Bethesda System (Thyroid FNA)

Bethesda Thyroid System

Cytopathology Management Suite

Cytology Category

Category Logic

Select a Bethesda category to see the malignancy risk and standard management path.

Guidelines & Evidence

Verified

Last Review: 2026-07-17

When to Use

What is the Bethesda System?

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is a standardized 6-tier classification system for thyroid fine-needle aspiration (FNA) results. It provides a uniform framework for cytopathology reporting, ensuring consistent communication between pathologists and clinicians. Each category includes a specific diagnosis, estimated risk of malignancy (ROM), and evidence-based management recommendations. The system was first published in 2007 and updated in 2017 to incorporate new data, including the reclassification of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) as a non-malignant entity.

Primary Indications

Thyroid nodule evaluation – Reporting cytology results for all thyroid FNAs performed for diagnostic evaluation of thyroid nodules (incidental or palpable)

Risk stratification – Providing standardized malignancy risk estimates (ROM) to guide management decisions

Guideline-concordant care – Enabling adherence to ATA (American Thyroid Association) and NCCN (National Comprehensive Cancer Network) clinical practice guidelines

Research and quality improvement – Standardizing data collection across institutions, enabling meta-analyses and comparative effectiveness research

Patient communication – Providing clear, evidence-based language for discussing results with patients (e.g., "Your nodule is Bethesda II, benign, with <3% risk of cancer")

Surgical triage – Identifying nodules requiring surgical resection (Bethesda IV-VI) vs those appropriate for surveillance (Bethesda II) vs those needing repeat FNA or molecular testing (Bethesda I, III)

Medicolegal documentation – Creating a documented standard of care for thyroid nodule management

When to Perform Thyroid FNA (Per ATA Guidelines)

Nodules ≥1.0 cm with high-suspicion ultrasound features (solid, hypoechoic, irregular margins, taller-than-wide, microcalcifications)

Nodules ≥1.5 cm with intermediate-suspicion ultrasound features (hypoechoic solid nodule without high-suspicion features)

Nodules ≥2.0 cm with low-suspicion ultrasound features (isoechoic or hyperechoic solid nodule, or partially cystic with other low-suspicion features)

Nodules with concerning features regardless of size (cervical lymphadenopathy, rapid growth, extra-thyroidal extension, suspicious cervical lymph nodes)

Nodules with prior Bethesda I (nondiagnostic) result – repeat FNA recommended

Nodules with prior Bethesda III (AUS/FLUS) result – repeat FNA or molecular testing

Comparison with Other Thyroid Reporting Systems

System	Tiers	Focus	Risk Estimates	Geographic Use	Advantages
Bethesda (TBSRTC)	6 tiers (I-VI)	Cytopathology + management	Yes (ROM by tier)	International (US, Europe, Asia, Australia)	Most widely adopted, standardized terminology, management recommendations included, updated 2017 with NIFTP
British Thyroid Association (Thy) System	5 tiers (Thy 1-5)	Cytopathology only (referral to guidelines for management)	Yes (ROM by tier)	United Kingdom, Europe	Simpler (5 tiers), integrated with UK guidelines, but fewer categories than Bethesda
Japanese System	5 categories	Cytopathology + management	Yes	Japan	Different categories (e.g., "follicular neoplasm" separate from "suspicious for malignancy")
Italian Consensus (SIAPEC)	5 classes (TIR 1-5)	Cytopathology only	Yes	Italy	Similar to Bethesda but 5 tiers, TIR-3 split into low-risk and high-risk subgroups
Papanicolaou Society System	6 categories	Pancreatic/biliary cytology (not thyroid)	Yes	US, Europe	Analogous to Bethesda but for pancreas
TI-RADS (Thyroid Imaging Reporting and Data System)	5 levels (TR 1-5)	Ultrasound imaging	Yes (based on imaging features, not cytology)	International	Imaging-based risk stratification, guides which nodules need FNA

How it Works

Bethesda System 6-Tier Classification (2017 Updated ROM)

