Definition/General
Introduction:
Medullary thyroid carcinoma (MTC) is a neuroendocrine tumor arising from parafollicular C-cells of the thyroid
On FNAC, it shows characteristic plasmacytoid to spindle-shaped cells with granular cytoplasm and may contain amyloid deposits
Accounts for 3-5% of thyroid malignancies and secretes calcitonin as a tumor marker.
Origin:
Arises from parafollicular C-cells (neuroendocrine cells) that secrete calcitonin
C-cells are derived from neural crest and normally constitute <0.1% of thyroid cells
May develop sporadically or as part of hereditary syndromes.
Classification:
Sporadic MTC (75-80%) occurs as solitary tumor
Hereditary MTC (20-25%) associated with MEN2A, MEN2B syndromes, or familial MTC
Bethesda System classifies as Category V or VI depending on certainty.
Epidemiology:
Accounts for 3-5% of thyroid cancers
Equal gender distribution
Mean age 50-55 years for sporadic, younger for hereditary (20-30 years)
RET mutations in hereditary cases (95-100%).
Clinical Features
Presentation:
Thyroid nodule or mass, often hard and fixed
May have palpable cervical lymph nodes at presentation (50% cases)
Diarrhea due to calcitonin secretion (30%)
Flushing episodes possible.
Symptoms:
Neck mass or nodule
Diarrhea and flushing (carcinoid syndrome)
Dysphagia if large
Hoarseness if recurrent laryngeal nerve involved
Bone pain if metastatic.
Risk Factors:
RET germline mutations (hereditary forms)
Family history of MTC or MEN syndromes
Previous radiation exposure
No association with iodine deficiency.
Screening:
Elevated serum calcitonin (>100 pg/mL highly suspicious)
CEA elevation (60% cases)
Thyroid ultrasound shows hypoechoic nodule with calcifications
Genetic testing for RET mutations.
Master Medullary Carcinoma Pathology with RxDx
Access 100+ pathology videos and expert guidance with the RxDx app
Gross Description
Appearance:
Gray-white to tan firm nodule
Cut surface may show gritty texture due to calcification and amyloid
Well-circumscribed to infiltrative borders
May show central necrosis.
Characteristics:
Size ranges 1-8 cm (mean 2-3 cm)
Firm to hard consistency
Calcifications common (70% cases)
Amyloid deposits visible as pink material
Multicentricity in hereditary cases.
Size Location:
Upper pole predilection in hereditary cases
Any location in sporadic cases
Bilateral involvement in hereditary MTC (60-90%)
Usually solitary in sporadic form.
Multifocality:
Multicentric disease common in hereditary forms (80-90%)
C-cell hyperplasia in background
Bilateral disease suggests hereditary syndrome
Lymph node metastasis frequent (50-70%).
Microscopic Description
Histological Features:
Solid sheets and nests of polygonal to spindle cells
Prominent vascularity
Amyloid deposits in 70-80% cases
C-cell hyperplasia in hereditary cases
Desmoplastic stroma possible.
Cellular Characteristics:
Medium-sized cells with eosinophilic granular cytoplasm
Eccentric nuclei with coarse chromatin
Nuclear pleomorphism variable
Plasmacytoid to spindle cell morphology
Mitoses variable.
Architectural Patterns:
Solid, nested, and trabecular patterns
Organoid arrangement typical of neuroendocrine tumors
Pseudopapillary pattern possible
Spindle cell areas may predominate.
Grading Criteria:
No established grading system
Aggressive features include large size (>4 cm), extensive necrosis, high mitotic rate (>5 per 10 HPF), vascular invasion.
Immunohistochemistry
Positive Markers:
Calcitonin positive (diagnostic, >95% cases)
Chromogranin A positive
Synaptophysin positive
CEA positive (60% cases)
TTF-1 usually positive
Thyroglobulin negative.
Negative Markers:
Thyroglobulin negative (key differentiating feature)
CK20 negative
PSA negative
CDX2 negative
Specific neuroendocrine markers distinguish from other thyroid tumors.
Diagnostic Utility:
Calcitonin is pathognomonic for MTC
Chromogranin and synaptophysin confirm neuroendocrine differentiation
Negative thyroglobulin excludes follicular cell origin.
Molecular Subtypes:
No established immunohistochemical subtypes
RET mutation status important for prognosis
Hereditary cases may show different staining patterns.
Molecular/Genetic
Genetic Mutations:
RET oncogene mutations in 95% hereditary and 50% sporadic cases
Most common RET codon 634 mutations in MEN2A
RET M918T in MEN2B
HRAS mutations in sporadic cases.
Molecular Markers:
High calcitonin and CEA levels (tumor markers)
Elevated chromogranin A
Variable Ki-67 (usually 5-20%)
p53 mutations in aggressive cases.
Prognostic Significance:
10-year survival 70-80% overall
Worse prognosis with lymph node involvement, age >45, large size >4 cm
RET M918T mutation associated with aggressive behavior.
Therapeutic Targets:
Vandetanib and cabozantinib (multikinase inhibitors) for advanced disease
Selpercatinib (RET-selective inhibitor) for RET-positive cases
Surgery primary treatment.
Differential Diagnosis
Similar Entities:
Hurthle cell neoplasm
Poorly differentiated thyroid carcinoma
Anaplastic thyroid carcinoma
Paraganglioma
Metastatic neuroendocrine tumor
Follicular carcinoma with oncocytic change.
Distinguishing Features:
Hurthle cells: thyroglobulin positive, calcitonin negative
Paraganglioma: extra-thyroidal location, different IHC
Metastatic NET: site-specific markers, clinical history
Follicular: thyroglobulin positive.
Diagnostic Challenges:
Spindle cell variant may mimic sarcoma
Papillary variant may confuse with papillary carcinoma
Small cell variant aggressive
Amyloid may be missed if scanty.
Rare Variants:
Papillary variant with follicular architecture
Small cell variant (aggressive)
Giant cell variant
Clear cell variant
Melanotic variant with pigment.
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
Cellularity
Moderate to high cellularity
Cellular Pattern
Dispersed single cells and loose clusters
Cellular Features
Plasmacytoid to spindle-shaped cells with granular cytoplasm
Nuclear Features
Eccentric nuclei with coarse chromatin and prominent nucleoli
Background
[Amyloid deposits present/absent], vascular background
Special Features
Neuroendocrine morphology, absence of follicular cells
Cytological Diagnosis
Suspicious for/Positive for medullary thyroid carcinoma - Bethesda Category V/VI
Recommendation
Serum calcitonin measurement, genetic counseling if familial history, surgical consultation