The 2023 Bethesda System for Reporting Thyroid Cytopathology

Since 2010 this system has allowed cytopathologist to use an international, standardized, category-based reporting system for thyroid fine needle aspirations (FNA). In third edition the 6 diagnostic categories were assigned with a single name:

(i)                  Nondiagnostic

(ii)                Benign

(iii)              Atypia of undetermined significance

(iv)              Follicular neoplasm

(v)                Suspicious for malignancy

(vi)              Malignant

Each of these categories has an implied risk of malignancy (ROM), in addition to expected range of cancer risk.

Every thyroid FNA report should begin with 1 of the 6 diagnostic categories. Indeterminate categories  (iii) to (v) may require molecular testing to tailor clinical decision.

(i)                 Nondiagnostic

Every thyroid FNA should be evaluated for sample adequacy, which is defined by both the quantity (minimum of 6 groups of well-preserved, well-visualized follicular cells, with each group comprising >= 10 cells, for an adequate sample) and quality (show cells that are well-preserved, well-stained, and easily visualized) of the cellular (mostly follicular) and colloid components. It increases the accurate interpretation of the FNA.

Aspirates that consist of cyst fluid only with or without macrophages continue to be interpreted as nondiagnostic (Bethesda I).

The ROM for a nondiagnostic FNA is difficult to calculate because most nodules are not surgically resected.

A repeat aspiration with ultrasound guidance is recommended for cytologically nondiagnostic nodules and will yield diagnostic results in 60%–80% of cases, particularly in the nodules with a smaller cystic component.

Is subclassify as:

·         Cyst fluid only

·         Virtually acellular specimen

·         Other (obscuring blood, clotting artifact, drying artifact, etc.)

(ii)               Benign

The clinical value of thyroid FNA is the ability to reliably identify benign thyroid nodules and avoid unnecessary surgical resection in patients with nodular thyroid disease. A benign (Bethesda II) FNA is associated with very low ROM (range, 2%–7%; average, 4%).

‘‘follicular nodular disease’’ is preferred to refer to the spectrum of changes previously designated as colloid nodule, hyperplastic nodule, adenomatous nodule, or benign follicular nodule.

Is subclassify as:

·         Consistent with follicular nodular disease (includes adenomatoid nodule, colloid nodule, etc.)

·         Consistent with chronic lymphocytic (Hashimoto) thyroiditis in the proper clinical context

·         Consistent with granulomatous (subacute) thyroiditis

·         Other

(iii)             Atypia of undetermined significance (AUS)

Is define as a specimen that contains cells of follicular, lymphoid, or other origin, contains architectural or nuclear atypia that is more than would be expected in benign nodule but that falls short of being suspicious for malignancy or follicular or oncocytic (Hürthle cell) neoplasm. Is one of the three “indeterminate” cytopathologic interpretations that convey a diagnosis that is not definitively benign or malignant. Among the 3 indeterminate categories AUS has the lowest ROM (average, 22%; range, 20%–32%).

AUS with nuclear atypia has a significantly higher ROM compared with AUS associated with other patterns. One study showed that nuclear atypia was associated with an ROM of 59% compared with 6.5% for architectural or oncocytic atypia.

AUS is subcategorized into 2 groups:

·         ‘‘nuclear’’ (previously ‘‘cytologic’’)

·         ‘‘other.’’

This 2-tiered subclassification is supported partly by molecular studies performed on AUS cases clearly delineating the ‘‘nuclear’’ from the ‘‘other’’ subgroup.

(iv)             Follicular neoplasm

The diagnostic criteria are aspirates that are at least moderately cellular and composed of follicular cells, most of which show significant architectural abnormality in the form of microfollicles and/or crowding, trabeculae, or single cells.

Prospective cytologic recognition of potential Non-Invasive Follicular Thyroid neoplasm with Papillarylike nuclear features (NIFTP) cases in thyroid FNAs is important to avoid overdiagnosing them as ‘‘malignant—papillary thyroid carcinoma’’ or ‘‘suspicious for malignancy—suspicious for papillary thyroid carcinoma,’’ diagnostic categories that could unnecessarily result in aggressive surgical procedures, because the recommended treatment for NIFTP is conservative surgery (lobectomy). If true papillae are absent and intranuclear pseudoinclusions are either absent or very rare, is best classify as Follicular Neoplasm (Bethesda IV).

Molecular testing results can be used to supplement the risk assessment in lieu of proceeding directly to surgery.

This diagnosis is associated with a significant ROM (range, 25%–50%).

Diagnostic criteria are virtually exclusive population of oncocytes, usually scant to absent colloid, rare to absent background lymphocytes, and, often, with the presence of nuclear and cellular size variations.