Category	Diagnostic Term	2017 Risk of Malignancy (Including NIFTP)	2017 Risk of Malignancy (Excluding NIFTP)	Usual Management
I	Nondiagnostic / Unsatisfactory	5-10%	5-10%	Repeat FNA with ultrasound guidance (immediately or at 3-6 months)
II	Benign	0-3%	0-3%	Clinical follow-up (no surgery unless large, growing, or compressive)
III	Atypia of Undetermined Significance (AUS) / Follicular Lesion of Undetermined Significance (FLUS)	10-30%	6-18% (lower after NIFTP reclassification)	Repeat FNA, or molecular testing (e.g., Afirma, ThyroSeq, ThyGenX), or diagnostic lobectomy (clinical decision)
IV	Follicular Neoplasm (FN) / Suspicious for Follicular Neoplasm (SFN)	25-40%	10-40% (wide range depends on NIFTP)	Diagnostic lobectomy (thyroid lobectomy + isthmusectomy)
V	Suspicious for Malignancy	50-75%	50-75% (NIFTP rare, mostly papillary carcinoma)	Near-total thyroidectomy OR lobectomy (depending on clinical factors, patient preference, ultrasound features, molecular testing)
VI	Malignant	97-99%	97-99%	Near-total thyroidectomy (or total thyroidectomy) + possible central neck dissection

Category I: Nondiagnostic / Unsatisfactory

Criteria: Insufficient cellularity (fewer than 6 groups of at least 10 benign follicular cells each), poor preservation, obscuring blood or clot, or air-drying artifact. Incidence: 5-15% of FNAs (higher in cystic nodules, highly vascular nodules, or less experienced operators). Management: Repeat FNA with ultrasound guidance (same-day repeat acceptable, or wait 3-6 months). If repeat FNA is also nondiagnostic (Bethesda I), consider surgical consultation for diagnostic lobectomy (especially if nodule has suspicious ultrasound features or is large >4 cm). Caveat: Nodules with abundant colloid (cystic) may have low cellularity but may still be benign if cyst fluid and few follicular cells; use clinical judgment.

Category II: Benign

Criteria: Cellular specimen with abundant colloid, benign follicular cells, macrophages (cyst contents), and characteristic patterns: nodular hyperplasia, colloid nodule, lymphocytic thyroiditis (Hashimoto), granulomatous thyroiditis (subacute). ROM (2017): 0-3% (excluding NIFTP), 0-3% (including NIFTP). Management: Clinical follow-up (no surgery). Repeat ultrasound in 12-24 months. If nodule grows (>50% volume increase or >2 mm in two dimensions) or develops new suspicious features, repeat FNA. False-negative rate: 1-3% (due to sampling error, cystic nodules with mural nodules, or co-existing incidental carcinoma).

Category III: AUS / FLUS (Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance)

Criteria: Cytologic atypia not sufficient for benign (II) but not enough for neoplasm (IV) or suspicious (V). Heterogeneous category includes: (1) architectural atypia (microfollicles but insufficient for follicular neoplasm), (2) nuclear atypia (nuclear enlargement, grooves, clearing but insufficient for papillary carcinoma), (3) combined architectural and nuclear atypia, (4) atypical lymphoid infiltrate, (5) scant cellularity with atypia, (6) cyst-lining cells with atypia. ROM (2017 with NIFTP): 10-30%; ROM (excluding NIFTP): 6-18%. Management (options): (1) Repeat FNA in 3-6 months (if repeat also AUS/FLUS, molecular testing or surgery), (2) Molecular testing (Afirma GSC, ThyroSeq v3, ThyGenX/ThyraMIR) to rule out malignancy or guide surgery, (3) Diagnostic lobectomy (especially if nodule large, growing, or suspicious ultrasound features). Note: AUS/FLUS is the most problematic category; institutional rates vary (2-20% of FNAs). Higher AUS rates (>10-15% of total FNA) suggest overly sensitive criteria or suboptimal specimen quality.

Category IV: FN / SFN (Follicular Neoplasm / Suspicious for Follicular Neoplasm)

Criteria: Cellular specimen with predominantly microfollicular architecture (crowded groups of follicular cells with scant colloid, often forming small rosettes or trabeculae), scant colloid, and minimal nuclear atypia. Cannot distinguish follicular adenoma (benign) from follicular carcinoma (malignant) on cytology alone because carcinoma diagnosis requires capsular or vascular invasion on surgical specimen. ROM (2017 with NIFTP): 25-40%; ROM (excluding NIFTP): 10-40% (wide range due to NIFTP reclassification). Subcategories: (1) Conventional follicular neoplasm (Hürthle cell type, once called oncocytic neoplasm, now considered a subtype), (2) Hürthle cell neoplasm (now separated in some systems). Management: Diagnostic lobectomy (thyroid lobectomy + isthmusectomy) is standard. Total thyroidectomy may be considered if: (1) contralateral nodule also suspicious, (2) patient has high-risk features (radiation exposure, family history of thyroid cancer), (3) large nodule (>4 cm), (4) patient preference to avoid potential second surgery if final pathology reveals malignancy. Note: On final pathology, 60-75% of Bethesda IV nodules are benign (follicular adenoma or nodular hyperplasia), 10-30% are NIFTP (non-malignant), and 10-25% are malignant (follicular carcinoma, follicular variant papillary carcinoma, Hürthle cell carcinoma).

