Fast track — ArticlesGalectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study
Introduction
Thyroid nodules are a common clinical problem. The prevalence of palpable thyroid proliferations in adults increases with age (mean prevalence 4–7% in the USA1), but is much higher when subclinical nodules are also counted.2 About 80–85% of these lesions are benign, therefore a reliable and systematic approach to their characterisation is needed.
Thyroid fine-needle aspiration (FNA) has substantially improved the characterisation of thyroid nodules and has led to decreases in health-care costs and improved diagnosis of malignant lesions when thyroidectomy is done. However, FNA has intrinsic limitations in distinguishing between benign (nodular hyperplasia, follicular adenoma and its variants) and malignant follicular lesions (follicular thyroid carcinoma, oncocytic carcinoma, and follicular variant of papillary carcinoma)1, 3, 4, 5, 6, 7 FNA fails to distinguish between benign and malignant disease in about 15–30% of tests, depending on the diagnostic centre.1, 3, 4, 5, 6, 7 Consequently, many patients with follicular proliferations are referred for thyroidectomy without real therapeutic necessity.7 Furthermore, final histology often confirms malignancy in about 10–15% of excised lesions.8, 9, 10
To improve the diagnostic accuracy of thyroid FNA cytology, we proposed a test method (galectin-3 thyrotest) based on expression analysis of galectin-3 on FNA-derived cell blocks.11 Galectin-3 is a β-galactosyl-binding molecule in the lectin group, and is involved in different biological functions, including cell adhesion, cell-cycle regulation, apoptosis, and tumour progression.12 We used the galectin-3 test method for the preoperative characterisation of thyroid nodules for several reasons: first, in normal conditions galectin-3 is not expressed in the cytoplasm of thyroid cells and its forced expression (by galectin-3 cDNA transfection) generates a transformed phenotype;12, 13, 14 conversely, inhibition of galectin-3 expression has been shown to revert the transformed phenotype in different tumour models.14, 15, 16 Second, the aberrant expression of galectin-3 blocks the apoptotic programme, a feature that favours the development of cancer.12, 17 Third, we had previously shown18 that galectin-3 is a physiological target of P53 transcriptional activity, and that P53-mediated down-regulation of galectin-3 is needed for P53-induced apoptosis. Fourth, published studies showed that well-differentiated thyroid carcinomas almost always express galectin-3, whereas healthy thyroid tissue and most benign thyroid proliferations do not.11, 19
The main reason that conventional FNA cytology fails to characterise reliably follicular thyroid nodules in a third of tests is because cytological criteria for distinguishing benign from malignant follicular proliferations do not exist, despite progress in FNA cytology.1, 3, 4, 5, 6, 7, 20 To assess the diagnostic accuracy of the galectin-3 test method we aimed to undertake a national, prospective, multicentre study of 465 patients in collaboration with 11 specialised thyroid institutions. The final histological diagnosis (considered as the gold standard) was compared with the preoperative diagnostic findings of the test method.
Section snippets
Patients and procedures
Candidate working groups were selected on the basis of their recorded clinical activity (eg, number of fine-needle aspirations of the thyroid (FNAB) each year; number of thyroid ultrasonographies each year; number of thyroid procedures each year) and pertinent publications on thyroid research. 11 specialised thyroid institutions in northern, central, and southern Italy were selected from 22 applications (constituting two groups in northern Italy, one group in central Italy, two groups in
Results
Galectin-3 expression was absent in 331 (71%) of 465 thyroid nodules assessed preoperatively (table 2). 280 (85%) of these galectin-3-negative lesions were diagnosed as benign at final histology, whereas 29 (9%) were diagnosed as thyroid cancer. These false-negative tumours included 19 follicular variants of papillary carcinomas (FVPCs), eight follicular carcinomas (including four oncocytic variants), and two poorly differentiated carcinomas.
8 (28%) of 29 false-negative carcinomas showed
Discussion
The high prevalence of thyroid nodules in the adult population (19–67% of randomly selected individuals2) and the low prevalence of thyroid cancers makes the diagnosis of thyroid cancer very difficult.2, 26, 27 Our findings show that 381 (88%) of 432 patients with follicular thyroid nodules who were referred for thyroidectomy were correctly classified preoperatively by use of the galectin-3 test. Therefore, many unnecessary thyroid operations could be avoided.11, 19, 28, 29 The overall
Glossary
- Thy3 proliferations
- Follicular lesions or suspected follicular tumours
References (35)
Improving accuracy of cytology for nodular thyroid lesions
Lancet
(2000)- et al.
Application of an immunodiagnostic method for improving preoperative diagnosis of nodular thyroid lesions
Lancet
(2001) - et al.
Malignant transformation of thyroid follicular cells by galectin-3
Cancer Lett
(2003) - et al.
Galectin-3 and HBME-1 expression in well-differentiated thyroid tumors with follicular architecture of uncertain malignant potential
Mod Pathol
(2005) - et al.
- et al.
Thyroid incidentalomas: management approaches to no palpable nodules discovered incidentally on thyroid imaging
Ann Intern Med
(1997) Thyroid
- et al.
Fine-needle aspiration of thyroid: an institutional experience
Thyroid
(1998) - et al.
Sources of diagnostic error in fine needle aspiration of the thyroid
Cancer
(1989) - et al.
Observer variation in the diagnosis of follicular variant of papillary thyroid carcinoma
Am J Surg Pathol
(2004)