Original Title: Avis: pertinence de l’utilisation des tests moléculaires pour préciser le diagnostic des nodules thyroïdiens à cytologie indéterminée

Authors' objectives: The Direction de la biovigilance et de la biologie médicale (DBBM) of the Direction générale des affaires universitaires, médicales, infirmières et pharmaceutiques (DGAUMIP) of the Ministère de la Santé et des Services sociaux (MSSS) asked INESSS to assess the advisability of using molecular tests to clarify the diagnosis of thyroid nodules with indeterminate cytology. The purpose of this report is to facilitate the requestor’s decision: 1) by evaluating the performance of the available molecular tests for predicting the histopathologic diagnosis of benign nodules (clinical and analytical validity); 2) by assessing the ability of these tests to reduce the number of unnecessary surgeries; 3) by examining the safety of observation for cytologically indeterminate nodules with a benign molecular test result; 4) by providing a picture of the current management of thyroid nodules with indeterminate cytology; and 5) by estimating the economic impact of covering this type of test.

Authors' results and conclusions: RESULT: Clinical validation data have been published for two of the three molecular tests currently available on the U.S. market. The benign call rate (BCR), which corresponds to the population likely to avoid surgery, was 61 % with ThyroSeq v3 and 54 % with Afirma GSC. Similar figures for sensitivity (> 90 %) and negative predictive value (> 95 %) were observed for both tests, while specificity was 82 % for ThyroSeq v3 and 68 % for Afirma GSC. Since the NPV varies according to the prevalence of the disease in the population in which the test is performed, the residual risk when the result is negative also varies according to the context. Bayes' theorem predicts that surgery can be safely avoided (with a residual risk ≤ 5 %) if the local disease prevalence is less than 40 % when the result is obtained with ThyroSeq v3 and less than 29 % when Afirma GSC is used. However, in a context where the use of molecular tests helps limit the number of nodules resected, the local prevalence rate for the disease is unknown. Many authors have used different approaches to estimate the residual risk of disease following a benign molecular test result. These approaches, however, yielded imprecise results, either because unresected nodules were excluded from the equation or because all unresected nodules were considered histologically benign from the outset. The literature review indicated that the use of the "indeterminate" category to characterize the cytology result varies widely from study to study. Some variation in the interpretation of the cytology result by different cytopathologists was also documented. Thus, each healthcare facility’s experience in the cytopathologic examination of thyroid fine-needle aspirates could influence the contents of the indeterminate category (disease prevalence) and, consequently, the residual risk of unresected molecularly benign nodules. In Québec, the analysis of the contextual data revealed significant differences in the annual number of FNABs compiled for each healthcare facility. Therefore, the residual risk of disease following a benign molecular test result is likely to vary greatly from one facility to another. Although disease prevalence has an impact on the tests’ local performance for identifying benign nodules, the experts consulted expressed little concern over this variable and its effect on the residual risk of disease in the case of a benign molecular test result. In their view, with the clinical/ultrasonographic monitoring reserved for molecularly benign nodules and with the slow progression of early-stage malignant lesions, it could be expected that any false-negative nodules that may have escaped molecular detection would be detected, if applicable, without this causing significant harm to the patients concerned. Nevertheless, molecularly benign nodules should be observed closely to ensure early identification of false-negative nodules that could progress to aggressive cancers. The case of patients lost to clinical follow-up is a concern in this regard. The thyroid surgery rate for cytologically indeterminate nodules subjected to molecular testing was identified in order to assess the clinical utility of each test (based on the version evaluated). In the absence of an adequate comparison with current practice (no testing), the data compiled for all the nodules analyzed with each test showed resection rates of 51 %, 27 %, 44 % and 44 % for Afirma GEC, Afirma GSC and ThyroSeq v2.1 and v3, respectively. According to the data from the same studies, the proportion of patients likely to avoid surgery based on the BCR (benign call rate) was 44 % with Afirma GEC, 68 % with the Afirma GSC, 74 % with the ThyroSeq v2.1 and 58 % with ThyroSeq v3. The proportion of molecularly benign nodules resected was 14 %, 6 %, 33 % and 7 % with Afirma GEC, Afirma GSC, and ThyroSeq v2.1 and v3, respectively. Overall, the level of evidence associated with the clinical utility demonstration is low. The published data for the currently available versions is limited. In the studies identified, the experimental group, which consisted of nodules subjected to molecular testing, was not directly compared with a group representing the standard practice and consisting of nodules with similar characteristics evaluated over the same period. In several studies, the criteria guiding the use of the test were not known or absent (systematic use). When the tests were used selectively, the selection criteria were rarely stated. In addition, because the median follow-up was rarely indicated by the authors, it was generally unclear whether the duration of follow-up was long enough to identify all the nodules resected after molecular testing. Thus, there is still some doubt as to the actual impact of these tests in the target population. However, the experts were of the opinion that the health need stemming from the diagnosis of thyroid nodules with indeterminate cytology is significant and that covering the molecular tests evaluated would have a favourable clinical and organizational impact.