Category V: Suspicious for Malignancy

Criteria: Cytologic features suspicious for papillary thyroid carcinoma (nuclear grooves, pseudoinclusions, nuclear enlargement, overlapping nuclei) but lacking sufficient quantity or quality for definitive malignant diagnosis. Also includes suspicious for medullary carcinoma (spindle cells, amyloid, calcitonin positivity), suspicious for metastatic tumor, suspicious for lymphoma. ROM (2017): 50-75% (most common malignancy: papillary carcinoma). Management: Near-total thyroidectomy or total thyroidectomy (most common), or lobectomy (if small <1 cm, no extra-thyroidal extension, no lymph node metastases, patient preference). Central neck dissection may be added if clinical or ultrasound evidence of lymph node metastases. Note: Intraoperative frozen section may be helpful to confirm malignancy but not always necessary given high pretest probability.

Category VI: Malignant

Criteria: Unequivocal cytologic features of malignancy. Most common: papillary thyroid carcinoma (classic, follicular variant, tall cell variant, etc.). Also: medullary carcinoma (positive calcitonin, C-cell hyperplasia), poorly differentiated carcinoma, anaplastic carcinoma, metastatic carcinoma, lymphoma. ROM (2017): 97-99% (false-positive rare, usually due to misinterpretation of Hürthle cells, parathyroid tissue, or atypia of Hashimoto thyroiditis). Management: Near-total thyroidectomy (or total thyroidectomy) + central neck dissection (level VI) if papillary carcinoma. Consider lateral neck dissection if cervical lymph node metastases present on ultrasound or preoperative imaging. Post-operative radioactive iodine (RAI) based on ATA risk stratification (low, intermediate, high risk).

NIFTP (Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features) Impact

NIFTP reclassification (2016): The term "non-invasive follicular thyroid neoplasm with papillary-like nuclear features" (NIFTP) replaced the previous "non-invasive encapsulated follicular variant of papillary thyroid carcinoma (EFVPTC)." NIFTP is now classified as a non-malignant neoplasm (borderline tumor) with excellent prognosis (near-zero recurrence or metastasis). Impact on Bethesda ROM: • Category III (AUS/FLUS): ROM decreased from 10-30% to 6-18% (excluding NIFTP). Many NIFTP cases previously classified as malignant are now reclassified, reducing ROM. • Category IV (FN/SFN): ROM decreased from 25-40% to 10-40% (wide range depends on NIFTP proportion). Some centers report NIFTP rates of 20-30% of surgically resected FN/SFN nodules. • Category V (Suspicious): Minimal change (NIFTP rarely diagnosed preoperatively as suspicious; mostly papillary carcinoma). • Management implication: Patients with Bethesda III-IV nodules may be offered diagnostic lobectomy rather than total thyroidectomy, with completion thyroidectomy only if final pathology reveals invasive carcinoma (not NIFTP).

Clinical Pearls

Critical Pearl #1: Bethesda III (AUS/FLUS) Is the Most Challenging Category

Bethesda III (AUS/FLUS) accounts for 2-20% of all thyroid FNAs (ideal rate: 5-10%). Higher rates (>15%) suggest overly sensitive diagnostic criteria or suboptimal specimen quality. Management challenges: (1) Wide ROM range (10-30%) means individual risk varies widely based on ultrasound features, clinical factors, and institutional pathology experience. (2) Repeat FNA yields a definitive diagnosis (Benign II or Malignant VI) in only 40-60% of cases; persistent AUS/FLUS on repeat FNA is common. (3) Molecular testing (Afirma, ThyroSeq) can reclassify 50-70% of AUS/FLUS nodules as benign (avoiding surgery) or suspicious (guiding surgery). Clinical approach: (1) For low-risk AUS/FLUS (small nodule, low-suspicion ultrasound, no family history, young patient): consider repeat FNA at 6 months or molecular testing. (2) For high-risk AUS/FLUS (large >4 cm, high-suspicion ultrasound, family history of thyroid cancer, older patient, growing nodule): consider diagnostic lobectomy directly. (3) Document shared decision-making with patient about risks of surgery (recurrent laryngeal nerve injury, hypoparathyroidism, scarring, anesthesia) vs risks of observation (missed malignancy, delayed diagnosis, anxiety).

