Impact of BRAF V600E Mutation on Surgical Management and Outcomes in Low-Risk Differentiated Thyroid Carcinoma (T1–2N0M0)

Impact of BRAF V600E Mutation on Surgical Management and Outcomes in Low-Risk Differentiated Thyroid Carcinoma (T1–2N0M0) | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Impact of BRAF V600E Mutation on Surgical Management and Outcomes in Low-Risk Differentiated Thyroid Carcinoma (T1–2N0M0) Robert Králik, Eva Takácsová, Štefan Durdík, Marianna Grigerová This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9407674/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 4 You are reading this latest preprint version Abstract Background The clinical relevance of the BRAF V600E mutation in the surgical management of early-stage differentiated thyroid carcinoma (DTC) remains unclear. Although common in papillary thyroid carcinoma, its role in guiding surgical decisions in low-risk disease is still debated. Methods We conducted a retrospective single-center study of patients with low-risk DTC (T1–2N0M0) treated surgically between 2000 and 2024. Preoperative BRAF V600E status was available in a subset of patients. The primary endpoint was the association between BRAF status and extent of surgery (lobectomy vs. total thyroidectomy). Secondary endpoints included central compartment lymph node metastases, use of postoperative radioiodine therapy, recurrence requiring reoperation, and overall outcomes. Results Of 196 patients, BRAF status was known in 91 (42 positive, 49 negative). Baseline characteristics were similar between groups. Total thyroidectomy was more frequent in BRAF-positive patients (69% vs. 35.7%; OR 4.199, p = 0.011). Central compartment lymph node metastases were also more common in BRAF-positive tumors (45.2% vs. 14.3%; OR 4.957, p = 0.014). However, rates of clinically significant metastases (≥ 5 nodes or > 2 mm) did not differ significantly. Radioiodine therapy was used more often in BRAF-positive patients (64.3% vs. 30.6%; OR 4.08, p = 0.013). No significant differences in overall treatment outcomes were observed at the end of follow-up. Conclusion BRAF V600E mutation was associated with higher rates of lymph node metastases and more aggressive treatment but did not impact long-term outcomes. These findings support current recommendations that BRAF status alone should not determine surgical extent in low-risk DTC. BRAF V600E differentiated thyroid carcinoma thyroidectomy lymph node metastases risk stratification Introduction Mutations in the BRAF gene occur in approximately 4–8% of all human malignancies and are particularly prevalent in melanoma, thyroid carcinoma, colorectal carcinoma, and non–small cell lung cancer (1). In thyroid malignancies, BRAF mutations are detected in approximately 45–50% of papillary thyroid carcinomas and in 25–30% of anaplastic thyroid carcinomas, whereas they are generally absent in follicular thyroid carcinoma and benign thyroid lesions (2). The BRAF V600E mutation leads to constitutive activation of the MAPK signaling pathway, promoting tumor proliferation, dedifferentiation, and resistance to apoptosis (3). Consequently, identification of BRAF mutation status has important diagnostic, prognostic, and therapeutic implications, particularly in patients with advanced or radioiodine-refractory disease, where targeted therapies such as combined BRAF and MEK inhibition may be beneficial (4,5). Despite these advances, the clinical relevance of BRAF mutation status in the management of early-stage differentiated thyroid carcinoma remains uncertain. While several studies have reported associations between BRAF mutation and aggressive clinicopathological features—including lymph node metastases, extrathyroidal extension, and disease recurrence—other studies have questioned its independent prognostic value, particularly in low-risk tumors. This uncertainty is reflected in current clinical guidelines. The American Thyroid Association recommends that BRAF mutation status should not be used in isolation to determine the extent of initial surgical treatment. Instead, it should be interpreted in conjunction with established clinicopathological risk factors (6). Given the increasing interest in molecular markers in thyroid cancer management, further evidence is needed to clarify whether BRAF mutation status has practical implications for surgical decision-making in patients with low-risk disease. Study Objective The objective of this study was to evaluate the impact of BRAF V600E mutation status on the surgical management of patients with initially low-risk differentiated thyroid carcinoma (T1–2N0M0). Specifically, we aimed to assess whether BRAF mutation status influences the extent of thyroid surgery, the incidence of central compartment lymph node metastases, and overall treatment outcomes. Patients and Methods Study Design and Ethics This single-center study was conducted over a five-year period (1.1.2020–31.12.2024). The study protocol was approved by the local ethics committee on April 23, 2026 under number 2/4/2026 without comments. Patients Patients aged 17–82 years, regardless of sex, were eligible for inclusion if they met the preoperative criteria for low-risk thyroid carcinoma, defined as a unifocal tumor measuring ≤ 4 cm, confined to the thyroid gland, and without evidence of lymph node or distant metastases. All included patients underwent preoperative testing for the BRAF V600E mutation. Preoperative Assessment Standard preoperative evaluation included neck ultrasonography and fine-needle aspiration biopsy of suspicious thyroid nodules. However, no standardized protocol regarding the extent of thyroidectomy was applied, and patients were referred either for lobectomy or total thyroidectomy according to the treating physician’s discretion. Follow-up and Outcomes Follow-up was conducted from February 1, 2020, to December 31, 2024 (range 1–60 months). The primary endpoint was the influence of preoperatively identified BRAF mutation status on the extent of thyroid surgery (lobectomy vs. total thyroidectomy). Secondary endpoints included: incidence and characteristics of central compartment lymph node metastases clinically significant metastases, defined as > 5 metastatic lymph nodes or metastatic deposits > 2 mm administration of postoperative radioactive iodine therapy disease recurrence requiring reoperation overall treatment outcomes, including biochemical or structural persistence of disease Statistical Analysis Continuous variables (Lymph node ratio and Lymph node size) were compared between groups using two-sample