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      A prospective cohort study to assess the role of FDG-PET in differentiating benign and malignant follicular neoplasms

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          Abstract

          Background

          Follicular and Hürthle cell neoplasms are diagnostic challenges. This prospective study was designed to evaluate the efficacy of [18F]-2-fluoro-2-deoxy- d-glucose (FDG) positron emission tomography/computed tomography (PET/CT) in predicting the risk of malignancy in follicular/Hürthle cell neoplasms.

          Materials and methods

          Fifty thyroid nodules showing follicular/Hürthle cell neoplasm on prior ultrasonography guided fine needle aspiration cytology (FNAC) were recruited into this study. A FDG-PET/CT scan, performed for neck and superior mediastinum, was reported by a single observer, blinded to the surgical and pathology findings. Receiver operating characteristic (ROC) curve analysis of maximum standardized uptake value (SUVmax) and the area under the curve (AUROC) were used to assess discrimination between benign from malignant nodules. Youden index was used to identify the optimal cut-off SUVmax for diagnosing malignancy. Sensitivity, specificity, predictive values and overall accuracy were used as measures of performance.

          Results

          Our study group comprises of 31 benign and 19 malignant thyroid nodules. After excluding all Hürthle cell adenomas, the AUROC for discriminating benign and malignant non-Hürthle cell neoplasms was 0.79 (95% CI, 0.64–0.94; p = 0.001); with SUVmax of 3.25 as the best cut-off for the purpose. PET/CT had sensitivity of 79% (95% CI, 54–93%), specificity of 83% (95% CI, 60–94%), positive predictive value (PPV) of 79% (95% CI, 54–93%), and negative predictive value (NPV) of 83% (95% CI, 60–94%). The overall accuracy was 81%.

          Conclusions

          FDG-PET/CT can help in differentiating benign and malignant non-Hürthle cell neoplasms. SUVmax of 3.25 was found to be the best for identifying malignant non-Hürthle cell follicular neoplasms.

          Highlights

          • •

            Earlier meta-analyses have not considered Hürthle cell neoplasm separate from other follicular neoplasm.

          • •

            Hürthle cell neoplasm are known to show high FDG uptake.

          • •

            FDG-PET/CT can help in differentiating benign and malignant non-Hürthle cell thyroid nodules.

          • •

            A cut-off SUVmax of 3.25 enhances the accuracy of FDG-PET/CT in identifying cancers in thyroid nodules.

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          Most cited references26

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          Estimation of the Youden Index and its associated cutoff point.

          Ronen Fluss, David Faraggi, Benjamin Reiser (2005)
          The Youden Index is a frequently used summary measure of the ROC (Receiver Operating Characteristic) curve. It both, measures the effectiveness of a diagnostic marker and enables the selection of an optimal threshold value (cutoff point) for the marker. In this paper we compare several estimation procedures for the Youden Index and its associated cutoff point. These are based on (1) normal assumptions; (2) transformations to normality; (3) the empirical distribution function; (4) kernel smoothing. These are compared in terms of bias and root mean square error in a large variety of scenarios by means of an extensive simulation study. We find that the empirical method which is the most commonly used has the overall worst performance. In the estimation of the Youden Index the kernel is generally the best unless the data can be well transformed to achieve normality whereas in estimation of the optimal threshold value results are more variable.
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            Tumor Treatment Response Based on Visual and Quantitative Changes in Global Tumor Glycolysis Using PET-FDG Imaging. The Visual Response Score and the Change in Total Lesion Glycolysis.