Critical Pearl #2: Molecular Testing Has Revolutionized Bethesda III-IV Management

Molecular testing options for indeterminate nodules (Bethesda III and IV): • Afirma Gene Sequencing Classifier (GSC): RNA-based gene expression classifier. Output: "Benign" (high negative predictive value, NPV 94-97%) or "Suspicious" (moderate positive predictive value, PPV 50-60%). Benign result → observe (avoid surgery in 50-70% of cases). Suspicious → surgery recommended. • ThyroSeq v3: DNA and RNA-based next-generation sequencing (NGS) panel of 112 genes. Output: Negative (low risk) or Positive (high risk). Also reports specific mutations (BRAF V600E, RAS, PAX8/PPARγ, etc.). BRAF mutation → highly suspicious for papillary carcinoma (PPV >99%). RAS mutation → indeterminate (10-40% risk, NIFTP common). • ThyGenX/ThyraMIR: Gene expression classifier (ThyGenX) + microRNA (miRNA) risk stratification (ThyraMIR). High sensitivity for malignancy. Clinical application: For Bethesda III/IV nodules, molecular testing reclassifies 50-70% as benign, sparing patients from unnecessary diagnostic lobectomy. Cost considerations: Molecular tests cost $3,500-5,000 (US) but may be covered by insurance and are cost-effective compared to surgery ($15,000-30,000). Guideline recommendation: ATA (2015) and NCCN (2023) recommend molecular testing for Bethesda III/IV nodules to guide management (especially when repeat FNA is also indeterminate).

Critical Pearl #3: Ultrasound-TIRADS and Bethesda Integration

Combined use of Bethesda (cytology) and TI-RADS (ultrasound) improves risk stratification beyond either alone. TI-RADS (Thyroid Imaging Reporting and Data System) levels: • TR1 (Benign): 0% ROM (no FNA needed) • TR2 (Not suspicious): <2% ROM (FNA if ≥2.5 cm) • TR3 (Mildly suspicious): 2-5% ROM (FNA if ≥1.5 cm) • TR4 (Moderately suspicious): 5-20% ROM (FNA if ≥1.0 cm) • TR5 (Highly suspicious): >20% ROM (FNA if ≥1.0 cm) Integration approach: • Bethesda II (Benign) + TR5 (highly suspicious): Discordant finding (low-risk cytology but high-risk ultrasound). Consider repeat FNA (possible sampling error) or short-interval follow-up (6 months). • Bethesda III (AUS) + TR4/5: Higher ROM (toward 30% upper bound). Strongly consider surgery rather than repeat FNA. • Bethesda III (AUS) + TR2/3: Lower ROM (toward 10% lower bound). Consider repeat FNA or molecular testing rather than immediate surgery. • Bethesda IV (FN) + TR5: Higher ROM (toward 40%). Surgery recommended. • Bethesda IV (FN) + TR2/3: Lower ROM (10-20%). May still recommend surgery but could consider molecular testing if patient prefers observation. Documentation: Include both Bethesda category and TI-RADS score in medical record to justify management decisions.

Critical Pearl #4: Institutional Variation in Bethesda III/IV Rates Affects ROM

Bethesda III (AUS/FLUS) rates vary widely (2-20%) across institutions. Causes: (1) Operator experience (inexperienced operators produce more nondiagnostic and AUS specimens), (2) Pathologist thresholds (some diagnose AUS liberally, others conservatively), (3) Patient population (higher atypia in Hashimoto thyroiditis, multinodular goiter, radiation history), (4) Nodule characteristics (cystic nodules produce fewer cells, more AUS). Clinical implication: If your institution's AUS rate is >10-15% of all FNAs, review quality improvement measures: (1) Ultrasound guidance for all FNAs, (2) On-site cytology adequacy assessment (rapid staining, immediate evaluation), (3) Pathologist feedback to proceduralists, (4) Use of liquid-based cytology (ThinPrep, SurePath) vs conventional smears. Risk of malignancy (ROM) adjustment: If your institution's AUS rate is high (e.g., 20%), the ROM for AUS may be lower than published (because many AUS diagnoses are "false positives" – non-neoplastic atypia). Conversely, if AUS rate is low (<5%), ROM for AUS may be higher (only the most atypical cases are called AUS). Discuss with your cytopathology laboratory to understand local ROM estimates.