t-tests, with the null hypothesis of equal means Categorical variables were analyzed using the Wald test for odds ratios with the null hypothesis of an odds ratio equal to 1. All statistical tests were conducted at a nominal significance level of α = 0.05, with Bonferroni correction applied for multiple comparisons. All statistical analyses were performed using R software ( https://www.r-project.org/ ). Results Between January 1, 2000, and December 31, 2024, a total of 196 patients (aged 17-82 years; median age, 41 years; 83,5% female), with low-risk differentiated thyroid carcinoma measuring 11–40 mm and without metastases (T1b–2N0M0) underwent surgery at the Department of Oncologic Surgery, Faculty of Medicine, Comenius University, and the St. Elizabeth Cancer Institute (see Table 1). BRAF V600E mutation status was evaluated in 91 patients included in the study. Among them, 42 patients were BRAF-positive and 49 were BRAF-negative. The two groups were comparable with respect to age, sex distribution, and tumor size (see Table 1). Total thyroidectomy was significantly more frequently performed in BRAF-positive patients (69%) compared with BRAF-negative patients (35.7%) (OR 4.199, p = 0.011). Among patients initially treated with lobectomy, no significant difference was observed in the presence of risk factors indicating the need for completion thyroidectomy (OR 0.764, p = 1.0). Central compartment lymph node metastases were significantly more frequent in BRAF-positive patients (45.2%) than in BRAF-negative patients (14.3%) (OR 4.957, p = 0.014). However, the proportion of clinically significant metastases (≥5 affected nodes or >2 mm) was similar in both groups (68.4% vs. 81.8%, OR 0.481, p = 1.0). No statistically significant differences were observed in the lymph node ratio or the size of metastatic lymph nodes. Radioiodine therapy was administered significantly more frequently in the BRAF-positive group (64.3% vs. 30.6%, OR 4.08, p = 0.013), reflecting the higher proportion of patients treated with total thyroidectomy. At the end of follow-up (December 31, 2024), treatment outcomes did not differ significantly between the groups. In the BRAF-positive group, five patients required reoperation due to cervical lymph node recurrence, and one patient demonstrated biochemical persistence of disease. In the BRAF-negative group, one patient had biochemical persistence and one developed pulmonary metastases. No reoperations for lymph node recurrence were required in the BRAF-negative group (see Table 2). Discussion Differentiated thyroid carcinoma is generally associated with an excellent prognosis, with cure rates approaching 95%, disease persistence of approximately 5%, and disease-specific mortality around 1.1% (7). Despite these favorable outcomes, the optimal individualization of treatment remains a matter of ongoing debate, particularly with regard to the clinical utility of molecular markers such as the BRAF V600E mutation. According to current American Thyroid Association guidelines, BRAF mutation status alone should not be used to determine the extent of initial surgery (6). Rather, its clinical relevance should be interpreted in the context of established clinicopathological risk factors to guide surgical management while avoiding overtreatment in low-risk patients. In our cohort, BRAF positivity was not associated with adverse histopathological features, such as extrathyroidal extension, angioinvasion, or other aggressive characteristics that would independently justify total thyroidectomy. These findings support the notion that BRAF mutation status alone is insufficient to guide surgical decision-making. Nevertheless, BRAF-positive tumors were more frequently associated with metastases in the central neck compartment. These were predominantly micrometastases involving fewer than five lymph nodes, consistent with a low-risk disease profile (8). No significant differences were observed in metastatic burden or lymph node size, suggesting that this association reflects a quantitative rather than qualitative difference in lymphatic spread. In our previous study (2017), we demonstrated that the prognostic significance of the BRAF mutation varies with patient age (9). Increased risk was observed in patients younger than 35 years and older than 60 years, whereas in the intermediate age group (35–60 years), BRAF mutation appeared to have a neutral or even protective effect. In the present cohort, with a median age of 43 years and the majority of patients within the intermediate age group, BRAF mutation was likewise not associated with worse prognosis. These findings are partially consistent with previous reports. Zhang et al. (10) identified BRAF V600E as an independent predictor of central lymph node metastases based on fine-needle aspiration biopsy. However, the impact of this association on long-term outcomes, particularly in low-risk tumors, remains unclear. Similarly, prior studies have shown that BRAF V600E status does not significantly increase recurrence rates in low-risk tumors ≤ 2 cm during short-term follow-up (11,12), underscoring the need for cautious interpretation of BRAF mutation as a sole indication for adjuvant therapy. Although BRAF mutation alone does not appear to significantly affect mortality, its combination with lymph node metastases has been associated with a markedly increased risk of death (HR 25.78), suggesting a synergistic interaction between molecular and anatomical risk factors (13). The role of ipsilateral diagnostic dissection of the central neck compartment in the presence of intraoperatively identified enlarged lymph nodes remains controversial. Raffaelli et al. have advocated intraoperative frozen section examination of suspicious lymph nodes, with completion of the surgical procedure to total thyroidectomy during the same operation if metastasis is confirmed (14). This approach may be particularly relevant in BRAF -positive tumors, given their higher incidence of central compartment metastases. Large multinational studies have also reported higher recurrence rates in BRAF-mutated papillary thyroid carcinomas larger than 2–3 cm, indicating that the prognostic impact of the mutation may be more pronounced in larger tumors (11,12). Accordingly, several authors caution against overinterpreting BRAF V600E as an independent marker of poor prognosis, particularly in tumors smaller than 2 cm (8,9). In such cases, lobectomy remains an adequate treatment option unless additional high-risk molecular alterations, such as TERT promoter mutations, are present (15). In our