Frozen Section-Guided Selective Ipsilateral Central Neck Dissection in Bethesda V-VI Thyroid Nodules

Frozen Section-Guided Selective Ipsilateral Central Neck Dissection in Bethesda V-VI Thyroid Nodules: A Pilot Cohort Study Informing Surgical Extent

The goal of this observational pilot cohort study is to evaluate the feasibility and clinical implications of frozen section analysis-guided selective ipsilateral central neck dissection in adult patients undergoing primary thyroid surgery for Bethesda V-VI thyroid nodules with a clinically node-negative neck.

The main questions it aims to answer are:

• Can intraoperative frozen section analysis of ipsilateral level VI lymph nodes meaningfully inform real-time surgical decision-making?
• Can this strategy support tailored escalation or de-escalation of central compartment surgery while minimizing unnecessary bilateral central neck dissection and its associated morbidity? Researchers will compare patients managed with ipsilateral central neck dissection and intraoperative frozen section analysis with patients managed without frozen section analysis, in order to evaluate differences in treatment adequacy, surgical decision-making, and pathological nodal assessment.

Participants will undergo primary thyroid surgery according to institutional practice. In patients managed with the frozen section analysis-guided strategy, one or more ipsilateral level VI lymph nodes will be removed during surgery and examined intraoperatively. The result of frozen section analysis may be used to guide the extent of central compartment surgery and the overall surgical strategy.

Study Overview

• Status: Completed
• Conditions: Papillary Thyroid Cancer; Lymph Node Metastasis
• Intervention / Treatment: Procedure: Frozen section analysis (FSA)

Detailed Description

This observational retrospective cohort study was conducted in a tertiary referral endocrine surgery unit and was based on prospectively collected institutional data. The study included consecutive adult patients undergoing primary thyroid surgery for cytologically suspicious or malignant thyroid nodules, classified as Bethesda V or VI according to the Bethesda System for Reporting Thyroid Cytopathology.

The study was designed to evaluate whether an intraoperative strategy based on ipsilateral central neck dissection (ipsiCND) with frozen section analysis (FSA) could improve the adequacy of surgical treatment in selected patients with low-risk thyroid cancer, potentially reducing both overtreatment and undertreatment. The institutional protocol incorporating ipsiCND-FSA was introduced in September 2023. Patients treated before implementation of this protocol generally underwent total thyroidectomy according to the standard institutional practice in place at that time. After implementation of the protocol, hemithyroidectomy combined with ipsilateral central neck lymph node sampling and intraoperative frozen section analysis was systematically proposed as the preferred surgical strategy in appropriately selected patients. Total thyroidectomy remained an option for patients who declined the conservative approach after counselling regarding the malignant or suspicious nature of the thyroid nodule and the available surgical alternatives.

Eligible patients were adults aged 18 years or older with a solitary thyroid nodule measuring less than 2.5 cm in maximum diameter, classified as Bethesda V or VI on preoperative cytology, with a clinically node-negative neck documented by preoperative cervical ultrasound. Patients were considered only if they underwent primary thyroid surgery and had complete histopathological data available for the thyroid specimen and, when removed, central compartment lymph nodes. Patients with previous thyroid or neck surgery, known distant metastases at the time of surgery, incomplete clinical or pathological data relevant to the study endpoints, or reoperations such as completion thyroidectomy or secondary lymph node dissection were excluded.

All patients received detailed preoperative counselling and provided written informed consent before surgery. The information provided included the planned procedure, the possible need for intraoperative modification of the surgical strategy according to real-time findings and frozen section results, and the potential risks and benefits of the available surgical options. Patients also consented to the inclusion of their clinical and pathological data in the institutional database and to their use for research purposes. The study was conducted in accordance with the principles of the Declaration of Helsinki, followed good clinical practice standards, and was approved by the local Ethics Committee under protocol PA-1-RETRO-2026-TBD. Reporting was planned in accordance with the STROCCS recommendations for observational studies.

All surgical procedures were performed or supervised by experienced endocrine surgeons. Intraoperative nerve monitoring was routinely used in all cases as part of the standard institutional practice. The extent of thyroid surgery, either total thyroidectomy or lobectomy/isthmectomy, and the strategy for management of the central neck compartment were planned preoperatively according to cytological diagnosis, imaging findings, clinical risk profile, and institutional practice. In patients managed according to the ipsiCND-FSA protocol, the operative plan could be modified intraoperatively on the basis of frozen section findings.