Common Pitfalls and Limitations

Bethesda I (Nondiagnostic) repeated inadequacy – If two consecutive FNAs are nondiagnostic (Bethesda I), the risk of malignancy is ~5-10% (similar to AUS). Consider diagnostic lobectomy, especially if nodule has suspicious ultrasound features (TR4/5), is large (>4 cm), or is growing.

False-negative Bethesda II (Benign) – Occurs in 1-3% of benign FNAs due to sampling error (cystic nodules with mural nodule, co-existing incidental microcarcinoma not sampled). Clinical clues: nodule growth (>50% volume increase or >2 mm in two dimensions), development of suspicious ultrasound features (microcalcifications, irregular margins, taller-than-wide shape). Repeat FNA if growth or new suspicious features.

False-positive Bethesda VI (Malignant) – Rare (1-3% of malignant diagnoses). Causes: Hürthle cell proliferation (Hashimoto thyroiditis) mimicking oncocytic carcinoma, parathyroid tissue misinterpreted as follicular neoplasm, cystic papillary carcinoma with degenerative atypia. If surgery reveals benign pathology, consider second opinion review of cytology slides.

Over-reliance on Bethesda without clinical context – Bethesda categories do not incorporate clinical factors: age (higher malignancy risk in older adults and children), sex (higher risk in males), family history of thyroid cancer (MEN2, familial non-medullary thyroid cancer), radiation exposure (childhood head/neck radiation increases risk), nodule size (larger nodules have higher malignancy risk), growth rate, and compressive symptoms. Adjust management based on clinical risk.

Ignoring ultrasound features in Bethesda III/IV – Ultrasound features modify the pretest probability. A Bethesda III nodule with TR5 (highly suspicious ultrasound) has ROM ~30% (upper bound of 10-30% range), while Bethesda III with TR2 (not suspicious) has ROM ~10% (lower bound). Use integrated risk assessment.

Not offering molecular testing for Bethesda III/IV – In 2024, molecular testing is standard of care for indeterminate nodules (ATA guideline recommendation). Failure to offer testing may lead to unnecessary surgery (50-70% of patients with Bethesda III/IV nodules could avoid surgery if molecular testing shows benign result). Ensure insurance coverage or discuss out-of-pocket costs with patients.

Inadequate surgical specimen for Bethesda IV – For Bethesda IV nodules, diagnostic lobectomy is standard, but the lobe must be submitted entirely for histologic evaluation to rule out capsular or vascular invasion (diagnosis of follicular carcinoma). Partial lobectomy or fragmented specimens may miss invasion, leading to false-benign diagnosis. Ensure surgeon understands the need for complete lobectomy with intact capsule.

Bethesda vs Molecular Testing vs Ultrasound: Integrated Risk Assessment

Bethesda Category	Low-Risk Ultrasound (TR1-3)	High-Risk Ultrasound (TR4-5)	Molecular Test Result (if performed)	Recommended Management
I (Nondiagnostic)	Repeat FNA (same-day or 3-6 months)	Repeat FNA (same-day or 3-6 months)	Not indicated	If two nondiagnostic FNAs → consider diagnostic lobectomy (ROM 5-10%)
II (Benign)	Clinical follow-up (repeat US in 12-24 months)	Clinical follow-up OR repeat FNA if growth/change	Not indicated (benign result already)	If nodule grows >50% volume or develops suspicious US features → repeat FNA
III (AUS/FLUS)	Repeat FNA (3-6 months) OR molecular testing OR observation	Molecular testing OR diagnostic lobectomy (higher pretest probability)	Benign → observe (50-70% of cases). Suspicious → surgery (lobectomy or near-total)	Repeat FNA yields definitive result (II or VI) in only 40-60% of cases. Persistent AUS → molecular testing or surgery
IV (FN/SFN)	Diagnostic lobectomy (standard) OR molecular testing	Diagnostic lobectomy OR total thyroidectomy (if high-risk features present)	Benign → may observe (controversial; some still recommend lobectomy due to sampling error risk). Suspicious → total thyroidectomy	Most (60-75%) benign on final pathology (follicular adenoma). Lobectomy is safe, with completion thyroidectomy if invasive carcinoma found
V (Suspicious)	Near-total thyroidectomy (or lobectomy if <1 cm, no ETE, no LNM)	Total thyroidectomy + central neck dissection	Positive molecular test confirms high ROM (not needed, already suspicious)	Frozen section may be helpful intraoperatively to confirm malignancy and guide extent of surgery
VI (Malignant)	Total or near-total thyroidectomy + central neck dissection	Total thyroidectomy + central neck dissection + possible lateral neck dissection if LNM	Molecular testing not indicated (confirms malignant diagnosis, may identify BRAF mutation for prognostication)	Post-operative RAI based on ATA risk stratification (low, intermediate, high risk)

