Elsevier

The Lancet Oncology

Volume 9, Issue 6, June 2008, Pages 543-549
The Lancet Oncology

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Galectin-3-expression analysis in the surgical selection of follicular thyroid nodules with indeterminate fine-needle aspiration cytology: a prospective multicentre study

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Summary

Background

In the USA, about 30 200 well-differentiated thyroid carcinomas were diagnosed in 2007, but the prevalence of thyroid nodules is much higher (about 5% of the adult population). Unfortunately, the preoperative characterisation of follicular thyroid nodules is still a challenge, and many benign lesions, which remain indeterminate after fine-needle aspiration (FNA) cytology are referred to surgery. About 85% of these thyroid nodules are classified as benign at final histology. We aimed to assess the diagnostic effect of galectin-3 expression analysis in distinguishing preoperatively benign from malignant follicular thyroid nodules when FNA findings were indeterminate.

Methods

544 patients were enrolled between June 1, 2003, and Aug 30, 2006. We used a purified monoclonal antibody to galectin-3, a biotin-free immunocytohistochemical assay, and a morphological and phenotypic analysis of FNA-derived cell-block preparations. Galectin-3-expression analysis was applied preoperatively on 465 follicular thyroid proliferations that were candidates for surgery, and its diagnostic accuracy was compared with the final histology.

Findings

31 patients were excluded because they had small galectin-3-negative thyroid nodules; we did not have data for 47 patients; and one patient with an oncocytic nodule was excluded. 331 (71%) of the assessable 465 preoperative thyroid FNA samples did not express galectin-3. 280 (85%) of these galectin-3-negative lesions were classified as benign at final histology. Galectin-3 expression was detected, instead, in 134 of 465 (29%) thyroid proliferations, 101 (75%) of which were confirmed as malignant. The overall sensitivity of the galectin-3 test was 78% (95% CI 74–82) and specificity was 93% (90–95). Estimated positive predictive value was 82% (79–86) and negative predictive value was 91% (88–93). 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. However, 29 (22%) of 130 cancers were missed by the galectin-3 method.

Interpretation

Our findings show that if the option of surgery was based theoretically on galectin-3 expression alone, only 134 thyroid operations would have been done in 465 patients; therefore a large proportion (71%) of unnecessary thyroid surgical procedures could be avoided, although a number of galectin-3-negative cancers could be potentially missed. The galectin-3 test proposed here does not replace conventional FNA cytology, but represents a complementary diagnostic method for those follicular nodules that remain indeterminate.

Funding

Compagnia di San Paolo, Turin, Italy, and Italian Association for Cancer Research (AIRC), Rome, Italy.

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

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