cohort, radioiodine therapy was more frequently administered to BRAF-positive patients, likely reflecting the higher rates of total thyroidectomy and central compartment metastases. Importantly, no significant differences were observed in recurrence, regional lymph node involvement, or distant metastases during follow-up, supporting a risk-adapted and individualized treatment approach. This observation is in line with the results reported by Leboulleux S. and colleagues, who also did not demonstrate a clear impact of BRAF mutation status on clinical outcomes when management was tailored according to established risk stratification systems (16). This study has several limitations. First, its retrospective design may be associated with inherent selection bias. Second, BRAF mutation status was available only in a subset of patients, which may limit the generalizability of the findings. Third, the sample size of the analyzed subgroups was relatively small, potentially reducing the statistical power to detect subtle differences in outcomes. In addition, the follow-up duration, although adequate for early outcomes, may not fully capture late recurrences typical of differentiated thyroid carcinoma. Finally, the study was conducted at a single center, which may limit the external validity of the results. Conclusion Our findings support the current trend toward individualized management of differentiated thyroid carcinoma. BRAF mutation status should not be interpreted in isolation but rather in the context of the patient’s overall clinical, pathological, and molecular profile. Given the higher incidence of central compartment lymph node metastases observed in BRAF-positive tumors, diagnostic ipsilateral central neck dissection may be considered in selected patients with low-risk differentiated thyroid carcinoma, particularly for tumors larger than 10 mm. However, further prospective studies with long-term follow-up are required to better define the prognostic and therapeutic significance of BRAF mutation in early-stage thyroid carcinoma. Declarations Funding This study was supported by the Cultural and Educational Grant Agency (KEGA), Grant No. 025UK-4/2024 Author Contribution R.K. wrote the main manuscript, E.T. collaborated on writing the discussion, M.G. collaborated on the acquisition of patient data. All authors reviewed the manuscript. Corresponding authors: Robert Králik and Eva Takácsová References Owsley J, Stein MK, Porter J, et al. Prevalence of class I–III BRAF mutations among 114,662 cancer patients in a large genomic database. Exp Biol Med 2021 246 31–39. (https://doi.org/10.1177/1535370220959657) Cohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003 95 625–627. (https://doi.org/10.1093/jnci/95.8.625) Xing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun;12(2):245-62. doi: 10.1677/erc.1.0978. PMID: 15947100. Scheffel, R. S., Dora, J. M., & Maia, A. L. (2022). BRAF mutations in thyroid cancer. Current opinion in oncology , 34 (1), 9–18. https://doi.org/10.1097/CCO.0000000000000797 Bapat, N., Ferraro, T., Esper, L., Joshi, A. S., Haroun, F., & Baldwin, C. K. (2024). Treatment of Unresectable BRAF V600E , TERT -Mutated Differentiated Papillary Thyroid Cancer With Dabrafenib and Trametinib. JCEM case reports , 2 (8), luae112. https://doi.org/10.1210/jcemcr/luae112 Ringel, M. D., Sosa, J. A., Baloch, Z., Bischoff, L., Bloom, G., Brent, G. A., Brock, P. L., Chou, R., Flavell, R. R., Goldner, W., Grubbs, E. G., Haymart, M., Larson, S. M., Leung, A. M., Osborne, J. R., Ridge, J. A., Robinson, B., Steward, D. L., Tufano, R. P., & Wirth, L. J. (2025). 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. Thyroid : official journal of the American Thyroid Association , 35 (8), 841–985. https://doi.org/10.1177/10507256251363120 Kim K, Kim JK, Lee CR, et al. Comparison of long-term prognosis for differentiated thyroid cancer according to the 7th and 8th editions of the AJCC/UICC TNM staging system. Ther Adv Endocrinol Metab , 2020; 11:2042018820921019; Crossref Randolph, G. W., Duh, Q. Y., Heller, K. S., LiVolsi, V. A., Mandel, S. J., Steward, D. L., Tufano, R. P., Tuttle, R. M., & American Thyroid Association Surgical Affairs Committee’s Taskforce on Thyroid Cancer Nodal Surgery (2012). The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. Thyroid : official journal of the American Thyroid Association , 22 (11), 1144–1152. https://doi.org/10.1089/thy.2012.0043 Takacsova, E., Kralik, R., Waczulikova, I., Zavodna, K., & Kausitz, J. (2017). A different prognostic value of BRAFV600E mutation positivity in various age groups of patients with papillary thyroid cancer. Neoplasma , 64 (1), 156–164. https://doi.org/10.4149/neo_2017_120 Zhang Z, Zhang X, Yin Y, Zhao S, Wang K, Shang M, Chen B, Wu X. Integrating BRAF V600E mutation, ultrasonic and clinicopathologic characteristics for predicting the risk of cervical central lymph node metastasis in papillary thyroid carcinoma. BMC Cancer. 2022 Apr 27;22(1):461. doi: 10.1186/s12885-022-09550-z. PMID: 35473554; PMCID: PMC9044661. Leboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer. N Engl J Med 2022, 386 923–932. (https://doi.org/10.1056/nejmoa2111953) Huang Y, Qu S, Zhu G, et al. BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. J Natl Cancer Inst 2018 110 362–370. (https://doi.org/10.1093/jnci/djx227 Tao Y, Wang F, Shen X, Zhu G, Liu R, 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, Sywak MS, Clifton-Bligh R, Bendlova B, Sýkorová V, Zhao S, Wang Y, Xing M. BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer. J Clin Endocrinol Metab. 2021 Oct 21;106(11):3228-3238. doi: 10.1210/clinem/dgab286. PMID: 34273152; PMCID: PMC8530728. Raffaelli, M., De Crea, C., Sessa, L., Tempera, S. E., Fadda, G., Pontecorvi, A., & Bellantone, R. (2021). Modulating the extension of thyroidectomy in patients with papillary thyroid carcinoma pre-operatively eligible for lobectomy: reliability of ipsilateral central neck dissection. Endocrine , 72 (2), 437–444. https://doi.org/10.1007/s12020-020-02456-5 Robenshtok E, Bachar G & Ritter A. Approach to the patient with thyroid cancer: selection and management of candidates for lobectomy. J Clin Endocrinol Metab 2025 110 e2327–e2337. (https://doi.org/10.1210/clinem/dgae903) Leboulleux, S., Bournaud, C., Chougnet, C. N., Zerdoud, S., Al Ghuzlan, A., Catargi, B., Do Cao, C., Kelly, A., Barge, M. L., Lacroix, L., Dygai, I., Vera, P., Rusu, D., Schneegans, O., Benisvy, D., Klein, M., Roux, J., Eberle, M. C., Bastie, D., Nascimento, C., … Borget, I. (2022). Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer. The New England journal of medicine , 386 (10), 923–932. https://doi.org/10.1056/NEJMoa2111953 Tables Table 1. Baseline Patient Characteristics Parameter BRAF + (n=42) BRAF − (n=49) Female sex, n (%) 34 (81.0) 42 (85.7) Median age, years (range) 42 (20–82) 40 (17–60) Median tumor size, mm (range) 13 (5–40) 16 (8–40) Table 2. Surgical and Oncologic Outcomes Parameter BRAF + (n=42) BRAF − (n=49) OR (95% CI) p-value Total thyroidectomy, n (%) 29 (69.0) 17 (35.7) 4.199 (1.742- 10.121) 0.011 Lobectomy with indication for completion TTE, n 7 5 0.764 1.0 Central lymph node metastases, n (%) 19 (45.2) 7 (14.3) 4.957 (1.38–17.79) 0.014 Clinically significant metastases, n (%) 13 (68.4) 9 (81.8) 0.481 (0.11–2.05) 1.0 Lymph node ratio, median (IQR) 0.5 (0.25–0.75) 0.3 (0.2–0.5) – 1.0 Lymph node size, median mm (IQR) 2.2 (1.5–3.1) 3.5 (2.5–4.0) – 1.0 Radioiodine therapy, n (%) 27 (64.3) 15 (30.6) 4.08 (1.35–12.32) 0.013 Reoperation for nodal recurrence, n 6 2 3.917 (0.746-20.561) 0.852 Biochemical persistence, n 1 1 – – Pulmonary metastases, n 0 1 – – Additional Declarations No competing interests reported. Cite Share Download PDF Status: Under Review Version 1 posted Editorial decision: Revision requested 17 Apr, 2026 Editor assigned by journal 17 Apr, 2026 Submission checks completed at journal 17 Apr, 2026 First submitted to journal 13 Apr, 2026 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9407674","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":625201868,"identity":"c33a5407-8106-4373-854f-bb11279b2c27","order_by":0,"name":"Robert Králik","email":"data:image/png;base64,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","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":true,"prefix":"","firstName":"Robert","middleName":"","lastName":"Králik","suffix":""},{"id":625201869,"identity":"a7c04f91-3336-4e2b-aa57-558ee4e62f79","order_by":1,"name":"Eva Takácsová","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Eva","middleName":"","lastName":"Takácsová","suffix":""},{"id":625201870,"identity":"d483db20-bbd0-4599-80b1-892a5d5c9c17","order_by":2,"name":"Štefan Durdík","email":"","orcid":"","institution":"Comenius University Bratislava","correspondingAuthor":false,"prefix":"","firstName":"Štefan","middleName":"","lastName":"Durdík","suffix":""},{"id":625201871,"identity":"8caa02bc-50aa-47de-bbde-c4b40ce9c3ef","order_by":3,"name":"Marianna Grigerová","email":"","orcid":"","institution":"Slovak Medical University","correspondingAuthor":false,"prefix":"","firstName":"Marianna","middleName":"","lastName":"Grigerová","suffix":""}],"badges":[],"createdAt":"2026-04-13 18:54:28","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9407674/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9407674/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":109481498,"identity":"cfcdcb15-2270-4a2a-b79c-80f31247d650","added_by":"auto","created_at":"2026-05-18 15:11:11","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":171343,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9407674/v1/9f1f2b35-725a-4608-a94b-0fadf2af5b00.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Impact of BRAF V600E Mutation on Surgical Management and Outcomes in Low-Risk Differentiated Thyroid Carcinoma (T1–2N0M0)","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMutations in the BRAF gene occur in approximately 4\u0026ndash;8% of all human malignancies and are particularly prevalent in melanoma, thyroid carcinoma, colorectal carcinoma, and non\u0026ndash;small cell lung cancer (1). In thyroid malignancies, BRAF mutations are detected in approximately 45\u0026ndash;50% of papillary thyroid carcinomas and in 25\u0026ndash;30% of anaplastic thyroid carcinomas, whereas they are generally absent in follicular thyroid carcinoma and benign thyroid lesions (2).\u003c/p\u003e \u003cp\u003eThe BRAF V600E mutation leads to constitutive activation of the MAPK signaling pathway, promoting tumor proliferation, dedifferentiation, and resistance to apoptosis (3). Consequently, identification of BRAF mutation status has important diagnostic, prognostic, and therapeutic implications, particularly in patients with advanced or radioiodine-refractory disease, where targeted therapies such as combined BRAF and MEK inhibition may be beneficial (4,5).\u003c/p\u003e \u003cp\u003eDespite these advances, the clinical relevance of BRAF mutation status in the management of early-stage differentiated thyroid carcinoma remains uncertain. While several studies have reported associations between BRAF mutation and aggressive clinicopathological features\u0026mdash;including lymph node metastases, extrathyroidal extension, and disease recurrence\u0026mdash;other studies have questioned its independent prognostic value, particularly in low-risk tumors.\u003c/p\u003e \u003cp\u003e This uncertainty is reflected in current clinical guidelines. The American Thyroid Association recommends that BRAF mutation status should not be used in isolation to determine the extent of initial surgical treatment. Instead, it should be interpreted in conjunction with established clinicopathological risk factors (6).\u003c/p\u003e \u003cp\u003eGiven the increasing interest in molecular markers in thyroid cancer management, further evidence is needed to clarify whether BRAF mutation status has practical implications for surgical decision-making in patients with low-risk disease.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e"},{"header":"Study Objective","content":"\u003cp\u003eThe objective of this study was to evaluate the impact of BRAF V600E mutation status on the surgical management of patients with initially low-risk differentiated thyroid carcinoma (T1\u0026ndash;2N0M0). Specifically, we aimed to assess whether BRAF mutation status influences the extent of thyroid surgery, the incidence of central compartment lymph node metastases, and overall treatment outcomes.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatients and Methods\u003c/h2\u003e \u003cdiv id=\"Sec4\" class=\"Section3\"\u003e \u003ch2\u003eStudy Design and Ethics\u003c/h2\u003e \u003cp\u003eThis single-center study was conducted over a five-year period (1.1.2020\u0026ndash;31.12.2024). The study protocol was approved by the local ethics committee on April 23, 2026 under number 2/4/2026 without comments.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e\n\u003ch3\u003ePatients\u003c/h3\u003e\n\u003cp\u003ePatients aged 17\u0026ndash;82 years, regardless of sex, were eligible for inclusion if they met the preoperative criteria for low-risk thyroid carcinoma, defined as a unifocal tumor measuring\u0026thinsp;\u0026le;\u0026thinsp;4 cm, confined to the thyroid gland, and without evidence of lymph node or distant metastases. All included patients underwent preoperative testing for the BRAF V600E mutation.