Definition/General
Introduction:
Anaplastic thyroid carcinoma (ATC) is a rare, highly aggressive undifferentiated malignant tumor of the thyroid with complete loss of follicular differentiation
On FNAC, it shows highly pleomorphic cells including giant cells, spindle cells, and epithelioid cells with marked nuclear atypia
Accounts for <2% of thyroid cancers but responsible for up to 50% of thyroid cancer deaths.
Origin:
Arises from follicular epithelial cells with complete dedifferentiation
Often develops from pre-existing well-differentiated thyroid carcinoma (papillary or follicular)
Shows epithelial-mesenchymal transition features.
Classification:
WHO recognizes three histological patterns: pleomorphic giant cell, spindle cell, and squamoid
Most tumors show mixed patterns
Bethesda System Category VI (Malignant) when diagnosed confidently.
Epidemiology:
Rare (<2% thyroid cancers)
Peak incidence 60-70 years
Slight female predominance
More common in goitrous regions
Extremely poor prognosis with median survival 3-6 months.
Clinical Features
Presentation:
Rapidly enlarging neck mass with rock-hard consistency
Often large at presentation (>6 cm)
Fixation to surrounding structures
Skin involvement and ulceration possible.
Symptoms:
Rapidly growing neck mass
Dysphagia and dyspnea (compressive symptoms)
Hoarseness (recurrent laryngeal nerve involvement)
Pain due to local invasion
Distant metastases at presentation (50%).
Risk Factors:
Pre-existing goiter or thyroid cancer
Advanced age >60 years
Iodine deficiency
Previous radiation exposure
p53 mutations common.
Screening:
Imaging shows large heterogeneous mass with calcifications
Extension beyond thyroid capsule common
Metastatic disease frequent at diagnosis
Elevated LDH and alkaline phosphatase.
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Gross Description
Appearance:
Large, irregular, poorly circumscribed mass
Gray-white to tan cut surface with extensive necrosis and hemorrhage
Firm to hard consistency
Invasion of surrounding structures.
Characteristics:
Size typically >5 cm at diagnosis
Extensive local invasion through capsule
Necrosis and hemorrhage prominent
May involve trachea, esophagus, and neck muscles.
Size Location:
Usually large tumors (mean 6-8 cm)
May involve entire thyroid lobe or bilateral disease
Extension beyond thyroid common
Lymph node involvement frequent.
Multifocality:
Often multifocal within thyroid
Bilateral involvement possible
Extensive local invasion typical
Distant metastases common (lungs, bone, liver, brain).
Microscopic Description
Histological Features:
Highly pleomorphic cells with complete loss of thyroid architecture
Giant cells, spindle cells, and epithelioid cells
Extensive necrosis and mitotic activity
Invasion of surrounding structures.
Cellular Characteristics:
Marked cellular and nuclear pleomorphism
Giant cells with multiple nuclei
Spindle-shaped cells
Bizarre mitotic figures common
High nuclear-cytoplasmic ratio.
Architectural Patterns:
Complete loss of follicular architecture
Sheets, fascicles, and storiform patterns
Extensive necrosis and hemorrhage
Invasion of blood vessels and lymphatics.
Grading Criteria:
High-grade by definition
Very high mitotic rate (>20 per 10 HPF)
Extensive necrosis (>50%)
Marked nuclear pleomorphism and atypia.
Immunohistochemistry
Positive Markers:
PAX-8 positive (may be focal/weak)
CK (AE1/AE3) positive
Vimentin often positive
p53 overexpressed (>90% cases)
Ki-67 very high (>50%).
Negative Markers:
Thyroglobulin negative (loss of differentiation)
TTF-1 usually negative or focal
Calcitonin negative
Chromogranin negative
Specific lineage markers negative.
Diagnostic Utility:
PAX-8 may be only marker confirming thyroid origin
Loss of thyroglobulin and TTF-1 indicates dedifferentiation
p53 overexpression nearly universal
Very high proliferation index.
Molecular Subtypes:
No established subtypes
Epithelial-mesenchymal transition features common
Loss of epithelial markers with gain of mesenchymal markers.
Molecular/Genetic
Genetic Mutations:
TP53 mutations nearly universal (>90%)
BRAF mutations common (20-30%)
PIK3CA/AKT pathway alterations
RAS mutations
TERT promoter mutations.
Molecular Markers:
Very high Ki-67 (>50%)
p53 overexpression (>90%)
Loss of p27
Overexpression of cyclins
High telomerase activity.
Prognostic Significance:
Extremely poor prognosis
Median survival 3-6 months
1-year survival <20%
Age, stage, and resectability affect prognosis
Distant metastases worsen outcome.
Therapeutic Targets:
Limited therapeutic options
Multimodal therapy (surgery + radiation + chemotherapy)
Tyrosine kinase inhibitors
Immunotherapy trials ongoing
Palliative care often appropriate.
Differential Diagnosis
Similar Entities:
Poorly differentiated thyroid carcinoma
Primary thyroid lymphoma
Sarcoma of thyroid
Metastatic carcinoma to thyroid
Medullary carcinoma (spindle variant).
Distinguishing Features:
PDTC: partial follicular differentiation, TTF-1 positive
Lymphoma: hematologic markers positive
Sarcoma: mesenchymal markers, no epithelial markers
Metastatic: site-specific markers, history.
Diagnostic Challenges:
Extreme pleomorphism may obscure diagnosis
Loss of thyroid markers complicates origin determination
May be confused with sarcoma or lymphoma
Clinical correlation essential.
Rare Variants:
Sarcomatoid variant with spindle cell predominance
Giant cell variant
Anaplastic carcinoma with heterologous differentiation
Mixed anaplastic-differentiated carcinoma.
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], Procedure: Fine needle aspiration cytology
Adequacy
Adequate for evaluation - highly cellular specimen
Cellularity
Very high cellularity with extensive necrosis
Cellular Features
Highly pleomorphic cells including giant cells and spindle cells
Nuclear Features
Extreme nuclear pleomorphism with bizarre mitotic figures
Architectural Pattern
Complete loss of follicular architecture, sheets and fascicles
Background
Extensive necrosis, hemorrhage, and inflammatory debris
Mitotic Activity
Very high mitotic activity with atypical forms
Cytological Diagnosis
Malignant - consistent with anaplastic thyroid carcinoma - Bethesda Category VI
Recommendation
URGENT: Immediate oncology consultation, staging studies, multidisciplinary team discussion