Next Steps

Step-by-Step Clinical Action Algorithm by Bethesda Category

Management Summary Card (for Clinical Reference)

Bethesda	Interpretation	ROM (2017)	Management (First Line)	Alternatives	Follow-up
I	Nondiagnostic	5-10%	Repeat FNA with US guidance	If 2x nondiagnostic → diagnostic lobectomy	Repeat in 3-6 months
II	Benign	0-3%	Clinical follow-up (no surgery)	If growth or suspicious US → repeat FNA	US in 12-24 months
III	AUS/FLUS	10-30%	Repeat FNA (3-6 months) OR molecular testing	Diagnostic lobectomy (high-risk features)	Repeat FNA in 3-6 months or molecular testing
IV	FN/SFN	25-40%	Diagnostic lobectomy	Molecular testing (if patient prefers to avoid surgery if benign)	Lobectomy; if benign (follicular adenoma) → discharge
V	Suspicious for Malignancy	50-75%	Near-total or total thyroidectomy	Lobectomy (if <1 cm, no ETE, no LNM)	Post-op RAI based on ATA risk
VI	Malignant	97-99%	Total thyroidectomy + central neck dissection	Lobectomy for small low-risk tumors (controversial)	Post-op RAI, surveillance US

Sample Clinical Documentation for Bethesda Results

Example Progress Note (Endocrinology Clinic): "Patient is a 52-year-old female with a 2.5 cm right thyroid nodule (TR4, moderately suspicious on ultrasound). FNA performed on [date] with on-site cytology adequacy assessment. Cytopathology report: Bethesda III – Atypia of Undetermined Significance (AUS). ROM 10-30% (institution-specific: 15%). Discussed three management options with patient: 1. Repeat FNA in 3-6 months (40-60% chance of definitive benign or malignant result) 2. Molecular testing (Afirma or ThyroSeq) to rule out malignancy (approx 70% chance benign result, avoiding surgery) 3. Diagnostic lobectomy (definitive diagnosis, but surgery with 1-2% risk of recurrent laryngeal nerve injury, 1-2% hypoparathyroidism) Patient preference: Molecular testing (ThyroSeq v3). Ordered and results pending. If benign, will observe with repeat US in 12 months. If suspicious, will refer to endocrine surgery for right thyroid lobectomy. Plan: 1. ThyroSeq v3 sent to reference laboratory 2. Return to clinic in 2 weeks to review results 3. No change in thyroid hormone replacement (patient on levothyroxine 100 mcg daily for Hashimoto thyroiditis; TSH last week 1.8)." Example when molecular testing returns benign: "ThyroSeq v3 result: NEGATIVE (no mutations or gene expression changes suggestive of malignancy). Negative predictive value 97% for excluding follicular carcinoma and papillary carcinoma. Risk of malignancy estimated <3% (comparable to Bethesda II). Patient counseled that surgery can be avoided. Plan: Clinical follow-up with thyroid ultrasound in 12 months. If nodule stable, discharge to annual follow-up. If nodule grows (>50% volume or >2 mm in two dimensions), repeat FNA will be considered."

Origins & History

The 2007 NCI State of the Science Conference

The Bethesda System was developed at the National Cancer Institute (NCI) Thyroid Fine Needle Aspiration State of the Science Conference, held October 22-23, 2007, in Bethesda, Maryland. The conference was organized by Dr. Sudha R. Kini (Henry Ford Hospital, Detroit) and Dr. Andrea Abati (NCI). Over 150 international experts attended, including cytopathologists, endocrinologists, surgeons, radiologists, and pathologists. The goal was to standardize terminology for thyroid FNA reporting, which previously varied widely (e.g., "follicular lesion" had different meanings across institutions). The conference produced a 6-tier system with specific diagnostic categories, malignancy risk estimates (derived from literature meta-analysis of 8,000+ surgically resected nodules), and management recommendations (developed by consensus of clinical experts). The first edition of The Bethesda System for Reporting Thyroid Cytopathology was published in 2010 (Springer). The 2017 second edition incorporated updates based on new data (including the NIFTP reclassification) and expanded sections on molecular testing, ancillary studies, and pediatric thyroid nodules.