\u003c/p\u003e\n\u003ch3\u003ePreoperative Assessment\u003c/h3\u003e\n\u003cp\u003eStandard preoperative evaluation included neck ultrasonography and fine-needle aspiration biopsy of suspicious thyroid nodules. However, no standardized protocol regarding the extent of thyroidectomy was applied, and patients were referred either for lobectomy or total thyroidectomy according to the treating physician\u0026rsquo;s discretion.\u003c/p\u003e\n\u003ch3\u003eFollow-up and Outcomes\u003c/h3\u003e\n\u003cp\u003eFollow-up was conducted from February 1, 2020, to December 31, 2024 (range 1\u0026ndash;60 months). The primary endpoint was the influence of preoperatively identified BRAF mutation status on the extent of thyroid surgery (lobectomy vs. total thyroidectomy).\u003c/p\u003e \u003cp\u003eSecondary endpoints included:\u003c/p\u003e \u003cp\u003e \u003cul\u003e \u003cli\u003e \u003cp\u003eincidence and characteristics of central compartment lymph node metastases\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eclinically significant metastases, defined as \u0026gt;\u0026thinsp;5 metastatic lymph nodes or metastatic deposits\u0026thinsp;\u0026gt;\u0026thinsp;2 mm\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eadministration of postoperative radioactive iodine therapy\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003edisease recurrence requiring reoperation\u003c/p\u003e \u003c/li\u003e \u003cli\u003e \u003cp\u003eoverall treatment outcomes, including biochemical or structural persistence of disease\u003c/p\u003e \u003c/li\u003e \u003c/ul\u003e \u003c/p\u003e \u003cdiv id=\"Sec8\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eContinuous variables (Lymph node ratio and Lymph node size) were compared between groups using two-sample t-tests, with the null hypothesis of equal means Categorical variables were analyzed using the Wald test for odds ratios with the null hypothesis of an odds ratio equal to 1.\u003c/p\u003e \u003cp\u003eAll statistical tests were conducted at a nominal significance level of α\u0026thinsp;=\u0026thinsp;0.05, with Bonferroni correction applied for multiple comparisons.\u003c/p\u003e \u003cp\u003eAll statistical analyses were performed using R software (\u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://www.r-project.org/\u003c/span\u003e\u003cspan address=\"https://www.r-project.org/\" targettype=\"URL\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003cspan type=\"Underline\" class=\"Underline\" name=\"Emphasis\"\u003e).\u003c/span\u003e\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eBetween January 1, 2000, and December 31, 2024, a total of 196 patients (aged 17-82 years; median age, 41 years; 83,5% female), with low-risk differentiated thyroid carcinoma measuring 11\u0026ndash;40 mm and without metastases (T1b\u0026ndash;2N0M0) underwent surgery at the Department of Oncologic Surgery, Faculty of Medicine, Comenius University, and the St. Elizabeth Cancer Institute (see Table 1).\u003c/p\u003e\n\u003cp\u003eBRAF V600E mutation status was evaluated in 91 patients included in the study. Among them, 42 patients were BRAF-positive and 49 were BRAF-negative. The two groups were comparable with respect to age, sex distribution, and tumor size (see Table 1).\u003c/p\u003e\n\u003cp\u003eTotal thyroidectomy was significantly more frequently performed in BRAF-positive patients (69%) compared with BRAF-negative patients (35.7%) (OR 4.199, p = 0.011).\u003c/p\u003e\n\u003cp\u003eAmong patients initially treated with lobectomy, no significant difference was observed in the presence of risk factors indicating the need for completion thyroidectomy (OR 0.764, p = 1.0).\u003c/p\u003e\n\u003cp\u003eCentral compartment lymph node metastases were significantly more frequent in BRAF-positive patients (45.2%) than in BRAF-negative patients (14.3%) (OR 4.957, p = 0.014). However, the proportion of clinically significant metastases (\u0026ge;5 affected nodes or \u0026gt;2 mm) was similar in both groups (68.4% vs. 81.8%, OR 0.481, p = 1.0).\u003c/p\u003e\n\u003cp\u003eNo statistically significant differences were observed in the lymph node ratio or the size of metastatic lymph nodes.\u003c/p\u003e\n\u003cp\u003eRadioiodine therapy was administered significantly more frequently in the BRAF-positive group (64.3% vs. 30.6%, OR 4.08, p = 0.013), reflecting the higher proportion of patients treated with total thyroidectomy.\u003c/p\u003e\n\u003cp\u003eAt the end of follow-up (December 31, 2024), treatment outcomes did not differ significantly between the groups. In the BRAF-positive group, five patients required reoperation due to cervical lymph node recurrence, and one patient demonstrated biochemical persistence of disease. In the BRAF-negative group, one patient had biochemical persistence and one developed pulmonary metastases. No reoperations for lymph node recurrence were required in the BRAF-negative group (see Table 2).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eDifferentiated thyroid carcinoma is generally associated with an excellent prognosis, with cure rates approaching 95%, disease persistence of approximately 5%, and disease-specific mortality around 1.1% (7). Despite these favorable outcomes, the optimal individualization of treatment remains a matter of ongoing debate, particularly with regard to the clinical utility of molecular markers such as the BRAF V600E mutation.\u003c/p\u003e \u003cp\u003e According to current American Thyroid Association guidelines, BRAF mutation status alone should not be used to determine the extent of initial surgery (6). Rather, its clinical relevance should be interpreted in the context of established clinicopathological risk factors to guide surgical management while avoiding overtreatment in low-risk patients.\u003c/p\u003e \u003cp\u003eIn our cohort, BRAF positivity was not associated with adverse histopathological features, such as extrathyroidal extension, angioinvasion, or other aggressive characteristics that would independently justify total thyroidectomy. These findings support the notion that BRAF mutation status alone is insufficient to guide surgical decision-making.