            Cecille Casilla, Paula Cohen, T Akhurst … (1999)
            "Functional" tumor treatment response parameters have been developed to measure treatment induced biochemical changes in the entire tumor mass, using positron emission tomography (PET) and [F-18] fludeoxyglucose (FDG). These new parameters are intended to measure global changes in tumor glycolysis. The response parameters are determined by comparing the pre- and posttreatment PET-FDG images either visually from the change in image appearance in the region of the tumor, or quantitatively based on features of the calibrated digital PET image. The visually assessed parameters are expressed as a visual response score (VRS), or visual response index (VRI), as the estimated percent response of the tumor. Visual Response Score (VRS) is recorded on a 5 point response scale (0-4): 0: no response or progression; 1: 1-33%; 2: >33%-66%; 3: >66%-99%; and 4: >99%, estimated response, respectively. The quantitative changes are expressed as total lesion glycolysis TLG or as the change in TLG during treatment, also called deltaTLG or Larson-Ginsberg Index (LGI), expressed as percent response. The volume of the lesion is determined from the PET-FDG images by an adaptive thresholding technique. This response index is computed as, deltaTLG (LGI) = {[(SUV(ave))(1) * (Vol)(1) - (SUV(ave))(2) * (Vol)(2)]/[(SUV(ave))(1) * (Vol)(1)]} * 100. Where "1" and "2" denote the pre- and posttreatment PET-FDG, scans respectively. Pre- and posttreatment PET-FDG scans were performed on a group of 41 locally advanced lung (2), rectal (17), esophageal (16) and gastric (6) cancers. These patients were treated before surgery with neoadjuvant chemo-radiation. Four experienced PET readers determined individual VRS and VRI blinded to each other as well as to the clinical history. Consensus VRS was obtained based on a discussion. The interobserver variability captured by intraclass correlation coefficient was 89.7%. In addition, reader reliability was assessed for the categorized VRS using Kendall's coefficient of concordance for ordinal data and was found to be equal to 85% This provided assurance that these response parameters were highly reproducible. The correlation of deltaTLG with % change in SUV(ave) and % change in SUV(max), as widely used parameters of response, were 0.73 and 0.78 (P <.0001) respectively. The corresponding correlation of VRI were 0.63 and 0.64 (P <.0001) respectively. Both deltaTLG and VRI showed greater mean changes than SUV maximum or average (59.7% and 76% vs. 46.9% and 46.8%). We conclude that VRS and deltaTLG are substantially correlated with other response parameters and are highly reproducible. As global measures of metabolic response, VRS, VRI and deltaTLG (LGI) should provide complementary information to more commonly used PET response parameters like the metabolic rate of FDG (MRFDG), or the standardized uptake value (SUV), that are calculated as normalized per gram of tumor. These findings set the stage for validation studies of the VRS and deltaTLG as objective measures of clinical treatment response, through comparison to the appropriate gold standards of posttreatment histopathology, recurrence free survival, and disease specific survival in well characterized populations of patients with locally advanced cancers.
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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.

              Armando Bartolazzi, Fabio Orlandi, Enrico Saggiorato … (2008)
              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. 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. 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. 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.
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                Author and article information

                Contributors
                K. Alok Pathak
                Journal
                Journal ID (nlm-ta): Ann Med Surg (Lond)
                Journal ID (iso-abbrev): Ann Med Surg (Lond)
                Title: Annals of Medicine and Surgery
                Publisher: Elsevier
                ISSN (Electronic): 2049-0801
                Publication date PMC-release: 31 October 2016
                Publication date Collection: December 2016
                Publication date (Electronic): 31 October 2016
                Volume: 12
                Pages: 27-31
                Affiliations
                [a ]Division of Surgical Oncology, Cancer Care Manitoba & University of Manitoba, Winnipeg Canada
                [b ]Section of Nuclear Medicine, Department of Radiology, University of Manitoba, Winnipeg Canada
                [c ]Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg Canada
                Author notes
                [∗ ]Corresponding author. Head and Neck Surgical Oncologist, Cancer Care Manitoba, ON2048, 675 McDermot Avenue, Winnipeg R3E 0V9, Canada.Head and Neck Surgical OncologistCancer Care ManitobaON2048, 675 McDermot AvenueWinnipegR3E 0V9Canada apathak@ 123456cancercare.mb.ca
                Article
                Publisher ID: S2049-0801(16)30145-5
                DOI: 10.1016/j.amsu.2016.10.008
                PMC ID: 5109254
                SO-VID: 6a7e6384-4632-40a0-b4e4-3fd9d12a6e3c
                Copyright © © 2016 The Authors
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 2 September 2016
                Date revision received : 26 October 2016
                Date accepted : 27 October 2016
                Categories
                Subject: Original Research

                Keywords: diagnosis,outcome,imaging,nuclear,follicular,neoplasm
                Data availability:
                Keywords: diagnosis, outcome, imaging, nuclear, follicular, neoplasm

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