Authors' recommendations: The Institut national d'excellence en santé et en services sociaux (INESSS) recognizes the promise held by ThyroSeq v3 and Afirma GSC for clarifying the diagnosis of thyroid nodules in certain cases of indeterminate cytology. However, given the uncertainty regarding these tests’ validity and clinical utility and the impact of certain variables on the costs of the molecular approach, INESSS feels that public coverage of these tests could constitute a fair and reasonable decision if the following conditions are met: • Their use should be limited to patients whose test result is likely to influence management. Eligible nodules should have the following characteristics: – Bethesda III (after a 2nd FNAB) or Bethesda IV category cytology; and – 1 to 4 cm in size; and – Exhibit intermediate clinical or ultrasonographic risk factors (equivocal or discordant). Molecular testing should not be proposed to patients for whom surgery is indicated (high-risk factors), those for whom diagnostic lobectomy is not being considered because of a low risk of malignancy, or those who express a preference for surgery or observation. • The prior implementation of a clinical validation step in the Québec context . • An agreement with the manufacturer to share the financial risk is concluded. Other items: • The patient must be informed of the residual risk of malignancy associated with the decision not to resect a cytologically indeterminate nodule with a benign molecular test result before opting for molecular testing. • Patients with a molecularly benign nodule should be followed every 12 to 24 months for 4 to 5 years to ensure early identification of any false-negative nodules that could progress to aggressive cancers. • INESSS suggests that prospective data be gathered to compile information regarding 1) the basic characteristics of nodules selected for molecular testing (Bethesda III or IV, size, ultrasonographic characteristics), 2) the choice of test (ThyroSeq v3 or Afirma GSC) and the test result (benign or suspicious) and 3) the subsequent management decision (observation or surgery). These data can then be examined, after which a review of the eligibility criteria or an optimal use guide could be proposed.

Authors' methods: A rapid review of the scientific literature was conducted to document the various aspects related to the performance and clinical utility of the molecular tests, the patient perspective, and the efficiency data published in other countries and provinces. The picture of current thyroid nodule management in Québec was constructed from experiential and contextual data from consultations with Québec experts and the Régie de l'assurance maladie du Québec (RAMQ)’s SMOD database. These data were also used to perform an economic analysis.

Project Status: Completed

URL for project: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/pertinence-dutilisation-des-tests-moleculaires-pour-preciser-le-diagnostic-des-nodules-thyroidiens-a-cytologie-indeterminee.html

Year Published: 2021

URL for published report: https://www.inesss.qc.ca/publications/repertoire-des-publications/publication/pertinence-dutilisation-des-tests-moleculaires-pour-preciser-le-diagnostic-des-nodules-thyroidiens-a-cytologie-indeterminee.html

English language abstract: An English language summary is available

Publication Type: Full HTA

Country: Canada

Province: Quebec

Organisation Name: Institut national d'excellence en sante et en services sociaux

Contact Address: L'Institut national d'excellence en sante et en services sociaux (INESSS) , 2021, avenue Union, bureau 10.083, Montreal, Quebec, Canada, H3A 2S9;Tel: 1+514-873-2563, Fax: 1+514-873-1369

Contact Name: demande@inesss.qc.ca

Contact Email: demande@inesss.qc.ca

Copyright: Gouvernement du Québec