Definition/General
Introduction:
Papillary thyroid carcinoma (PTC) is the most common thyroid malignancy, accounting for 80-85% of all thyroid cancers
It is characterized by distinctive nuclear features including nuclear grooves, intranuclear pseudoinclusions, and overlapping nuclei
FNAC diagnosis shows high sensitivity and specificity (85-95%) when adequate material is obtained
The tumor shows papillary architecture and characteristic nuclear morphology
Bethesda Category VI (Malignant) is assigned to classic cases.
Origin:
Papillary thyroid carcinoma originates from follicular epithelial cells of the thyroid gland
It develops through multistep carcinogenesis involving genetic alterations
RET/PTC rearrangements and BRAF mutations are key driver mutations
The tumor shows papillary growth pattern with fibrovascular cores
Lymphatic invasion is common leading to regional lymph node metastases
Radiation exposure is a known etiological factor.
Classification:
Classified as Bethesda System Category VI (Malignant) for classic papillary carcinoma
Variants include classic papillary carcinoma, follicular variant, tall cell variant, columnar cell variant, and solid variant
Follicular variant may be categorized as Bethesda IV (Suspicious) if nuclear features are subtle
Aggressive variants require specific recognition and reporting
Microcarcinomas (<1 cm) have excellent prognosis.
Epidemiology:
Peak incidence in 4th-5th decades of life (30-50 years)
Female predominance with 3-4:1 female-to-male ratio
Accounts for 80-85% of thyroid cancers globally
Increasing incidence due to improved detection methods
Geographic variation with higher rates in iodine-sufficient areas
Indian population shows similar demographics with increasing urban prevalence.
Clinical Features
Presentation:
Asymptomatic thyroid nodule is the most common presentation (70-80%)
Palpable thyroid mass with or without lymphadenopathy
Incidental discovery on imaging studies (20-30%)
Family history of thyroid cancer may be present
Previous radiation exposure to head and neck region
Rapid growth may occur in aggressive variants
Multifocal disease present in 20-30% of cases.
Symptoms:
Most patients are euthyroid with normal thyroid function tests
Hoarseness due to recurrent laryngeal nerve involvement (advanced cases)
Dysphagia or odynophagia with large tumors
Cervical lymphadenopathy may be the presenting feature (10-15%)
Compressive symptoms rare unless tumor is very large
Constitutional symptoms uncommon in differentiated thyroid cancer.
Risk Factors:
Female gender (3-4 fold increased risk)
Radiation exposure especially in childhood
Iodine sufficiency (paradoxically increases papillary carcinoma risk)
Family history of thyroid cancer (5-10% familial cases)
Genetic syndromes (Carney complex, Cowden syndrome)
Previous benign thyroid disease
Reproductive factors in women (pregnancy, estrogen exposure).
Screening:
High-resolution thyroid ultrasound shows suspicious features (hypoechogenicity, microcalcifications, irregular margins)
Doppler studies may show increased vascularity
FNAC indicated for nodules with suspicious sonographic features regardless of size
Bethesda System provides risk stratification
Molecular testing may be helpful in indeterminate cases
Clinical correlation with family history and radiation exposure.
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Gross Description
Appearance:
FNAC specimen shows moderate to high cellularity with characteristic papillary fragments and nuclear features
Three-dimensional tissue fragments with papillary architecture
Overlapping nuclei create crowded appearance
Relatively clean background without extensive colloid
Psammoma bodies may be present (pathognomonic when seen)
Cystic change may be present in some cases.
Characteristics:
Papillary tissue fragments with fibrovascular cores when present
Cellular overlapping and crowding characteristic
Nuclear grooves best seen in air-dried, Giemsa-stained preparations
Intranuclear pseudoinclusions pathognomonic when identified
Metaplastic changes may be present (squamous, columnar)
Cell block preparation helpful for architectural assessment and immunohistochemistry.
Size Location:
Neoplastic cells measure 12-20 micrometers in diameter, larger than normal follicular cells
Nuclear size increased (8-12 μm) compared to normal follicular cells (6-8 μm)
Nuclear-to-cytoplasmic ratio increased (1:1 to 1:2)
Papillary fragments may be large and complex
Psammoma bodies measure 50-100 micrometers when present
Cellular pleomorphism variable depending on variant.
