboli P, Ulisse S, Graziano FM, Marzullo A, Ruggieri M, Calvanese A, Piccirilli F, Cavaliere R, Fumarola A, D’Armiento M: Trend in thyroid carcinoma size, age at diagnosis, and histology in a retrospective study of 500 cases diagnosed over 20 years. Thyroid. 2006, 16: 1151-1155. 10.1089/thy.2006.16.1151.View ArticlePubMedGoogle Scholar
- Trimboli P, Guglielmi R, Monti S, Misischi I, Graziano F, Nasrollah N, Amendola S, Morgante SN, Deiana MG, Valabrega S, Toscano V, Papini E: Ultrasound sensitivity for thyroid malignancy is increased by real-time elastography: a prospective multicenter study. J Clin Endocrinol Metab. 2012, 97: 4524-4530. 10.1210/jc.2012-2951.View ArticlePubMedGoogle Scholar
- Carling T, Udelsman R: Thyroid tumors. Cancer: Principles and Practice of Oncology. Edited by: DeVita VT Jr, Lawrence TS, Rosenberg SA. 2011, Lippincott Williams & Wilkins, Philadelphia, PA, 1457-1472. 9Google Scholar
- Andrioli M, Trimboli P, Amendola S, Valabrega S, Fukunari N, Mirella M, Persani L: Elastographic presentation of medullary thyroid carcinoma. Endocrine. 2014, 45: 153-155. 10.1007/s12020-013-0062-4.View ArticlePubMedGoogle Scholar
- Solivetti FM, Elia F, Guerrisi A, Desiderio F, Santaguida M, Sperduti I, Cavallotti C, Di Carlo A: Cutaneous melanoma follow-up: appropriateness of requests for ultrasound tests – the S. Gallicano National Referral Centre Experience. J Exp Clin Cancer Res. 2013, 32: 73-10.1186/1756-9966-32-73.PubMed CentralView ArticlePubMedGoogle Scholar
- Solivetti FM, Elia F, Graceffa D, Di Carlo A: Ultrasound morphology of inguinal lymph nodes may not herald an associated pathology. J Exp Clin Cancer Res. 2012, 31: 88-10.1186/1756-9966-31-88.PubMed CentralView ArticlePubMedGoogle Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.