Thyroid Fine Needle Biopsy and Impact on Pain and Diagnostic Adequacy (THY-BPSY)

Material and methods Study Design and Ethics This prospective, randomized, single-blind clinical trial was conducted at the Radiology Department of İzmir Katip Çelebi University Atatürk Training and Research Hospital between Januray 2024 and March 2024. The study protocol was approved by the Institutional Review Board of İzmir Katip Çelebi University (IRB No: 0001/2024, approval date: 18.01.2024) and was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. The trial was registered prior to patient enrollment. Written informed consent was obtained from all participants after explaining the procedure, potential risks, and benefits.

Patient Selection Consecutive patients referred for ultrasound-guided thyroid fine-needle biopsy (FNB) were screened for eligibility. Inclusion criteria were: (1) age ≥18 years; (2) presence of at least one thyroid nodule with maximum diameter ≥10 mm meeting American Thyroid Association 2015 guidelines for FNB; (3) nodule with entirely intrathyroidal location confirmed by ultrasound. Exclusion criteria were: (1) coagulopathy defined as INR >1.5 or platelet count <50,000/μL; (2) use of anticoagulant or antiplatelet agents within 7 days prior to procedure; (3) prior thyroid surgery, radioiodine therapy, or external beam radiation to the neck; (4) substernal extension of goiter preventing safe access; (5) pregnancy; (6) inability to understand or complete the Visual Analog Scale. A total of 159 patients with 159 dominant nodules were enrolled. Each patient underwent FNB of a single nodule; if multiple nodules were present, the most suspicious nodule based on ACR TI-RADS criteria was selected.

Randomization and Blinding Eligible patients were randomly assigned in a 1:1 ratio to undergo FNB with either a 21-gauge (21G) or 27-gauge (27G) needle. Randomization was performed using a computer-generated permuted block sequence with a block size of 4 to ensure balanced allocation. Allocation concealment was maintained using sequentially numbered, sealed, opaque envelopes opened by a study nurse immediately before the procedure. Patients were blinded to the needle gauge assignment. Due to the visual difference in needle diameter, the performing radiologist could not be blinded. All cytopathological specimens were evaluated by two board-certified cytopathologists who were blinded to the needle gauge used.

FNB Procedure All biopsies were performed by a single fellowship-trained interventional radiologist with 12 years of experience in thyroid FNB (>2500 procedures) to minimize operator-dependent variability. Patients were positioned supine with mild neck hyperextension. After skin disinfection with 70% isopropyl alcohol, a high-resolution ultrasound system (Samsung HS50, Seoul, South Korea) equipped with a 12-15 MHz linear transducer was used for real-time guidance. No local anesthesia or skin infiltration was administered, consistent with routine clinical practice at our institution. Under sterile conditions, a 21G (0.8 × 40 mm) or 27G (0.4 × 40 mm) needle was inserted using a freehand capillary technique without aspiration. The needle tip was advanced to the center of the target nodule, followed by rapid back-and-forth movements for 5-10 seconds using wrist motion only. Material was expelled onto glass slides for smear preparation and into formalin for cell block. A single pass was routinely performed; a second pass was permitted only if the operator visually assessed the specimen as macroscopically inadequate. The total number of passes was recorded for each patient.

Outcome Assessment The primary outcome was patient-reported pain intensity measured immediately after needle withdrawal. Within 5 minutes post-procedure, while still in the supine position, each patient was asked to mark their pain level on a 100-mm horizontal Visual Analog Scale (VAS) anchored by "0 = no pain" and "100 = worst imaginable pain." The distance from 0 to the patient's mark was measured in millimeters. Secondary outcomes included: (1) Diagnostic adequacy, defined as satisfactory for evaluation per The Bethesda System for Reporting Thyroid Cytopathology, determined by blinded cytopathologists; (2) Number of needle passes per nodule; (3) Complications, categorized as minor (self-limited hematoma <2 cm, transient vasovagal reaction) or major (hematoma requiring intervention, recurrent laryngeal nerve injury, tracheal puncture). Nodule characteristics including maximum diameter, echotexture ( Hypoechoic, Heterogeneous, Hyperechoic) were recorded pre-procedure.

Sample Size Calculation and Statistical Analysis Sample size was calculated based on the primary outcome. Assuming a clinically significant difference of 10 mm on the VAS, a standard deviation of 22 mm from pilot data, a two-sided α of 0.05, and power of 80%, 77 patients per group were required. To compensate for an anticipated 5% dropout rate, 159 patients were enrolled. Data normality was evaluated using the Shapiro-Wilk test. Continuous variables were expressed as mean ± standard deviation or median (interquartile range) and compared using the independent samples t-test or Mann-Whitney U test, as appropriate. Categorical variables were compared using the χ² test or Fisher's exact test. Correlation between VAS score and continuous variables was assessed using Spearman's rank correlation coefficient. Multivariable linear regression analysis was performed to identify independent predictors of post-procedural pain. All analyses were conducted using IBM SPSS Statistics version 27.0 (IBM Corp., Armonk, NY, USA). A two-tailed P-value <0.05 was considered statistically significant.