Active Surveillance for Bethesda IV Thyroid Nodules

Active Surveillance for Small Thyroid Nodules With Bethesda IV Cytology: A Prospective Cohort Study Protocol

The traditional surgical approach for Bethesda IV thyroid nodules burdens healthcare systems and patients with costs, perioperative morbidity, and potential long-term consequences of hemithyroidectomy, including hypothyroidism (requiring lifelong thyroid hormone replacement), nerve damage, infection, voice discomfort and postoperative bleeding. Moreover, patient-reported anxiety and reduced quality of life often follow surgery, regardless of benign final pathology. Conversely, surveillance strategies that include periodic ultrasound assessment, clinical examination, and patient education may reduce overtreatment, preserve thyroid function, and optimize resource utilization.

This prospective cohort protocol seeks to address these gaps by systematically evaluating the safety, feasibility, patient experience, and clinicopathologic predictors of progression for Bethesda IV nodules <2 cm managed with active surveillance.

Our hypothesis is: In patients with thyroid nodules smaller than 2 cm and cytology consistent with Bethesda IV, active surveillance is a safe and feasible alternative to immediate surgery. We hypothesize that only a minority of patients will demonstrate clinically significant tumor progression or require surgical intervention within five years, and that prospective surveillance can prevent unnecessary thyroid operations without compromising patient safety or long-term outcomes.

The primary aim of this study is to determine the proportion of patients with Bethesda IV thyroid nodules <2 cm who undergo surgical intervention or experience disease progression over a 1-, 2- and 5 year AS period.

Study Overview

• Status: Recruiting
• Conditions: Thyroid Cancer; Thyroid Nodule
• Intervention / Treatment: Other: Active surveillance (6, 12, 18, 24, 36, 48, 60 months)

• Study Type: Interventional
• Enrollment (Estimated): 165
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Nicoline Thorup, MD, PhD Fellow; Phone Number: 0045 45356863; Email: nicoline.thorup@regionh.dk

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • Recruiting
    • Department of Otolaryngology, Head and Neck SurgeryRigshospitalet
    • Contact: Nicoline Thorup, MD, PhD Fellow; Phone Number: 0045 45356863; Email: nicoline.thorup@regionh.dk

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• age of 30 years or older AND
• a single nodule with a Follicular neoplasm or suspicious for a follicular neoplasm (category IV in the Bethesda system) AND
• tumor size of less than 2 cm in all dimensions AND
• EU-TIRADS 3 or 4 in Ultrasound imaging examination.

Exclusion Criteria:

• EU-TIRADS 5 in Ultrasound imaging examination.
• suspicion of disseminated disease because of PET-positive lymph nodes; suspect lymph-nodes by US or by CT-scan; or signs of capsular invasion of the tumor, or irregular shape or margins, extrathyroidal growth OR
• tumor placement at a high-risk location (in the thyroid capsule with extracapsular extension toward vessels, RLN, or the trachea) OR
• previous thyroid surgery OR
• concomitant hyperparathyroidism (ionized calcium > 1.32 mmol/L and PTH > 6 pmol/L) OR
• if the patient is pregnant OR
• If the patient is unable to give informed consent. OR
• If calcitonin is elevated above normal level

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Active Surveillance; Active surveillance with ultrasound and clinical follow-up in a 5 year period	Other: Active surveillance (6, 12, 18, 24, 36, 48, 60 months); Active Surveillance og thyroid nodules with Bethesda IV cytology instead of surgery (diagnostic hemithyroidectomy).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Number of participants who undergo surgical intervention or experience disease progression during active surveillance	From enrollment in to active surveillance to the end of the follow-up programe at 5 years

Collaborators and Investigators

• Sponsor: Christian Grønhøj Larsen
• Collaborators: Rigshospitalet, Denmark

Study record dates

Study Major Dates

• Study Start (Actual): January 16, 2026
• Primary Completion (Estimated): January 16, 2033
• Study Completion (Estimated): January 16, 2033

Study Registration Dates

• First Submitted: January 19, 2026
• First Submitted That Met QC Criteria: January 19, 2026
• First Posted (Actual): January 27, 2026

Study Record Updates

• Last Update Posted (Actual): January 27, 2026
• Last Update Submitted That Met QC Criteria: January 19, 2026
• Last Verified: January 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Thyroid Diseases; Thyroid Nodule; Thyroid Neoplasms; Health Services Administration; Quality of Health Care; Outcome Assessment, Health Care; Outcome and Process Assessment, Health Care; Watchful Waiting
• Other Study ID Numbers: 25047119

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No