Multifocality:
Multifocal disease present in 20-30% of cases requiring bilateral thyroid sampling if clinically indicated
Lymph node sampling may be performed if adenopathy present
Different areas of the same tumor may show varying degrees of papillary architecture
Cystic areas may yield different cellular morphology
Follicular areas may predominate in follicular variant
Representative sampling essential for accurate diagnosis.
Microscopic Description
Histological Features:
Papillary tissue fragments with complex three-dimensional architecture and overlapping nuclei
Characteristic nuclear features: enlarged, oval nuclei with irregular contours
Nuclear grooves (longitudinal nuclear folds) in 60-80% of cells
Intranuclear pseudoinclusions (invaginations of cytoplasm into nucleus) pathognomonic when present
Ground-glass nuclear chromatin with peripheral margination
Prominent nucleoli may be present.
Cellular Characteristics:
Enlarged epithelial cells with increased nuclear-to-cytoplasmic ratio
Nuclear features: oval shape, irregular contours, ground-glass chromatin, nuclear grooves
Intranuclear pseudoinclusions appear as sharply demarcated clear areas within nuclei
Cytoplasm moderate to abundant, may be eosinophilic or amphophilic
Cell borders distinct in papillary fragments
Mitotic activity variable, usually low in classic type.
Architectural Patterns:
Papillary architecture with branching papillae and fibrovascular cores (when present in aspirate)
Three-dimensional cell clusters with significant overlapping
Follicular pattern may be present especially in follicular variant
Solid areas may be seen in solid variant
Single cell dispersion less common than in other thyroid malignancies
Psammoma bodies (laminated calcified concretions) pathognomonic when present.
Grading Criteria:
Bethesda System Category VI (Malignant) for classic papillary carcinoma with typical nuclear features
Bethesda Category V (Suspicious for Malignancy) when nuclear features are present but less pronounced
Bethesda Category IV (Follicular Neoplasm) for follicular variant with subtle nuclear features
Nuclear feature assessment is key to diagnosis
Clinical and sonographic correlation important for final categorization.
Immunohistochemistry
Positive Markers:
Thyroglobulin positive (confirms thyroidal origin) in 90-95% of cases
TTF-1 positive in nuclei (thyroid lineage marker)
PAX8 positive in nuclei (specific for thyroid follicular cells)
Cytokeratin 19 (CK19) strongly positive (90-95%) - useful diagnostic marker
HBME-1 positive (85-90%) - mesothelioma marker but positive in PTC
Galectin-3 positive (80-90%) - distinguishes from benign lesions.
Negative Markers:
Calcitonin negative (excludes medullary carcinoma)
Chromogranin A negative (excludes neuroendocrine differentiation)
CD68 negative (excludes macrophages)
S-100 negative (excludes neural differentiation)
Vimentin typically negative (excludes mesenchymal origin)
p63 negative (excludes squamous differentiation unless metaplasia present).
Diagnostic Utility:
CK19 positivity highly sensitive and specific for papillary carcinoma vs
benign lesions
HBME-1 useful in distinguishing PTC from follicular lesions
Galectin-3 helps differentiate malignant from benign follicular lesions
Thyroglobulin confirms thyroidal origin when metastatic disease suspected
TTF-1 and PAX8 support thyroid follicular cell lineage
Panel approach recommended rather than single marker.
Molecular Subtypes:
RET/PTC-positive subtype (30-40% of cases) - associated with radiation exposure
BRAF-positive subtype (40-45% of cases) - associated with classic morphology and aggressive behavior
RAS-positive subtype (10-15% of cases) - often follicular variant morphology
Triple-negative subtype (10-15% of cases) - no major driver mutations identified
Fusion-positive subtypes - various partner genes with RET.
Molecular/Genetic
Genetic Mutations:
BRAF V600E mutation (40-45% of papillary carcinomas) - associated with aggressive behavior
RET/PTC rearrangements (30-40% of cases) - more common in radiation-associated tumors
RAS mutations (NRAS, HRAS, KRAS) in 10-15% - often in follicular variant
TERT promoter mutations (10-15%) - associated with poor prognosis
PIK3CA mutations (5-10%) - oncogenic pathway activation
TP53 mutations rare in well-differentiated papillary carcinoma.
