In a retrospective study of patients with differentiated thyroid cancer (DTC) from the California Cancer Registry, Park et al. (1) showed that the rate of I-131 ablation decreased significantly from 67.4% in 1999 to 48.6% in 2015 for patients with localized tumors between 2 and 4 cm (no extrathyroidal extension, lymph node, or distant metastases) after the implementation of the 2009 American Thyroid Association (ATA) guidelines. They concluded that many patients with low-risk DTC still underwent potentially unnecessary I-131 ablation for tumors 2 to 4 cm with localized disease. However, many other factors should be considered before stratifying 2- to 4-cm localized tumors as low risk and before determining that I-131 ablation is unnecessary. First, some of the patients stratified as low risk in their study may be at intermediate risk. Not all 2- to 4-cm localized tumors, which, using the tumor–node–metastasis (TNM) staging system, are stage II T2N0M0, can be categorized as low risk because the risk of recurrence stratification in the 2009 ATA guidelines is not based solely on primary tumor size. In the Park et al. (1) study, “low-risk DTC was classified by both tumor size and summary stage at the time of diagnosis, in accordance with the 2009 ATA guidelines.” However, in addition to the major criteria in the 7th American Joint Committee on Cancer TNM staging system, the risk for recurrence is predicted by several other histopathologic features. Low-risk DTC needed to have complete resection, no aggressive histology (e.g., tall cell, insular, columnar, solid variant), and no invasion of locoregional tissues or structures. Furthermore, nonpapillary histologies (such as follicular and Hürthle cells) were considered as higher risk tumors. Second, the 2009 ATA guideline’s recommendation on I-131 ablation is based on risk stratification and not solely on tumor size and extension. The guidelines did not make recommendations against I-131 ablation for 2- to 4-cm localized tumors; instead, it recommended for I-131 ablation in a selected group of T2N0M0 patients (2). Patient age and histology are other factors that predict intermediate to high risk of recurrence or mortality (3). If a 2- to 4-cm primary tumor confined to the thyroid had higher risk features, the patient may be stratified as intermediate or high risk of recurrence, then I-131 ablation is recommended per the 2009 ATA guidelines recommendation 32b. Therefore, it is still appropriate that selected patients with higher risk features and older age receive I-131 ablation for 2- to 4-cm intrathyroidal DTC. In the absence of histologic information, the decision for I-131 ablation depends on clinical judgment. Hence, it is inappropriate to conclude that “many patients with low-risk DTC still receive I-131 ablation unnecessarily” in a retrospective study when the factors for considering I-131 ablation in patients with 2- to 4-cm localized DTC were not assessed in the study. Their study reminds us that in the future with the current updated 2015 ATA guidelines (4), there are even more factors to consider when deciding I-131 ablation for 2- to 4-cm localized DTC (e.g., BRAF mutation and TERT mutation). BRAFV600E mutation has been shown to be associated with a higher rate of recurrence (8%, 8 of 106) compared with wild-type (1%, 2 of 213) in patients with 0.1- to 4-cm N0M0 DTC (5). In 2- to 4-cm solitary intrathyroidal tumors specifically, recurrence rates were 16.5% (13 of 79) in BRAFV600E mutation vs 3.6% (5 of 139) in wild-type patients (6). Furthermore, the combination of TERT mutation and BRAF mutation within the same tumor was associated with a higher risk of structural disease recurrence and disease-specific mortality than single mutation or wild-type (7, 8). Additionally, increasing patient age has demonstrated a linear association with increasing mortality in patients with BRAFV600E mutation (9). Given that the decision to give I-131 therapy