Patients were stratified according to intraoperative management of the central compartment. In the FSA group, one or more ipsilateral level VI lymph nodes were removed during hemithyroidectomy and immediately submitted for frozen section analysis. Lymph nodes were processed using standard cryostat techniques, stained with hematoxylin and eosin, and evaluated intraoperatively by an experienced pathologist. The intraoperative nodal status was reported as positive or negative for metastatic disease. Definitive paraffin-embedded histopathology served as the reference standard for final assessment. In the non-FSA group, no intraoperative frozen section analysis of central compartment lymph nodes was performed. In this cohort, patients underwent total thyroidectomy, reflecting the inability to obtain sufficiently reliable preoperative risk stratification according to the standard approach used before implementation of the new protocol.

The primary objective of the study was to assess treatment adequacy. Treatment adequacy was defined as the concordance between the surgical procedure actually performed and the minimum surgical treatment considered necessary to achieve appropriate locoregional disease control on the basis of final histopathological findings. The minimum necessary extent of surgery was determined retrospectively, with particular attention to definitive tumor characteristics, including tumor focality and laterality, extrathyroidal extension, vascular invasion, aggressive histological variants, and nodal involvement.

Overtreatment was defined as performance of total thyroidectomy in patients who were ultimately found to have a solitary unilateral carcinoma without microscopic or macroscopic extrathyroidal extension, vascular invasion, or aggressive histological variants. Undertreatment was defined as an insufficient extent of surgery in the presence of adverse pathological features requiring a more comprehensive oncological procedure. These definitions were applied irrespective of study group allocation. For comparative analyses, overtreatment and undertreatment were also combined into a composite endpoint of surgical mis-treatment.

Secondary objectives included evaluation of the diagnostic performance of frozen section analysis for detecting central compartment lymph node metastases. Diagnostic performance was assessed by calculating sensitivity, specificity, positive predictive value, negative predictive value, overall accuracy, and the area under the receiver operating characteristic curve, using definitive histopathology as the reference standard. Additional secondary outcomes included postoperative complications and length of hospital stay. Postoperative complications included major complications such as recurrent laryngeal nerve injury, hypoparathyroidism, postoperative hemorrhage, and minor complications such as seroma, hematoma, and wound infection.

Clinical, surgical, pathological, and postoperative data were extracted from the prospectively maintained institutional database and cross-checked against source documents, including operative reports, pathology reports, ultrasound reports, discharge summaries, and postoperative follow-up records. Data quality was supported by predefined data fields, standardized definitions of variables and endpoints, internal consistency checks, and verification of missing or inconsistent values against the original clinical documentation. Missing data were handled by excluding patients with incomplete information relevant to the primary endpoint or key secondary endpoints. No formal sample size calculation was performed because of the retrospective observational design; all consecutive eligible patients treated between January 2023 and June 2025 were included.

Statistical analyses were planned to compare baseline characteristics, surgical management, treatment adequacy, diagnostic performance of frozen section analysis between study groups. Diagnostic performance of frozen section analysis was evaluated against definitive histopathology as the reference standard. Additional analyses were planned to account for potential confounding and to assess the robustness of the primary findings.

• Study Type: Observational
• Enrollment (Actual): 66

Contacts and Locations

Study Locations

• Italy
  • Sicily
    • Palermo, Sicily, Italy, 90127
      • Policlinico "P. Giaccone" University of Palermo

Participation Criteria

Eligibility Criteria

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

• Sampling Method: Non-Probability Sample

Study Population

The study population includes consecutive adult patients treated in a tertiary referral endocrine surgery unit who underwent primary thyroid surgery for cytologically suspicious or malignant thyroid nodules. Eligible patients had Bethesda V or VI thyroid cytology, a solitary low-risk thyroid nodule smaller than 2.5 cm, and a clinically node-negative neck documented by preoperative cervical ultrasound. All patients were managed according to institutional surgical protocols and had prospectively collected clinical, surgical, and histopathological data available for analysis.

Description

Inclusion Criteria:

• age 18 years or older.
• Adult patients undergoing primary thyroid surgery.
• Preoperative thyroid cytology classified as Bethesda V or Bethesda VI according to the Bethesda System for Reporting Thyroid Cytopathology.
• Presence of a solitary thyroid nodule.
• Maximum nodule diameter less than 2.5 cm.
• Low-risk thyroid nodule according to clinical, cytological, and ultrasound criteria.
• Clinically node-negative neck, documented by preoperative cervical ultrasound.
• Availability of complete histopathological report for the thyroid specimen.
• Availability of complete histopathological report for central compartment lymph nodes, when removed.
• Written informed consent for surgery and for the use of clinical and pathological data for research purposes.

