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 Table of Contents  
Year : 2013  |  Volume : 10  |  Issue : 4  |  Page : 22-23

Beyond cytology-molecular diagnostic testing for thyroid nodules

Division of Endocrinology, Diabetes and Metabolism Perelman School of Medicine, University of Pennsylvania Perelman Center for Advanced Medicine, Pennsylvania, USA

Date of Web Publication2-Feb-2013

Correspondence Address:
Susan J Mandel
Division of Endocrinology, Diabetes and Metabolism Perelman School of Medicine, University of Pennsylvania Perelman Center for Advanced Medicine, 4th floor, west 3400 Civic Center Blvd, Philadelphia PA 19003
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0973-0354.106817

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How to cite this article:
Mandel SJ. Beyond cytology-molecular diagnostic testing for thyroid nodules. Thyroid Res Pract 2013;10, Suppl S1:22-3

How to cite this URL:
Mandel SJ. Beyond cytology-molecular diagnostic testing for thyroid nodules. Thyroid Res Pract [serial online] 2013 [cited 2022 Dec 5];10, Suppl S1:22-3. Available from: https://www.thetrp.net/text.asp?2013/10/4/22/106817

  Introduction Top

Fine-needle aspiration (FNA) biopsy of thyroid nodules provides essential cytology information that allows the clinician to better stratify the likelihood of malignancy, reducing the number of surgeries for patients with benign nodules, and appropriately triaging those with ahigher likelihood of cancer to surgery. Unfortunately, cytology results cannot be simply dichotomized into benign and malignant. After ascertaining that adequate cellularity is present, cytology results have traditionally been categorized as benign, malignant, and indeterminate, but terminology has varied significantly among laboratories, with some using subclassifications within the indeterminate group. To address these inconsistencies in reporting, in 2008, the National Cancer Institute (NCI) of the National Institutes of Health organized a conference of expert cytopathologists to standardize the reporting of FNA cytology, which led to the resulting six category scheme called the "Bethesda System". [1] Each of its five diagnostic categories is associated with a risk estimate for thyroid cancer, and the indeterminate group was separated into three distinct diagnostic groups: Atypia of uncertain significance (AUS)/follicular lesion of uncertain significance (FLUS) (cancer risk 10-15%), follicular neoplasm (FN) (cancer risk 20-30%), and suspicious for malignancy (SUSP) (cancer risk 50-75%). [1]

Over the ensuing 5 years, the Bethesda system has been widely adapted and with recent estimates that about 15-20% of all FNA cytology results are diagnosed as FLUS or FN. [2] The traditional paradigm of care for this group of patients has involved diagnostic lobectomy for definitive histological diagnosis. Molecular testing is rapidly emerging as a useful test in the evaluation of these cytologically indeterminate nodules. Two commercial tests are available, with different test performance characteristics that can aid clinicians in either recommending surveillance or surgery. Both require ribonucleic acid (RNA) obtained from nodule FNA for analysis and are intended to be used after an indeterminate cytology diagnosis.

One approach is to identify specific mutations associated with key cell-signaling cascades known to be strongly associated with thyroid cancer. These include testing for point mutation in BRAF and RAS, both involved in the MAP Kinase pathway, as well as for rearrangements of RET/PTC (a tyrosine kinase proto-oncogene) and PAX8/PPAR0γ (a transcription factor). Overall, 70-75% of papillary thyroid cancers (PTC) harbor one of these mutations, with BRAF V600E being most common (present in 40%). The prevalence of the mutation/rearrangement also varies with the specific PTC subtype. For example, 60% of tall cell PTC is associated with BRAF mutations but RAS mutations are more common in the follicular variant of PTC (20%). Furthermore, about 70% of follicular thyroid cancers harbor mutations in KRAS codon12/13, HRAS or NRAS codon 61 or a PAX8/PPARγ rearrangement. [3] However, since 30% of thyroid cancers do not express a mutation, this molecular test panel does not have optimal sensitivity, and the false negative rate is high. Hence, a negative result from this test panel does not assure benignity. In addition, since the majority of nodules with FLUS or FN cytology are benign (over 70%), the frequency of detecting these mutational markers is low for these cytology groups, but increases if applied to SUSP cytology nodules. On the other hand, this panel has high specificity (>95%) and, hence, high positive predictive value (PPV), with the only false positive results associated with RAS mutations that prove to be follicular adenomas at surgery. [4] Therefore, the results from this test should not be used to counsel against surgical intervention, but the test can be helpful when deciding whether the initial surgical procedure should be lobectomy or thyroidectomy. In this scenario, it has been found to be cost effective, provided the cost of the test is <870USD. [5]