for 2- to 4-cm localized DTC is based on more than primary tumor size and TNM staging, we need to remember the additional factors to consider for higher risk of recurrence and risk of mortality. It is important to stratify risk in patients with DTC as accurately as possible and to reconsider I-131 therapy in those who are upstaged or dynamically restratified in follow-up. Also, new evidence in support of updating the criteria for low-risk stratification is being evaluated. Abbreviations: Abbreviations: ATA American Thyroid Association DTC differentiated thyroid cancer TNM tumor–node–metastasis. Acknowledgments Disclosure Summary: The authors have nothing to disclose. References 1. Park KW , Wu JX , Du L , Leung AM , Yeh MW , Livhits MJ . Decreasing use of radioactive iodine for low-risk thyroid cancer in California, 1999 to 2015 . J Clin Endocrinol Metab . 2018 ; 103 ( 3 ): 1095 – 1101 . Google Scholar CrossRef Search ADS PubMed 2. Cooper DS , Doherty GM , Haugen BR , Kloos RT , Lee SL , Mandel SJ , Mazzaferri EL , McIver B , Pacini F , Schlumberger M , Sherman SI , Steward DL , Tuttle RM ; American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer . Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer . Thyroid . 2009 ; 19 ( 11 ): 1167 – 1214 . Google Scholar CrossRef Search ADS PubMed 3. Adam MA , Thomas S , Hyslop T , Scheri RP , Roman SA , Sosa JA . Exploring the relationship between patient age and cancer-specific survival in papillary thyroid cancer: rethinking current staging systems . J Clin Oncol . 2016 ; 34 ( 36 ): 4415 – 4420 . Google Scholar CrossRef Search ADS PubMed 4. Haugen BR , Alexander EK , Bible KC , Doherty GM , Mandel SJ , Nikiforov YE , Pacini F , Randolph GW , Sawka AM , Schlumberger M , Schuff KG , Sherman SI , Sosa JA , Steward DL , Tuttle RM , Wartofsky L . 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer . Thyroid . 2016 ; 26 ( 1 ): 1 – 133 . Google Scholar CrossRef Search ADS PubMed 5. Elisei R , Viola D , Torregrossa L , Giannini R , Romei C , Ugolini C , Molinaro E , Agate L , Biagini A , Lupi C , Valerio L , Materazzi G , Miccoli P , Piaggi P , Pinchera A , Vitti P , Basolo F . The BRAFV600E mutation is an independent, poor prognostic factor for the outcome of patients with low-risk intrathyroid papillary thyroid carcinoma: single-institution results from a large cohort study . J Clin Endocrinol Metab . 2012 ; 97 ( 12 ): 4390 – 4398 . Google Scholar CrossRef Search ADS PubMed 6. Huang Y , Qu S , Zhu G , Wang F , Liu R , Shen X , Viola D , Elisei R , Puxeddu E , Fugazzola L , Colombo C , Jarzab B , Czarniecka A , Lam AK , Mian C , Vianello F , Yip L , Riesco-Eizaguirre G , Santisteban P , O’Neill CJ , Xing M , Sywak MS , Clifton-Bligh R , Bendlova B , Sýkorová V . BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment [published online ahead of print 18 November 2017] . J Natl Cancer Inst . doi: 10.1093/jnci/djx227. 7. Xing M , Liu R , Liu X , Murugan AK , Zhu G , Zeiger MA , Pai S , Bishop J . BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence . J Clin Oncol . 2014 ; 32 ( 25 ): 2718 – 2726 . Google Scholar CrossRef Search ADS PubMed 8. Liu R , Bishop J , Zhu G , Zhang T , Ladenson PW , Xing M . Mortality risk stratification by combining BRAF V600E and TERT promoter mutations in papillary thyroid cancer: genetic duet of BRAF and TERT promoter mutations in thyroid cancer mortality . JAMA Oncol . 2017 ; 3 ( 2 ): 202 – 208 . Google Scholar CrossRef Search ADS 9. Shen X , Zhu G , Liu R , Viola D , Elisei R , Puxeddu E , Fugazzola L , Colombo C , Jarzab B , Czarniecka A . Patient age–associated mortality risk is differentiated by BRAFV600E status in papillary thyroid cancer . J Clin Oncol . 2018 ; 36 ( 5 ): 438 – 445 . Google Scholar CrossRef Search ADS PubMed Copyright © 2018 Endocrine Society
Journal of Clinical Endocrinology and Metabolism – Oxford University Press
Published: Mar 13, 2018
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