Definition/General
Introduction:
Normal thyroid fine needle aspiration cytology (FNAC) represents the baseline cellular morphology of healthy thyroid tissue
It demonstrates uniform follicular epithelial cells arranged in cohesive groups with abundant colloid
Normal thyroid FNAC shows Bethesda Category II features with benign follicular epithelium
Understanding normal cytology is fundamental for recognizing pathological changes
Adequate sampling includes both cellular and colloid components.
Origin:
Normal thyroid cytology originates from the thyroid follicles composed of follicular epithelial cells surrounding colloid-filled lumina
Follicular cells are responsible for thyroid hormone synthesis and storage
Parafollicular cells (C-cells) are rarely seen in normal FNAC
Colloid contains thyroglobulin and represents stored thyroid hormone precursors
Age-related changes may affect cellular morphology and colloid characteristics.
Classification:
Classified as Bethesda System Category II (Benign) for thyroid cytopathology
Adequate specimens contain at least 6 groups of benign follicular cells with 10 cells each
Colloid should be present in adequate quantity
Cystic lesions require 20 groups of benign epithelial cells
Background inflammation may modify adequacy criteria
Clinical correlation always recommended.
Epidemiology:
Normal thyroid FNAC findings represent the majority (60-70%) of thyroid cytology specimens
Most common in young to middle-aged adults (20-50 years)
Female predominance (4:1) due to higher frequency of thyroid nodules in women
Geographic variation exists with iodine deficiency areas showing different patterns
Indian population shows high prevalence of multinodular goiter requiring careful interpretation.
Clinical Features
Presentation:
Usually performed for evaluation of thyroid nodules detected on clinical examination or imaging
Palpable thyroid nodules are present in 4-7% of adults
Incidental nodules found on ultrasound in up to 50% of population
Most nodules are benign (85-95%) and show normal cytology
Asymptomatic nodules are the most common indication
Family history of thyroid disease may prompt evaluation.
Symptoms:
Most patients are asymptomatic with normal thyroid function
Euthyroid status is typical in patients with benign nodules
No compressive symptoms unless nodules are very large
No voice changes or dysphagia in typical cases
Cosmetic concerns may be present with visible nodules
Anxiety about malignancy is common reason for seeking evaluation.
Risk Factors:
Female gender (4:1 female predominance for thyroid nodules)
Increasing age (nodule prevalence increases with age)
Iodine deficiency (endemic in certain geographic regions)
Radiation exposure (especially in childhood)
Family history of thyroid disease
Autoimmune conditions may be associated
Previous neck irradiation for benign conditions.
Screening:
Clinical examination includes inspection and palpation of thyroid gland
Thyroid function tests (TSH, T3, T4) typically normal
Thyroid ultrasound characterizes nodule size, echogenicity, and suspicious features
FNAC indicated for nodules >1 cm or smaller nodules with suspicious features
Bethesda System provides standardized reporting framework
Clinical correlation guides further management.
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Gross Description
Appearance:
FNAC specimen shows adequate cellular material with characteristic appearance of normal thyroid tissue
Viscous, colloid-rich aspirate is typical finding
Pink to amber-colored thick material on slides due to colloid content
Good cellular preservation with well-defined cell groups
Abundant background colloid creates characteristic appearance
Minimal blood contamination in well-performed aspirations.
Characteristics:
Air-dried smears (Giemsa stain) show excellent colloid detail and nuclear chromatin
Alcohol-fixed smears (Papanicolaou stain) demonstrate cytoplasmic details
Thick colloid may require dilution for optimal viewing
Cell groups should be well-preserved without crush artifacts
Colloid cracks are artifacts and should not be misinterpreted
Even distribution of cellular material across slides.
Size Location:
Follicular epithelial cells measure 8-12 micrometers in diameter
Nuclei are round to oval measuring 6-8 micrometers
Nuclear-to-cytoplasmic ratio approximately 1:2 to 1:3
Colloid appears as thick, homogeneous material in background
Cell groups typically contain 10-20 cells in honeycomb arrangement
Uniform cell size within normal follicular epithelium.
Multifocality:
Representative sampling from different areas of nodule or thyroid gland
Uniform appearance should be maintained across different samples
Colloid characteristics may vary slightly between different follicles
Cellular morphology remains consistent in normal tissue
Age-related changes may affect colloid density and cellular appearance
Sampling adequacy requires material from lesional tissue.
Microscopic Description
Histological Features:
Cohesive groups of follicular epithelial cells arranged in honeycomb or macrofollicular pattern
Abundant thick colloid in background with characteristic pink appearance on Papanicolaou stain
Uniform follicular cells with round to oval nuclei and moderate cytoplasm
Fine, evenly distributed chromatin without coarsening or hyperchromasia
Small, inconspicuous nucleoli occasionally present
Clean background without inflammation or necrosis.
Cellular Characteristics:
Follicular epithelial cells with round to oval nuclei and moderate amount of cytoplasm
Nuclear chromatin fine and evenly distributed without hyperchromasia
Nuclear membranes smooth and regular
Nucleoli small and inconspicuous when present
Cytoplasm moderate in amount, finely granular, and pale to amphophilic
Cell borders well-defined in cohesive arrangements
No mitotic figures in normal resting follicular cells.
Architectural Patterns:
Macrofollicular pattern with large, flat sheets of follicular cells
Honeycomb arrangement with well-defined cell borders and uniform spacing
Microfollicular groups may be present but are not predominant
Colloid in background and within follicular lumina
No papillary architecture or complex branching patterns
Absence of single cell dispersion or loss of cohesion.