\u003c/p\u003e \u003cp\u003eNevertheless, BRAF-positive tumors were more frequently associated with metastases in the central neck compartment. These were predominantly micrometastases involving fewer than five lymph nodes, consistent with a low-risk disease profile (8). No significant differences were observed in metastatic burden or lymph node size, suggesting that this association reflects a quantitative rather than qualitative difference in lymphatic spread.\u003c/p\u003e \u003cp\u003eIn our previous study (2017), we demonstrated that the prognostic significance of the BRAF mutation varies with patient age (9). Increased risk was observed in patients younger than 35 years and older than 60 years, whereas in the intermediate age group (35\u0026ndash;60 years), BRAF mutation appeared to have a neutral or even protective effect. In the present cohort, with a median age of 43 years and the majority of patients within the intermediate age group, BRAF mutation was likewise not associated with worse prognosis.\u003c/p\u003e \u003cp\u003eThese findings are partially consistent with previous reports. Zhang et al. (10) identified BRAF V600E as an independent predictor of central lymph node metastases based on fine-needle aspiration biopsy. However, the impact of this association on long-term outcomes, particularly in low-risk tumors, remains unclear.\u003c/p\u003e \u003cp\u003eSimilarly, prior studies have shown that BRAF V600E status does not significantly increase recurrence rates in low-risk tumors\u0026thinsp;\u0026le;\u0026thinsp;2 cm during short-term follow-up (11,12), underscoring the need for cautious interpretation of BRAF mutation as a sole indication for adjuvant therapy.\u003c/p\u003e \u003cp\u003eAlthough BRAF mutation alone does not appear to significantly affect mortality, its combination with lymph node metastases has been associated with a markedly increased risk of death (HR 25.78), suggesting a synergistic interaction between molecular and anatomical risk factors (13).\u003c/p\u003e \u003cp\u003eThe role of ipsilateral diagnostic dissection of the central neck compartment in the presence of intraoperatively identified enlarged lymph nodes remains controversial. Raffaelli et al. have advocated intraoperative frozen section examination of suspicious lymph nodes, with completion of the surgical procedure to total thyroidectomy during the same operation if metastasis is confirmed (14). This approach may be particularly relevant in \u003cem\u003eBRAF\u003c/em\u003e-positive tumors, given their higher incidence of central compartment metastases.\u003c/p\u003e \u003cp\u003eLarge multinational studies have also reported higher recurrence rates in BRAF-mutated papillary thyroid carcinomas larger than 2\u0026ndash;3 cm, indicating that the prognostic impact of the mutation may be more pronounced in larger tumors (11,12).\u003c/p\u003e \u003cp\u003eAccordingly, several authors caution against overinterpreting BRAF V600E as an independent marker of poor prognosis, particularly in tumors smaller than 2 cm (8,9). In such cases, lobectomy remains an adequate treatment option unless additional high-risk molecular alterations, such as TERT promoter mutations, are present (15).\u003c/p\u003e \u003cp\u003eIn our cohort, radioiodine therapy was more frequently administered to BRAF-positive patients, likely reflecting the higher rates of total thyroidectomy and central compartment metastases. Importantly, no significant differences were observed in recurrence, regional lymph node involvement, or distant metastases during follow-up, supporting a risk-adapted and individualized treatment approach. This observation is in line with the results reported by Leboulleux S. and colleagues, who also did not demonstrate a clear impact of BRAF mutation status on clinical outcomes when management was tailored according to established risk stratification systems (16).\u003c/p\u003e \u003cp\u003eThis study has several limitations. First, its retrospective design may be associated with inherent selection bias. Second, \u003cem\u003eBRAF\u003c/em\u003e mutation status was available only in a subset of patients, which may limit the generalizability of the findings. Third, the sample size of the analyzed subgroups was relatively small, potentially reducing the statistical power to detect subtle differences in outcomes. In addition, the follow-up duration, although adequate for early outcomes, may not fully capture late recurrences typical of differentiated thyroid carcinoma. Finally, the study was conducted at a single center, which may limit the external validity of the results.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eOur findings support the current trend toward individualized management of differentiated thyroid carcinoma. BRAF mutation status should not be interpreted in isolation but rather in the context of the patient\u0026rsquo;s overall clinical, pathological, and molecular profile.\u003c/p\u003e \u003cp\u003eGiven the higher incidence of central compartment lymph node metastases observed in BRAF-positive tumors, diagnostic ipsilateral central neck dissection may be considered in selected patients with low-risk differentiated thyroid carcinoma, particularly for tumors larger than 10 mm.\u003c/p\u003e \u003cp\u003eHowever, further prospective studies with long-term follow-up are required to better define the prognostic and therapeutic significance of BRAF mutation in early-stage thyroid carcinoma.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eFunding\u003c/h2\u003e \u003cp\u003eThis study was supported by the Cultural and Educational Grant Agency (KEGA), Grant No. 025UK-4/2024\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eR.K. wrote the main manuscript, E.T. collaborated on writing the discussion, M.G. collaborated on the acquisition of patient data. All authors reviewed the manuscript. Corresponding authors: Robert Kr\u0026aacute;lik and Eva Tak\u0026aacute;csov\u0026aacute;\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eOwsley J, Stein MK, Porter J, et al. Prevalence of class I\u0026ndash;III BRAF mutations among 114,662 cancer patients in a large genomic database. Exp Biol Med 2021 246 31\u0026ndash;39. (https://doi.org/10.1177/1535370220959657)\u003c/li\u003e\n\u003cli\u003eCohen Y, Xing M, Mambo E, et al. BRAF mutation in papillary thyroid carcinoma. J Natl Cancer Inst 2003 95 625\u0026ndash;627. (https://doi.org/10.1093/jnci/95.8.625)\u003c/li\u003e\n\u003cli\u003eXing M. BRAF mutation in thyroid cancer. Endocr Relat Cancer. 2005 Jun;12(2):245-62. doi: 10.1677/erc.1.0978. PMID: 15947100.