Definition/General
Introduction:
Follicular carcinoma is a well-differentiated thyroid carcinoma arising from follicular epithelial cells
On FNAC, it cannot be definitively distinguished from follicular adenoma and falls under Bethesda Category IV (Follicular Neoplasm)
The diagnosis requires histological demonstration of capsular and/or vascular invasion
Accounts for 10-15% of thyroid malignancies.
Origin:
Arises from thyroid follicular epithelial cells
Develops through multi-step carcinogenesis process
May arise from pre-existing adenoma or de novo
Shows invasion through capsule and/or blood vessels.
Classification:
WHO classification includes minimally invasive follicular carcinoma (limited capsular invasion) and widely invasive follicular carcinoma (extensive invasion)
Hurthle cell carcinoma considered separate entity
Bethesda Category IV or V.
Epidemiology:
Second most common thyroid malignancy (10-15%)
Female predominance (3:1)
Peak incidence 40-60 years
More common in iodine-deficient areas
Better prognosis than anaplastic but worse than papillary.
Clinical Features
Presentation:
Solitary thyroid nodule, often larger than benign adenomas
May be hard and fixed if invasive
Rapid growth suggests aggressive behavior
Lymph node involvement uncommon.
Symptoms:
Usually asymptomatic initially
Large tumors may cause compressive symptoms
Hoarseness if recurrent laryngeal nerve involvement
Bone pain if distant metastases present.
Risk Factors:
Iodine deficiency (most important)
Radiation exposure
Female gender
Age >45 years
Previous benign thyroid disease
Genetic syndromes rare.
Screening:
Thyroid ultrasound shows hypoechoic nodule with irregular margins
Increased vascularity on Doppler
Elevated thyroglobulin levels
Thyroid scintigraphy shows cold nodule.
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Gross Description
Appearance:
Encapsulated tumor with areas of capsular breach
Cut surface shows tan-brown color with possible necrosis
Firm to hard consistency
May extend beyond capsule.
Characteristics:
Size typically larger than adenomas (2-6 cm)
Capsular thickening and irregularity
Areas of hemorrhage and necrosis in aggressive cases
Vascular invasion may be visible.
Size Location:
Usually 2-8 cm diameter
Can occur anywhere in thyroid
Unifocal in most cases
Large tumors may involve multiple areas of one lobe.
Multifocality:
Usually unifocal disease
Bilateral involvement uncommon (<5%)
Local extension possible in widely invasive type
Lymph node metastasis rare (5-10%).
Microscopic Description
Histological Features:
Follicular architecture with capsular and/or vascular invasion
Microfollicular, macrofollicular, or solid patterns
Nuclear atypia variable
Invasion is the defining feature.
Cellular Characteristics:
Follicular cells with variable nuclear atypia
Increased nuclear size and pleomorphism
Chromatin may be coarse
Nucleoli prominent in some cases
Mitotic activity variable.
Architectural Patterns:
Predominantly microfollicular pattern
Solid and trabecular areas common
Loss of normal follicular architecture
Capsular penetration and vascular invasion defining features.
Grading Criteria:
No universal grading system
Classification based on extent of invasion: minimally invasive (limited capsular penetration) vs widely invasive (extensive invasion with vascular involvement).
Immunohistochemistry
Positive Markers:
Thyroglobulin positive (diagnostic marker)
TTF-1 positive
PAX-8 positive
CK19 may be positive but less than papillary carcinoma
Ki-67 higher than adenoma.
Negative Markers:
Calcitonin negative (excludes medullary carcinoma)
Chromogranin negative
Synaptophysin negative
CK20 negative
CEA usually negative.
Diagnostic Utility:
Thyroglobulin confirms follicular differentiation
TTF-1 and PAX-8 support thyroid origin
Higher Ki-67 than benign adenoma
p53 may be positive in aggressive cases.
Molecular Subtypes:
No established immunohistochemical subtypes
Higher proliferation markers than adenoma
p53 accumulation in aggressive tumors
BRAF mutation typically negative.
Molecular/Genetic
Genetic Mutations:
RAS mutations most common (40-50%)
PAX8/PPARγ rearrangements (25-35%)
PIK3CA mutations
PTEN mutations in aggressive cases
TP53 mutations in advanced disease.
Molecular Markers:
Higher Ki-67 than adenoma (>5%)
p53 overexpression in aggressive cases
Loss of p27 expression
Telomerase reactivation common.
Prognostic Significance:
Overall good prognosis if minimally invasive (>90% 10-year survival)
Widely invasive type has worse prognosis (60-80% 10-year survival)
Age >45 years adverse factor.
Therapeutic Targets:
Radioactive iodine therapy for metastatic disease
Tyrosine kinase inhibitors for radioactive iodine-refractory disease
TSH suppression therapy
Targeted therapy based on mutations.
Differential Diagnosis
Similar Entities:
Follicular adenoma
Adenomatoid nodule
Papillary thyroid carcinoma (follicular variant)
Hurthle cell neoplasm
Metastatic carcinoma
Poorly differentiated thyroid carcinoma.
Distinguishing Features:
Follicular adenoma: no capsular/vascular invasion
Papillary carcinoma: nuclear features, lymph node spread
Hurthle cells: oncocytic cytoplasm
Metastatic: site-specific markers, clinical history.
Diagnostic Challenges:
Cannot distinguish from adenoma on cytology alone
Requires histological examination of entire capsule
Minimal invasion may be missed
Vascular invasion assessment crucial.
Rare Variants:
Insular carcinoma (poorly differentiated)
Clear cell variant
Signet ring cell variant
Follicular carcinoma with spindle cell features
Follicular carcinoma with squamous differentiation.
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.
Site and Procedure
Site: Thyroid [right/left/isthmus], Procedure: Fine needle aspiration cytology
Adequacy
Adequate for evaluation (>6 groups of follicular cells, each with >10 cells)
Cellularity
High cellularity
Architectural Pattern
Predominantly microfollicular pattern with cellular crowding
Colloid
Scant to absent colloid
Cellular Features
Follicular epithelial cells with possible mild nuclear atypia
Nuclear Features
Variable nuclear enlargement and atypia, cannot definitively assess for invasion
Background
Clean background with minimal inflammatory cells
Cytological Diagnosis
Follicular neoplasm, cannot exclude follicular carcinoma - Bethesda Category IV
Recommendation
Surgical consultation mandatory for histopathological examination and capsular invasion assessment