Key Contributors and Timeline

Year	Contributor(s)	Institution	Contribution
2007	Abati A, Kini SR (Conference Co-Chairs)	National Cancer Institute (NCI), Henry Ford Hospital	Organized the NCI State of the Science Conference in Bethesda, MD. Defined the 6-tier classification system.
2007	Cibas ES, Ali SZ (Conference Faculty)	Brigham and Women's Hospital, Johns Hopkins Hospital	Drafted the initial diagnostic criteria and management recommendations. Became lead editors of the Bethesda System textbook.
2010	Ali SZ, Cibas ES (Editors)	Johns Hopkins Hospital, Brigham and Women's Hospital	Published 1st edition of The Bethesda System for Reporting Thyroid Cytopathology (Springer). Established standard ROM estimates.
2016	Nikiforov YE, Seethala RR, Tallini G, et al.	University of Pittsburgh, Yale University, University of Bologna	NIFTP reclassification (non-invasive follicular thyroid neoplasm with papillary-like nuclear features). Impacted Bethesda III-IV ROM.
2016-2019	Patel KN, Steward DL, Angell TE, et al.	NYU Langone, University of Cincinnati, University of Southern California	Validation studies of Afirma GSC and ThyroSeq v3 for Bethesda III/IV nodules, enabling molecular testing to guide management.
2017	Ali SZ, Cibas ES (Editors)	Johns Hopkins Hospital, Brigham and Women's Hospital	Published 2nd edition of Bethesda System with updated ROM (incorporating NIFTP) and expanded molecular testing section.
2015/2016 (published 2015, updated 2024 pending)	Haugen BR, Alexander EK, Bible KC, et al. (ATA)	American Thyroid Association	ATA guidelines incorporated Bethesda system for management recommendations (endorsed 6-tier system).

Future Directions and Limitations

Roman numeral system complexity – Some clinicians find 6 categories excessive; proposals for simplified 3-tier (benign, indeterminate, malignant) but rejected due to loss of risk stratification.

Artificial intelligence (AI) integration – Machine learning algorithms for thyroid cytopathology are in development (e.g., deep learning image analysis to classify Bethesda categories). May reduce inter-observer variability and improve AUS/FLUS reclassification.

NIFTP continues to evolve – Some experts now recommend NIFTP be classified as "low-risk neoplasm" with ROM of 0% (malignancy). Ongoing debate about how to handle NIFTP in Bethesda system (may be moved to category III or removed entirely).

Pediatric thyroid nodules – ROM in children is higher for all Bethesda categories (e.g., Bethesda II benign in child has ROM ~5-10%, vs 0-3% in adults). Age-specific ROM estimates and management guidelines are needed.

RAS mutation dilemma – RAS mutations (detected on ThyroSeq) carry 10-40% risk of malignancy, but many are NIFTP or follicular carcinoma. Optimal management of RAS-positive Bethesda III/IV nodules is debated (surgery vs observation).

Institutional variability – Wide variation in AUS/FLUS rates (2-20%) complicates multi-center research and quality benchmarking. Standardization of diagnostic criteria and on-site adequacy assessment remains a priority for the next edition.

Last Comprehensive Review: 2026-07-17

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System

Tiers

Focus

Risk Estimates

Geographic Use

Advantages

Bethesda (TBSRTC)

6 tiers (I-VI)

Cytopathology + management

Yes (ROM by tier)

International (US, Europe, Asia, Australia)

Most widely adopted, standardized terminology, management recommendations included, updated 2017 with NIFTP

British Thyroid Association (Thy) System

5 tiers (Thy 1-5)

Cytopathology only (referral to guidelines for management)

Yes (ROM by tier)

United Kingdom, Europe

Simpler (5 tiers), integrated with UK guidelines, but fewer categories than Bethesda

Japanese System

5 categories

Cytopathology + management

Yes

Japan

Different categories (e.g., "follicular neoplasm" separate from "suspicious for malignancy")

Italian Consensus (SIAPEC)

5 classes (TIR 1-5)

Cytopathology only

Yes

Italy

Similar to Bethesda but 5 tiers, TIR-3 split into low-risk and high-risk subgroups

Papanicolaou Society System

6 categories

Pancreatic/biliary cytology (not thyroid)

Yes

US, Europe

Analogous to Bethesda but for pancreas

TI-RADS (Thyroid Imaging Reporting and Data System)

5 levels (TR 1-5)

Ultrasound imaging

Yes (based on imaging features, not cytology)

International

Imaging-based risk stratification, guides which nodules need FNA

Bethesda System (Thyroid FNA)

When to Use

What is the Bethesda System?