\u003c/li\u003e\n\u003cli\u003eScheffel, R. S., Dora, J. M., \u0026amp; Maia, A. L. (2022). BRAF mutations in thyroid cancer. \u003cem\u003eCurrent opinion in oncology\u003c/em\u003e, \u003cem\u003e34\u003c/em\u003e(1), 9\u0026ndash;18. https://doi.org/10.1097/CCO.0000000000000797\u003c/li\u003e\n\u003cli\u003eBapat, N., Ferraro, T., Esper, L., Joshi, A. S., Haroun, F., \u0026amp; Baldwin, C. K. (2024). Treatment of Unresectable \u003cem\u003eBRAF V600E\u003c/em\u003e, \u003cem\u003eTERT\u003c/em\u003e-Mutated Differentiated Papillary Thyroid Cancer With Dabrafenib and Trametinib. \u003cem\u003eJCEM case reports\u003c/em\u003e, \u003cem\u003e2\u003c/em\u003e(8), luae112. https://doi.org/10.1210/jcemcr/luae112\u003c/li\u003e\n\u003cli\u003eRingel, M. D., Sosa, J. A., Baloch, Z., Bischoff, L., Bloom, G., Brent, G. A., Brock, P. L., Chou, R., Flavell, R. R., Goldner, W., Grubbs, E. G., Haymart, M., Larson, S. M., Leung, A. M., Osborne, J. R., Ridge, J. A., Robinson, B., Steward, D. L., Tufano, R. P., \u0026amp; Wirth, L. J. (2025). 2025 American Thyroid Association Management Guidelines for Adult Patients with Differentiated Thyroid Cancer. \u003cem\u003eThyroid : official journal of the American Thyroid Association\u003c/em\u003e, \u003cem\u003e35\u003c/em\u003e(8), 841\u0026ndash;985. https://doi.org/10.1177/10507256251363120\u003c/li\u003e\n\u003cli\u003eKim K, Kim JK, Lee CR, et al. Comparison of long-term prognosis for differentiated thyroid cancer according to the 7th and 8th editions of the AJCC/UICC TNM staging system. \u003cem\u003eTher Adv Endocrinol Metab\u003c/em\u003e, 2020; 11:2042018820921019; Crossref\u003c/li\u003e\n\u003cli\u003eRandolph, G. W., Duh, Q. Y., Heller, K. S., LiVolsi, V. A., Mandel, S. J., Steward, D. L., Tufano, R. P., Tuttle, R. M., \u0026amp; American Thyroid Association Surgical Affairs Committee\u0026rsquo;s Taskforce on Thyroid Cancer Nodal Surgery (2012). The prognostic significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension. \u003cem\u003eThyroid : official journal of the American Thyroid Association\u003c/em\u003e, \u003cem\u003e22\u003c/em\u003e(11), 1144\u0026ndash;1152. https://doi.org/10.1089/thy.2012.0043\u003c/li\u003e\n\u003cli\u003eTakacsova, E., Kralik, R., Waczulikova, I., Zavodna, K., \u0026amp; Kausitz, J. (2017). A different prognostic value of BRAFV600E mutation positivity in various age groups of patients with papillary thyroid cancer. \u003cem\u003eNeoplasma\u003c/em\u003e, \u003cem\u003e64\u003c/em\u003e(1), 156\u0026ndash;164. https://doi.org/10.4149/neo_2017_120\u003c/li\u003e\n\u003cli\u003eZhang Z, Zhang X, Yin Y, Zhao S, Wang K, Shang M, Chen B, Wu X. Integrating BRAF\u003csup\u003eV600E\u003c/sup\u003e mutation, ultrasonic and clinicopathologic characteristics for predicting the risk of cervical central lymph node metastasis in papillary thyroid carcinoma. BMC Cancer. 2022 Apr 27;22(1):461. doi: 10.1186/s12885-022-09550-z. PMID: 35473554; PMCID: PMC9044661.\u003c/li\u003e\n\u003cli\u003eLeboulleux S, Bournaud C, Chougnet CN, et al. Thyroidectomy without radioiodine in patients with low-risk thyroid cancer. N Engl J Med 2022, 386 923\u0026ndash;932. (https://doi.org/10.1056/nejmoa2111953)\u003c/li\u003e\n\u003cli\u003eHuang Y, Qu S, Zhu G, et al. BRAF V600E mutation-assisted risk stratification of solitary intrathyroidal papillary thyroid cancer for precision treatment. J Natl Cancer Inst 2018 110 362\u0026ndash;370. (https://doi.org/10.1093/jnci/djx227\u003c/li\u003e\n\u003cli\u003eTao Y, Wang F, Shen X, Zhu G, Liu R, 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\u0026apos;Neill CJ, Sywak MS, Clifton-Bligh R, Bendlova B, S\u0026yacute;korov\u0026aacute; V, Zhao S, Wang Y, Xing M. BRAF V600E Status Sharply Differentiates Lymph Node Metastasis-associated Mortality Risk in Papillary Thyroid Cancer. J Clin Endocrinol Metab. 2021 Oct 21;106(11):3228-3238. doi: 10.1210/clinem/dgab286. PMID: 34273152; PMCID: PMC8530728.\u003c/li\u003e\n\u003cli\u003eRaffaelli, M., De Crea, C., Sessa, L., Tempera, S. E., Fadda, G., Pontecorvi, A., \u0026amp; Bellantone, R. (2021). Modulating the extension of thyroidectomy in patients with papillary thyroid carcinoma pre-operatively eligible for lobectomy: reliability of ipsilateral central neck dissection. \u003cem\u003eEndocrine\u003c/em\u003e, \u003cem\u003e72\u003c/em\u003e(2), 437\u0026ndash;444. https://doi.org/10.1007/s12020-020-02456-5\u003c/li\u003e\n\u003cli\u003eRobenshtok E, Bachar G \u0026amp; Ritter A. Approach to the patient with thyroid cancer: selection and management of candidates for lobectomy. J Clin Endocrinol Metab 2025 110 e2327\u0026ndash;e2337. (https://doi.org/10.1210/clinem/dgae903)\u003c/li\u003e\n\u003cli\u003eLeboulleux, S., Bournaud, C., Chougnet, C. N., Zerdoud, S., Al Ghuzlan, A., Catargi, B., Do Cao, C., Kelly, A., Barge, M. L., Lacroix, L., Dygai, I., Vera, P., Rusu, D., Schneegans, O., Benisvy, D., Klein, M., Roux, J., Eberle, M. C., Bastie, D., Nascimento, C., \u0026hellip; Borget, I. (2022). Thyroidectomy without Radioiodine in Patients with Low-Risk Thyroid Cancer. \u003cem\u003eThe New England journal of medicine\u003c/em\u003e, \u003cem\u003e386\u003c/em\u003e(10), 923\u0026ndash;932. https://doi.org/10.1056/NEJMoa2111953\u003c/li\u003e\n\u003c/ol\u003e\n"},{"header":"Tables","content":"\u003cp\u003e\u003cstrong\u003eTable 1. Baseline Patient Characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003ctable cellspacing=\"3\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBRAF + (n=42)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBRAF \u0026minus; (n=49)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eFemale sex, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e34 (81.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42 (85.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian age, years (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e42 (20\u0026ndash;82)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e40 (17\u0026ndash;60)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eMedian tumor size, mm (range)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (5\u0026ndash;40)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e16 (8\u0026ndash;40)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\n\u003cp\u003e\u003cstrong\u003eTable 2. Surgical and Oncologic Outcomes\u003c/strong\u003e\u003c/p\u003e\n\u003ctable cellspacing=\"3\" class=\"fr-table-selection-hover\"\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eParameter\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBRAF + (n=42)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eBRAF \u0026minus; (n=49)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003eOR (95% CI)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u003cstrong\u003ep-value\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eTotal thyroidectomy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e29 (69.