Grading Criteria:
Bethesda System Category II (Benign) assigned to normal thyroid cytology
Adequacy criteria: minimum 6 groups of 10 benign follicular cells each
Colloid presence required for adequate interpretation
Absence of atypia or suspicious features
Clinical correlation recommended for all benign diagnoses
Follow-up protocols based on clinical and sonographic features.
Immunohistochemistry
Positive Markers:
Thyroglobulin strongly positive in follicular epithelial cells and colloid (95-100%)
TTF-1 (Thyroid Transcription Factor-1) positive in follicular cell nuclei
PAX8 positive in follicular cell nuclei (thyroid lineage marker)
Cytokeratins (CK7, CK19) positive in follicular cells
E-cadherin positive (maintains cell-cell adhesion)
Ki-67 very low proliferation index (<2%).
Negative Markers:
Calcitonin negative in normal follicular cells (specific for C-cells)
Chromogranin A negative in follicular cells
CK20 typically negative
p53 negative (wild-type expression pattern)
RET/PTC rearrangements absent in normal tissue
BRAF mutations absent in normal follicular cells.
Diagnostic Utility:
Immunohistochemistry rarely required for normal thyroid FNAC diagnosis
Thyroglobulin staining confirms thyroidal origin when necessary
TTF-1 positivity supports thyroid follicular cell lineage
Research applications in studying thyroid development and physiology
Quality control in establishing normal reference ranges
Educational purposes for resident training.
Molecular Subtypes:
No molecular subtypes recognized for normal thyroid tissue
Baseline gene expression serves as reference for pathological conditions
Normal thyroid development genes (PAX8, TTF-1, FOXE1) expressed appropriately
TSH receptor signaling intact and functional
Iodine metabolism genes normally expressed
Reference standards for comparison with neoplastic lesions.
Molecular/Genetic
Genetic Mutations:
No pathological mutations expected in normal thyroid tissue
Wild-type gene expression for all major thyroid-related genes
RET/PTC rearrangements absent
BRAF mutations absent
RAS mutations absent
PTEN wild-type expression
p53 wild-type function maintained.
Molecular Markers:
Normal thyroid-specific gene expression including thyroglobulin, TPO, NIS
Transcription factors (TTF-1, PAX8) normally expressed
Very low proliferation with Ki-67 <2%
Intact apoptosis pathways (BCL2, BAX normally balanced)
DNA repair mechanisms functioning properly
Telomerase activity low in normal somatic cells.
Prognostic Significance:
Excellent prognosis with normal thyroid FNAC findings
Low risk of malignancy (<1%) in Bethesda Category II
Routine follow-up based on clinical and sonographic features
Repeat FNAC typically not required unless clinical changes occur
Reassurance to patients about benign nature of findings
Long-term surveillance based on risk stratification.
Therapeutic Targets:
No therapeutic intervention required for normal thyroid tissue
Observation and clinical monitoring appropriate management
Thyroid hormone supplementation not indicated unless hypothyroidism present
Patient education about normal findings and follow-up
Lifestyle counseling regarding iodine intake and thyroid health
Genetic counseling if strong family history present.
Differential Diagnosis
Similar Entities:
Benign follicular nodule shows similar cytology but may have increased cellularity
Multinodular goiter demonstrates variable follicular cell morphology
Hashimoto thyroiditis shows lymphocytic infiltration and Hürthle cell change
Follicular adenoma shows increased cellularity with microfollicular pattern
Colloid nodule demonstrates abundant colloid with sparse cellularity
Cystic thyroid lesions show hemorrhage and hemosiderin-laden macrophages.
Distinguishing Features:
Normal thyroid shows uniform follicular cells with abundant colloid and no atypia
Follicular nodule demonstrates increased cellularity and possible microfollicular pattern
Hashimoto thyroiditis shows lymphoplasmacytic infiltrate and Hürthle cells
Follicular adenoma demonstrates predominant microfollicular architecture
Colloid nodule shows predominantly colloid with minimal cellularity
Cystic lesions demonstrate cyst macrophages and hemorrhage.
Diagnostic Challenges:
Sampling adequacy assessment crucial for accurate interpretation
Age-related changes may affect cellular morphology
Technical factors (preparation, staining) may influence appearance
Borderline cellular atypia may create interpretive challenges
Cystic change may reduce cellular yield
Clinical correlation essential for appropriate categorization.
Rare Variants:
Age-related involution with reduced cellularity and increased fibrosis
Pregnancy-related changes with increased cellular activity
Iodine deficiency changes with altered colloid characteristics
Post-radiation changes affecting normal tissue morphology
Medication effects (lithium, amiodarone) on thyroid morphology
Seasonal variations in thyroid activity and morphology.
Sample Pathology Report
Template Format
Sample Pathology Report
Complete Report: This is an example of how the final pathology report should be structured for this condition.
Specimen Information
Fine needle aspiration cytology from thyroid [location], [number] slides examined
Specimen Adequacy
Adequate for evaluation - [number] groups of benign follicular cells present
Cytological Findings
Cohesive groups of uniform follicular epithelial cells in honeycomb arrangement with abundant background colloid
Cellular Features
Uniform follicular cells with round to oval nuclei, fine chromatin, and moderate cytoplasm
Colloid
Abundant thick colloid present in background, consistent with normal thyroid tissue
Background
Clean background without inflammation, necrosis, or atypical cells
Diagnosis
Bethesda Category II - Benign (Consistent with normal thyroid tissue)
Bethesda System Category
Category II: Benign - Normal thyroid parenchyma
Risk of Malignancy
<1% (Bethesda Category II)
Recommendations
Clinical correlation recommended. Routine follow-up based on sonographic and clinical features.