(v)               Suspicious for malignancy  (SFM)

Used when cytomorphologic features of a thyroid FNA are worrisome for papillary thyroid carcinoma, medullary thyroid carcinoma, lymphoma, or another malignant neoplasm, but are quantitatively and/or qualitatively insufficient to malignant (Bethesda V) diagnosis.

Most cases under SFM are classified as ‘‘suspicious for papillary thyroid carcinoma.’’ As the usual management is surgical (either lobectomy or near total thyroidectomy), the diagnosis of SFM should be used judicially. Some, but not all, of the cases in this category raise the possibility of a follicular variant of papillary thyroid carcinoma or NIFTP.

Is subclassify as:

·         Suspicious for papillary thyroid carcinoma

·         Suspicious for medullary thyroid carcinoma

·         Suspicious for metastatic carcinoma

·         Suspicious for lymphoma

·         Other

 

(vi)             Malignant

Used whenever the cytomorphologic features are conclusive for malignancy.

The new term ‘‘high-grade follicular-derived thyroid carcinoma’’ is now endorsed, which replaces the older nomenclature of ‘‘poorly differentiated thyroid carcinoma.’ (4)

Is subclassify as:

·         Papillary thyroid carcinoma

o   Most common endocrine malignancy

o   Cells arranged in groups, syncytial sheets, papillary tissue fragments, and avascular papillary fronds

o   Oval nuclei with irregular membrane, nuclear grooves, nuclear overlap, fine, powdery chromatin, psammoma bodies

o   Intranuclear inclusions, multinucleated giant cells, dense squamoid cytoplasm, thick colloid

o   Follicular variant may have abundant watery colloid

o   Prognosis is excellent (10-year survival rate > 90%)

 

·         High-grade follicular-derived carcinoma

o   Death from disease is common, often years later

o   Not responsive to conventional therapy

o   Highly cellular smears with scant colloid

o   Monotonous, small to intermediate-sized cells

o   Bland nuclei with fine chromatin and small nucleoli

o   Necrosis and mitoses are common

 

·         Medullary thyroid carcinoma

o   Medullary thyroid carcinoma (MTC) arises from C cells

o   Spindle, polygonal, or bipolar cells often with eccentric nuclei and ill-defined cell borders

o   Hyperchromatic nuclei with coarse chromatin and moderate pleomorphism

o   Abundant eosinophilic or amphophilic cytoplasm with fibrillar quality

o   Metachromic red (azurophilic) cytoplasmic granules in Diff Quik

o   5-year survival rate: 60-80%

o   10-year survival rate: 40-70%

·         Undifferentiated (anaplastic) carcinoma

o   Most patients have history of nodular hyperplasia

o   Rapidly progressive with poor prognosis

o   Highly cellular neoplasm with absent colloid

o   Background of necrotic debris and inflammatory cells

o   Markedly pleomorphic nuclei with prominent nucleoli and ample eosinophilic cytoplasm

o   Varying malignant cellular population consisting of osteoclastic and pleomorphic giant cells, squamoid, signet-ring, spindle, rhabdoid, stellate, and carcinosarcomatous patterns

o   Paucicellular and angiomatoid variants also described

o   Primary squamous cell carcinoma of thyroid is categorized as anaplastic thyroid carcinoma

·         Squamous cell carcinoma

o   Coarse to pyknotic chromatin, irregular nuclear contours, and prominent nucleoli

o   Vacuolated to dense and orangeophilic cytoplasm

·         Metastatic malignancy

o   Thyroid is vascular and predisposed to metastases

o   Carcinomas are most common metastases (~ 80%)

o   Renal cell carcinoma is most common carcinoma; melanoma and leiomyosarcoma are most common noncarcinomas

o   Cytomorphology resembles primary tumor

o   Smears are cellular with 2 distinct cell populations if background thyroid is sampled

o   Thyroglobulin may diffuse into adjacent tissue or become "entrapped" within metastatic deposits

 

·         Non-Hodgkin lymphoma

o   Generally associated with lymphocytic thyroiditis

o   Hypercellular aspirate of noncohesive lymphoid cells

o   Lymphoglandular bodies are usually present; best seen on Diff-Quik

o   May see lymphoepithelial lesions or germinal centers

 

·         Other

o   Cribriform-Morular Carcinoma

o   Carcinoma Showing Thymus-Like Differentiation

o   Spindle Epithelial Tumor With Thymus-Like Differentiation (SETTLE)

o   Sclerosing Mucoepidermoid Carcinoma With Eosinophilia

o   Neuroendocrine/Small Cell Carcinoma

 

Bibliography   

4.        Ali SZ, Baloch ZW, Cochand-Priollet B, Schmitt FC, Vielh P, VanderLaan PA. The 2023 Bethesda System for reporting thyroid cytopathology. J Am Soc Cytopathol. 2023 Sep;12(5):319–25.