Another available test is a proprietary multigene expression classifier (GEC) developed in the USA that analyzes cellular RNA expression signatures based upon the pattern of expression of 142 different genes. The test was developed to have high sensitivity for detection of thyroid cancer, with the ultimate goal of leading to a high negative predictive value (NPV) in cytologically indeterminate nodules (FLUS or FN, malignancy risk ~25%) so that diagnostic lobectomy could be avoided if the test is considered negative. The GEC was recently validated in a prospective multicenter study. [6] Based upon GEC results, the nodule is classified as either benign or suspicious. For nodules with FLUS or FN cytology, the NPV of a benign result was 94%. However, the NPV decreases significantly if the test is used forcytologically SUSP nodules where the a priori cancer risk is higher (60-75%); therefore, the GEC should not be performed for these nodules. In the validation study, the missed cancers among the FLUS or FN cytology nodules were largely attributed to borderline follicular cell nucleic acid content in the submitted samples. Cost effectiveness analysis of this test must take into account all of the costs of continued surveillance over a patient's lifetime and the possibilities of additional FNA, as well as the costs of missed cancers. The one published cost effectiveness analysis employed only a 5-year follow-up period and was computed using higher sensitivity and specificity estimates than reported in the final validation study. [7] Therefore, it likely overestimates the cost savings of avoiding surgery with a benign GEC result compared to what should be expected in real practice.

Currently, both clinical experience with molecular testing and publications investigating the application of these molecular methods are limited. The performance of both the GEC and the mutation analysis panelare dependent upon the now well-recognized interobserver classification of indeterminate nodule cytologies into the specific subcategories of FLUS, FN, or SUSP. [8] This directly impacts the associated histologic malignancy rates and subsequently the NPV and PPV estimates associated with each molecular test. Ongoing research in this field will continue to identify new molecular markers and future clinical trials are needed that will better refine both the utility and limitations of these markers in clinical practice.

  References Top

1.Baloch ZW, LiVolsi VA, Asa SL, Rosai J, Merino MJ, Randolph G, et al. Diagnostic terminology and morphologic criteria for cytologic diagnosis of thyroid lesions: A synopsis of the National Cancer Institute Thyroid Fine-Needle Aspiration State of the Science Conference. Diagn Cytopathol 2008;36:425-37.  Back to cited text no. 1
2.Bongiovanni M, Spitale A, Faquin WC, Mazzucchelli L, Baloch ZW. The Bethesda System for Reporting Thyroid Cytopathology: A meta-analysis. Acta Cytol 2012;56:333-9.  Back to cited text no. 2
3.Nikiforov YE, Nikiforova MN. Molecular genetics and diagnosis of thyroid cancer. Nat Rev Endocrinol 2011;7:569-80.  Back to cited text no. 3
4.Nikiforov YE, Ohori NP, Hodak SP, Carty SE, LeBeau SO, Ferris RL, et al. Impact of mutational testing on the diagnosis and management of patients with cytologically indeterminate thyroid nodules: A prospective analysis of 1056 FNA samples. J Clin Endocrinol Metab 2011;96:3390-7.  Back to cited text no. 4
5.Yip L, Farris C, Kabaker AS, Hodak SP, Nikiforova MN, McCoy KL, et al. Cost impact of molecular testing for indeterminate thyroid nodule fine-needle aspiration biopsies. J Clin Endocrinol Metab 2012;97:1905-12.  Back to cited text no. 5
6.Alexander EK, Kennedy GC, Baloch ZW, Cibas ES, Chudova D, Diggans J, et al. Preoperative diagnosis of benign thyroid nodules with indeterminate cytology. N Engl J Med 2012;367:705-15.  Back to cited text no. 6
7.Li H, Robinson KA, Anton B, Saldanha IJ, Ladenson PW. Cost-effectiveness of a novel molecular test for cytologically indeterminate thyroid nodules. J Clin Endocrinol Metab 2011;96:E1719-26.  Back to cited text no. 7
8.Walts AE, Bose S, Fan X, Frishberg D, Scharre K, de Peralta-Venturina M, et al. A simplified Bethesda System for reporting thyroid cytopathology using only four categories improves intra- and inter-observer diagnostic agreement and provides non-overlapping estimates of malignancy risks. Diagn Cytopathol 2012;40(Suppl 1):E62-8.  Back to cited text no. 8


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