Molecular Markers:
High expression of thyroid differentiation markers (thyroglobulin, TPO, NIS)
CK19 overexpression (diagnostic marker)
Galectin-3 overexpression (malignancy marker)
BRAF protein expression when V600E mutation present
RET protein expression in RET/PTC-positive cases
Ki-67 proliferation index variable (5-20%) depending on variant and grade.
Prognostic Significance:
Generally excellent prognosis for classic papillary carcinoma (>95% 10-year survival)
BRAF V600E mutation associated with more aggressive behavior and higher recurrence risk
RET/PTC rearrangements generally associated with good prognosis
Tall cell variant and other aggressive variants have worse prognosis
Age >55 years important prognostic factor
Tumor size >4 cm and extrathyroidal extension worsen prognosis.
Therapeutic Targets:
Radioactive iodine therapy for intermediate and high-risk cases
BRAF inhibitors (vemurafenib, dabrafenib) for BRAF-positive advanced disease
Multi-kinase inhibitors (sorafenib, lenvatinib) for radioiodine-refractory disease
RET inhibitors (selpercatinib, pralsetinib) for RET/PTC-positive cases
mTOR inhibitors under investigation
Immunotherapy (pembrolizumab) for mismatch repair-deficient cases.
Differential Diagnosis
Similar Entities:
Follicular adenoma/carcinoma lacks characteristic nuclear features of papillary carcinoma
Hürthle cell neoplasm shows oncocytic cytoplasm without papillary nuclear features
Anaplastic carcinoma shows high-grade pleomorphic cells with necrosis
Medullary carcinoma demonstrates neuroendocrine features and calcitonin positivity
Lymphoma shows monotonous lymphoid cells
Metastatic carcinoma shows organ-specific features.
Distinguishing Features:
Papillary carcinoma shows diagnostic nuclear features (grooves, pseudoinclusions, ground-glass chromatin)
Follicular neoplasms lack nuclear grooves and pseudoinclusions
Hürthle cell tumors show abundant granular eosinophilic cytoplasm
Anaplastic carcinoma demonstrates marked pleomorphism and necrosis
Medullary carcinoma shows plasmacytoid cells with neuroendocrine granules
Lymphoma shows lymphoid morphology and lacks epithelial markers.
Diagnostic Challenges:
Follicular variant of papillary carcinoma may lack classic nuclear features
Cystic papillary carcinoma may show degenerative changes obscuring nuclear details
Scant cellular yield may limit assessment of nuclear features
Preparation artifacts may mimic or obscure nuclear grooves
Radiation-related atypia in benign tissue may mimic malignancy
Hashimoto thyroiditis with atypia may create diagnostic confusion.
Rare Variants:
Tall cell variant shows cells twice as tall as they are wide with intensely eosinophilic cytoplasm
Columnar cell variant demonstrates prominent nuclear stratification and pseudostratification
Solid variant shows solid growth pattern with minimal follicular architecture
Diffuse sclerosing variant shows extensive fibrosis and lymphocytic infiltration
Warthin-like variant shows papillary architecture with lymphocytic stroma
Cribriform-morular variant associated with FAP syndrome.
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 - cellular material with diagnostic features present
Cytological Findings
Cellular aspirate with papillary tissue fragments and characteristic nuclear features of papillary carcinoma
Cellular Features
Enlarged epithelial cells with overlapping nuclei, nuclear grooves, and ground-glass chromatin
Nuclear Features
Nuclear enlargement, oval shape, nuclear grooves present. Ground-glass chromatin pattern identified.
Architectural Pattern
Three-dimensional papillary fragments with overlapping nuclei and cellular crowding
Special Features
Intranuclear pseudoinclusions [present/absent]. Psammoma bodies [present/absent].
Background
Relatively clean background with minimal colloid and inflammatory cells
Diagnosis
Bethesda Category VI - Malignant: Papillary thyroid carcinoma
Bethesda System Category
Category VI: Malignant - Papillary thyroid carcinoma
Risk of Malignancy
95-99% (Bethesda Category VI)
Recommendations
Surgical management recommended. Molecular testing may guide extent of surgery and adjuvant therapy.