Exclusion Criteria:

• Age younger than 18 years.
• Previous thyroid or neck surgery, including completion thyroidectomy or secondary lymph node dissection
• Known cervical lymph node metastases or distant metastases at the time of surgery.
• Thyroid nodule measuring 2.5 cm or more in maximum diameter.
• Incomplete clinical and pathological data relevant to the study endpoints.

Study Plan

How is the study designed?

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
non-FSA Group; Participants in the non-FSA group underwent total thyroidectomy according to the 2015 American Thyroid Association guidelines and the institutional standard practice. The surgical strategy was based on preoperative cytology, cervical ultrasound findings, clinical risk assessment, and multidisciplinary evaluation. Central compartment lymph node management was performed according to the surgeon's judgment and preoperative findings.
FSA Group; Participants in the FSA group underwent hemithyroidectomy with selective ipsilateral central neck dissection. One or more ipsilateral level VI lymph nodes were removed during surgery and submitted for intraoperative frozen section analysis (FSA). The frozen section result was used to inform real-time surgical decision-making and to guide possible escalation or de-escalation of the surgical strategy.	Procedure: Frozen section analysis (FSA); Frozen section analysis (FSA) is an intraoperative pathological technique used to provide a rapid assessment of excised tissue during surgery. In this study, ipsilateral level VI lymph nodes were removed and immediately sent to the pathology department, where they were frozen, sectioned using standard cryostat techniques, stained with hematoxylin and eosin, and examined by an experienced pathologist. The result was reported intraoperatively as positive or negative for lymph node metastasis and used to support real-time surgical decision-making.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Treatment adequacy	concordance between the surgical procedure performed and the minimum surgical treatment considered necessary for appropriate locoregional disease control, as determined retrospectively on the basis of final histopathological findings. Surgical treatment will be classified as adequate, overtreatment, or undertreatment. Overtreatment is defined as total thyroidectomy in patients ultimately found to have a solitary unilateral carcinoma without adverse pathological features. Undertreatment is defined as an insufficient surgical extent in the presence of adverse pathological features requiring a more comprehensive oncological procedure.	From surgery to availability of final histopathological report, approximately 2-4 weeks after surgery.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Length of hospital stay	Length of hospital stay will be measured as the number of days from the date of surgery to the date of hospital discharge.	From surgery to hospital discharge, usually within 1-3 days after surgery.
Complications	Complications will be assessed after thyroid surgery and classified as major or minor. Major complications include recurrent laryngeal nerve injury, hypoparathyroidism, and postoperative haemorrhage. Minor complications include seroma, haematoma, and wound infection.	From surgery to postoperative follow-up, approximately 30-60 days after surgery.

Collaborators and Investigators

• Sponsor: Eleonora Lori, MD
• Collaborators: University of Palermo
• Investigators: Principal Investigator: Gregorio Scerrino, MD, Policlinico "P. Giaccone" University of Palermo

Study record dates

Study Major Dates

• Study Start (Actual): January 9, 2023
• Primary Completion (Actual): June 27, 2025
• Study Completion (Actual): September 19, 2025

Study Registration Dates

• First Submitted: June 15, 2026
• First Submitted That Met QC Criteria: June 15, 2026
• First Posted (Actual): June 22, 2026

Study Record Updates

• Last Update Posted (Actual): June 24, 2026
• Last Update Submitted That Met QC Criteria: June 19, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Papillary Thyroid Cancer; Frozen section analysis; Central Neck Dissection; Clinically Node-Negative Thyroid Cancer; Intraoperative Decision-Making; Treatment Adequacy
• Additional Relevant MeSH Terms: Endocrine System Diseases; Pathologic Processes; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Thyroid Neoplasms; Endocrine Gland Neoplasms; Head and Neck Neoplasms; Neoplasms, Glandular and Epithelial; Adenocarcinoma; Neoplastic Processes; Carcinoma; Thyroid Diseases; Neoplasm Metastasis; Adenocarcinoma, Papillary; Pathological Conditions, Signs and Symptoms; Thyroid Cancer, Papillary; Lymphatic Metastasis
• Other Study ID Numbers: PA-1-RETRO-2026-TBD

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: Individual participant data will not be made available to other researchers. The study is based on institutional clinical and pathological data collected during routine care, and data sharing is restricted by privacy regulations and institutional policies. Only aggregate and anonymized data supporting the results may be reported in the final manuscript and related publications.

Drug and device information, study documents

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