Primary Indications

When to Perform Thyroid FNA (Per ATA Guidelines)

Comparison with Other Thyroid Reporting Systems

How it Works

Bethesda System 6-Tier Classification (2017 Updated ROM)

Category I: Nondiagnostic / Unsatisfactory

Category II: Benign

Category III: AUS / FLUS (Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance)

Category IV: FN / SFN (Follicular Neoplasm / Suspicious for Follicular Neoplasm)

Category V: Suspicious for Malignancy

Category VI: Malignant

NIFTP (Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features) Impact

Clinical Pearls

Critical Pearl #1: Bethesda III (AUS/FLUS) Is the Most Challenging Category

Critical Pearl #2: Molecular Testing Has Revolutionized Bethesda III-IV Management

Critical Pearl #3: Ultrasound-TIRADS and Bethesda Integration

Critical Pearl #4: Institutional Variation in Bethesda III/IV Rates Affects ROM

Common Pitfalls and Limitations

Bethesda vs Molecular Testing vs Ultrasound: Integrated Risk Assessment

Next Steps

Step-by-Step Clinical Action Algorithm by Bethesda Category

Management Summary Card (for Clinical Reference)

Sample Clinical Documentation for Bethesda Results

The Evidence

Primary Source: The Bethesda System (1st and 2nd Editions)

The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes (2nd Edition)

NIFTP Reclassification and Impact on Bethesda ROM

Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in the Bethesda System for Reporting Thyroid Cytopathology

Molecular Testing Validation Studies

Performance of a genomic sequencing classifier for the preoperative diagnosis of cytologically indeterminate thyroid nodules

Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: a prospective blinded multicenter study

Guideline Recommendations (ATA, NCCN)

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer

Thyroid Carcinoma Guidelines (Version 3.2023)

Origins & History

The 2007 NCI State of the Science Conference

Key Contributors and Timeline

Future Directions and Limitations

In Recent Clinical News

Bethesda System (Thyroid FNA)

When to Use

What is the Bethesda System?

Primary Indications

When to Perform Thyroid FNA (Per ATA Guidelines)

Comparison with Other Thyroid Reporting Systems

How it Works

Bethesda System 6-Tier Classification (2017 Updated ROM)

Category I: Nondiagnostic / Unsatisfactory

Category II: Benign

Category III: AUS / FLUS (Atypia of Undetermined Significance / Follicular Lesion of Undetermined Significance)

Category IV: FN / SFN (Follicular Neoplasm / Suspicious for Follicular Neoplasm)

Category V: Suspicious for Malignancy

Category VI: Malignant

NIFTP (Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features) Impact

Clinical Pearls

Critical Pearl #1: Bethesda III (AUS/FLUS) Is the Most Challenging Category

Critical Pearl #2: Molecular Testing Has Revolutionized Bethesda III-IV Management

Critical Pearl #3: Ultrasound-TIRADS and Bethesda Integration

Critical Pearl #4: Institutional Variation in Bethesda III/IV Rates Affects ROM

Common Pitfalls and Limitations

Bethesda vs Molecular Testing vs Ultrasound: Integrated Risk Assessment

Next Steps

Step-by-Step Clinical Action Algorithm by Bethesda Category

Management Summary Card (for Clinical Reference)

Sample Clinical Documentation for Bethesda Results

The Evidence

Primary Source: The Bethesda System (1st and 2nd Editions)

The Bethesda System for Reporting Thyroid Cytopathology: Definitions, Criteria, and Explanatory Notes (2nd Edition)

NIFTP Reclassification and Impact on Bethesda ROM

Nomenclature revision for encapsulated follicular variant of papillary thyroid carcinoma: a paradigm shift to reduce overtreatment of indolent tumors

Impact of reclassifying noninvasive follicular variant of papillary thyroid carcinoma on the risk of malignancy in the Bethesda System for Reporting Thyroid Cytopathology

Molecular Testing Validation Studies

Performance of a genomic sequencing classifier for the preoperative diagnosis of cytologically indeterminate thyroid nodules

Performance of a multigene genomic classifier in thyroid nodules with indeterminate cytology: a prospective blinded multicenter study

Guideline Recommendations (ATA, NCCN)

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer