What is the purpose and categorization of the Bethesda system for thyroid cytopathology?

Bethesda System for Thyroid Cytopathology

The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) is a standardized six-category classification system that stratifies thyroid nodules by malignancy risk to guide clinical management decisions, with each category carrying a specific risk of malignancy that directly determines whether observation, repeat biopsy, molecular testing, or surgery is indicated. 1

Purpose and Framework

The Bethesda System establishes uniform diagnostic terminology for thyroid fine-needle aspiration (FNA) specimens, allowing cytopathologists to communicate findings consistently across institutions and enabling evidence-based risk stratification. 2, 3 Every thyroid FNA report must begin with one of six diagnostic categories, each linked to an implied cancer risk and specific management recommendations. 1, 2

The Six Diagnostic Categories

Category I: Nondiagnostic or Unsatisfactory

• Represents specimens with insufficient cellular material for diagnosis 1
• Accounts for approximately 10-20% of thyroid FNAs in clinical practice 4, 5
• Management: Repeat FNA under ultrasound guidance is recommended 6

Category II: Benign

• Includes nodular goiter, colloid goiter, hyperplastic/adenomatoid nodule, and Hashimoto's thyroiditis 1
• Represents the largest category, comprising approximately 60-70% of all thyroid FNAs 4, 5
• Risk of malignancy: 0-3% 2, 5
• Management: Clinical and ultrasound surveillance; highly reliable for ruling out malignancy 6

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

• Represents cytologic findings that are neither clearly benign nor clearly suspicious 1
• Accounts for approximately 12-27% of thyroid FNAs 4, 5
• Risk of malignancy: 6-18% (updated in 2017 revision) 2, 5
• Management: Molecular diagnostic testing (BRAF V600E, RET/PTC, RAS, PAX8/PPARγ) or gene expression classifiers may assist in management decisions rather than proceeding directly to surgery 1, 6
• If molecular testing predicts malignancy risk ≤5% (comparable to benign FNA), active surveillance is appropriate 1

Category IV: Follicular Neoplasm or Suspicious for Follicular Neoplasm

• Includes Hürthle cell neoplasm 1
• Represents approximately 3-8% of thyroid FNAs 4, 5
• Risk of neoplasm: 67% (including benign and malignant) 5
• Risk of malignancy: 22% 5
• Management: Surgery should be considered when FNA shows follicular neoplasia with normal TSH and "cold" appearance on thyroid scan 6
• Molecular testing may help refine risk stratification 1, 6

Category V: Suspicious for Malignancy

• Represents cytologic findings highly suggestive of malignancy but not definitively diagnostic 1
• Accounts for approximately 2-3% of thyroid FNAs 4, 5
• Risk of malignancy: 56-75% 2, 5
• Management: Immediate surgical consultation for total or near-total thyroidectomy 6

Category VI: Malignant

• Includes papillary thyroid carcinoma, medullary thyroid carcinoma (MTC), anaplastic thyroid carcinoma (ATC), or lymphoma 1
• Represents approximately 3-4% of thyroid FNAs 4, 5
• Risk of malignancy: Virtually 100% 2, 5
• Management: Immediate surgical consultation for total or near-total thyroidectomy 6

Clinical Application and Key Considerations

The BRAF V600E mutation occurs in approximately 45% of papillary carcinomas and is the most common mutation; when occurring with a TERT promoter mutation, it is linked to poor prognosis. 1

The predictive value of molecular diagnostics is significantly influenced by the pretest probability of disease associated with the various FNA cytology groups. 1 For indeterminate categories (III and IV), molecular testing using multigene assays or individual mutational analysis can help determine whether active surveillance versus surgical resection is appropriate. 1

Important Pitfalls

Follicular neoplasms cannot be definitively diagnosed by FNA alone and require histological examination to determine capsular and/or vascular invasion. 7, 6 This limitation means that Category IV lesions often require surgical excision for definitive diagnosis, with malignancy rates ranging from 12-34% depending on subcategory. 6

The 2017 revision updated malignancy risks based on post-2010 data and accounts for the reclassification of some thyroid neoplasms as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), which has implications for risk stratification. 2