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e17 (35.7)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.199\u003c/p\u003e\n \u003cp\u003e\u0026nbsp;(1.742- 10.121)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.011\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLobectomy with indication for completion TTE, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.764\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eCentral lymph node metastases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e19 (45.2)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e7 (14.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.957 (1.38\u0026ndash;17.79)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.014\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eClinically significant metastases, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e13 (68.4)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e9 (81.8)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.481 (0.11\u0026ndash;2.05)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLymph node ratio, median (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.5 (0.25\u0026ndash;0.75)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.3 (0.2\u0026ndash;0.5)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eLymph node size, median mm (IQR)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2.2 (1.5\u0026ndash;3.1)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.5 (2.5\u0026ndash;4.0)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1.0\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eRadioiodine therapy, n (%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e27 (64.3)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e15 (30.6)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e4.08 (1.35\u0026ndash;12.32)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.013\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eReoperation for nodal recurrence, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e3.917 (0.746-20.561)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0.852\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003eBiochemical persistence, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd\u003e\n \u003cp\u003ePulmonary metastases, n\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd\u003e\n \u003cp\u003e\u0026ndash;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bratislava-medical-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Bratislava Medical Journal](https://link.springer.com/journal/44411)","snPcode":"44411","submissionUrl":"https://submission.springernature.com/new-submission/44411/3","title":"Bratislava Medical Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"BRAF V600E, differentiated thyroid carcinoma, thyroidectomy, lymph node metastases, risk stratification","lastPublishedDoi":"10.21203/rs.3.rs-9407674/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9407674/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThe clinical relevance of the BRAF V600E mutation in the surgical management of early-stage differentiated thyroid carcinoma (DTC) remains unclear. Although common in papillary thyroid carcinoma, its role in guiding surgical decisions in low-risk disease is still debated.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eWe conducted a retrospective single-center study of patients with low-risk DTC (T1\u0026ndash;2N0M0) treated surgically between 2000 and 2024. Preoperative BRAF V600E status was available in a subset of patients. The primary endpoint was the association between BRAF status and extent of surgery (lobectomy vs. total thyroidectomy). Secondary endpoints included central compartment lymph node metastases, use of postoperative radioiodine therapy, recurrence requiring reoperation, and overall outcomes.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eOf 196 patients, BRAF status was known in 91 (42 positive, 49 negative). Baseline characteristics were similar between groups. Total thyroidectomy was more frequent in BRAF-positive patients (69% vs. 35.7%; OR 4.199, p\u0026thinsp;=\u0026thinsp;0.011). Central compartment lymph node metastases were also more common in BRAF-positive tumors (45.2% vs. 14.3%; OR 4.957, p\u0026thinsp;=\u0026thinsp;0.014). However, rates of clinically significant metastases (\u0026ge;\u0026thinsp;5 nodes or \u0026gt;\u0026thinsp;2 mm) did not differ significantly. Radioiodine therapy was used more often in BRAF-positive patients (64.3% vs. 30.6%; OR 4.08, p\u0026thinsp;=\u0026thinsp;0.013). No significant differences in overall treatment outcomes were observed at the end of follow-up.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eBRAF V600E mutation was associated with higher rates of lymph node metastases and more aggressive treatment but did not impact long-term outcomes. These findings support current recommendations that BRAF status alone should not determine surgical extent in low-risk DTC.\u003c/p\u003e","manuscriptTitle":"Impact of BRAF V600E Mutation on Surgical Management and Outcomes in Low-Risk Differentiated Thyroid Carcinoma (T1–2N0M0)","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-05-18 15:10:03","doi":"10.21203/rs.3.rs-9407674/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2026-04-17T21:23:16+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-17T04:47:59+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-04-17T04:47:00+00:00","index":"","fulltext":""},{"type":"submitted","content":"Bratislava Medical Journal","date":"2026-04-13T18:41:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bratislava-medical-journal","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"Learn more about [Bratislava Medical Journal](https://link.springer.com/journal/44411)","snPcode":"44411","submissionUrl":"https://submission.springernature.com/new-submission/44411/3","title":"Bratislava Medical Journal","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b86e16e0-aba2-4df2-b7d6-d21266d61754","owner":[],"postedDate":"May 18th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[],"tags":[],"updatedAt":"2026-05-18T15:10:03+00:00","versionOfRecord":[],"versionCreatedAt":"2026-05-18 15:10:03","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9407674","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9407674","identity":"rs-9407674","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}