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Summary Table

Category	Description
Risk Factors	History of head and neck irradiation in childhood, female sex (3:1 ratio), family history of thyroid cancer, MEN 2A/2B syndromes (medullary type), iodine deficiency (follicular), high iodine intake (papillary), Cowden syndrome, Hashimoto thyroiditis (lymphoma)
Etiology	BRAF V600E mutations and RET/PTC rearrangements (papillary); RAS mutations and PAX8/PPARγ fusion (follicular); germline or somatic RET proto-oncogene mutations (medullary); TP53 mutations (anaplastic)
Patient Presentation	Painless, slowly enlarging neck mass or solitary thyroid nodule discovered incidentally; less commonly hoarseness, dysphagia, dyspnea, or a rapidly enlarging fixed mass with airway symptoms (anaplastic)
Classic Physical Exam	Firm, irregular, non-tender nodule that moves with swallowing; ipsilateral cervical lymphadenopathy (papillary); fixed hard mass with vocal cord paralysis (anaplastic); pheochromocytoma and mucosal neuromas (MEN 2B)
Key Diagnostic Results	Normal TSH in most cases; ultrasound showing hypoechoic nodule with microcalcifications, irregular margins, and taller-than-wide shape; fine needle aspiration biopsy confirms cytology; elevated serum calcitonin and CEA (medullary); cold nodule on radioiodine scan
Management	Surgery is the cornerstone (lobectomy for low-risk small tumors, total thyroidectomy for larger or higher-risk disease); radioactive iodine ablation for differentiated cancers; levothyroxine for TSH suppression; total thyroidectomy with central neck dissection plus genetic testing for medullary; tyrosine kinase inhibitors for advanced or refractory disease
Keywords	"Solitary cold nodule," "Orphan Annie eye nuclei," "Psammoma bodies," "Painless neck mass with lymphadenopathy," "Childhood radiation exposure," "MEN 2 syndrome," "Elevated calcitonin," "Amyloid stroma," "Rapidly enlarging neck mass in elderly"

1. Pathophysiology

The thyroid gland contains two functionally distinct cell populations, and recognizing this is the foundation of understanding thyroid cancer. Follicular epithelial cells produce thyroid hormone and give rise to four of the five major cancer subtypes. Parafollicular C cells secrete calcitonin and give rise to medullary carcinoma. Each subtype follows a predictable pattern of behavior, spread, and prognosis dictated by its cell of origin and driver mutation.

Papillary thyroid carcinoma is the most common subtype and is driven primarily by BRAF V600E point mutations or RET/PTC rearrangements, both of which constitutively activate the MAPK signaling pathway. The defining behavior is lymphatic spread, which explains why patients so often present with cervical lymphadenopathy even when the primary tumor is small. Despite frequent nodal metastasis, the ten-year survival exceeds 95 percent. Pathognomonic histology includes "Orphan Annie eye" nuclei (empty, ground-glass appearance), nuclear grooves, intranuclear inclusions, and laminated calcifications called psammoma bodies.

Follicular thyroid carcinoma also originates from follicular cells but behaves quite differently. Driver mutations involve RAS or the PAX8/PPARγ fusion gene, and the tumor spreads hematogenously rather than through lymphatics. This produces distant metastases to lung and bone (often presenting as a pathologic fracture). A critical exam concept: fine needle aspiration cannot distinguish follicular adenoma from follicular carcinoma because the diagnosis requires demonstration of capsular or vascular invasion, which can only be assessed on a complete excised specimen.

Medullary thyroid carcinoma arises from neuroendocrine parafollicular C cells. Approximately 75 percent are sporadic, while 25 percent are hereditary as part of MEN 2A (medullary cancer, pheochromocytoma, parathyroid hyperplasia), MEN 2B (medullary cancer, pheochromocytoma, mucosal neuromas, marfanoid habitus), or familial medullary thyroid cancer. All hereditary forms involve germline RET proto-oncogene mutations. Because C cells secrete calcitonin, serum calcitonin serves as both a diagnostic marker and a postoperative surveillance tool. Histology reveals amyloid deposits that stain apple-green with Congo red under polarized light.

Anaplastic thyroid carcinoma represents the undifferentiated end of the spectrum, typically arising in elderly patients from a long-standing differentiated tumor that has accumulated additional mutations, particularly in TP53. It loses iodine uptake, thyroglobulin production, and TSH responsiveness. Clinically, it presents as a rapidly enlarging, stony-hard, fixed neck mass that invades the trachea and esophagus, producing airway compromise within weeks. Median survival is measured in months.

2. Classification of Clinical Manifestations

Type	Frequency	Cell Origin	Spread Pattern	Histology	Tumor Marker	Prognosis (10-yr survival)
Papillary	80%	Follicular	Lymphatic	Orphan Annie nuclei, psammoma bodies, nuclear grooves	Thyroglobulin (post-op)	>95%
Follicular	10%	Follicular	Hematogenous (lung, bone)	Capsular and vascular invasion	Thyroglobulin (post-op)	~85%
Medullary	5%	Parafollicular C cells	Lymphatic and hematogenous	Amyloid stroma (Congo red positive)	Calcitonin and CEA	~75% sporadic, variable in hereditary
Anaplastic	1-2%	Dedifferentiated follicular	Aggressive local invasion and distant	Pleomorphic giant and spindle cells	None reliable	<10% (median survival 3-6 months)

3. Diagnostic Workup

Test	Purpose	Indication
Serum TSH	First test for any thyroid nodule	Always order first
Thyroid ultrasound	Best initial imaging; assesses nodule features and lymph nodes	Any palpable nodule or incidental finding
Radioiodine (I-123) scan	Differentiates hot from cold nodules	Only if TSH is suppressed (low)
Fine needle aspiration biopsy (FNAB)	Confirmatory cytology for most subtypes	Nodules > 1 cm with suspicious features, or > 1.5-2 cm without
Serum calcitonin	Diagnostic and prognostic marker	Suspected medullary carcinoma or family history
Plasma metanephrines	Rule out pheochromocytoma	Before surgery in any medullary carcinoma case
Genetic testing (RET)	Identifies hereditary syndromes	All medullary cancers
Thyroglobulin	Post-treatment surveillance for differentiated cancers	After total thyroidectomy and ablation
Neck CT or MRI	Evaluates extrathyroidal extension and bulky nodal disease	Advanced or anaplastic disease (use non-iodinated contrast to avoid delaying RAI)

The workup begins with serum TSH, which is the single most important first step. If TSH is normal or elevated, proceed directly to thyroid ultrasound, which is the best initial imaging study and characterizes the nodule based on echogenicity, margins, calcifications, shape, and vascularity. Suspicious features include hypoechogenicity, microcalcifications, irregular margins, taller-than-wide shape, and extrathyroidal extension. Risk stratification systems (such as the ACR TI-RADS or ATA classification) translate these findings into a probability of malignancy and guide whether to biopsy.

If the TSH is suppressed (low), the workflow shifts. A low TSH suggests an autonomously functioning ("hot") nodule, which is rarely malignant. In this scenario, the next step is a radioiodine uptake scan, not biopsy. Hot nodules require management for hyperthyroidism rather than oncologic workup, while cold nodules (decreased uptake) require biopsy because roughly 15 percent are malignant.

Fine needle aspiration biopsy is the most accurate and confirmatory test for papillary, medullary, and anaplastic carcinomas. Cytology is reported using the Bethesda System (six categories ranging from non-diagnostic to malignant). The major exception is follicular neoplasm: FNA can identify follicular cells but cannot distinguish adenoma from carcinoma because that requires histologic evidence of capsular or vascular invasion. Therefore, indeterminate follicular lesions proceed to diagnostic lobectomy for definitive diagnosis.

For suspected medullary carcinoma, measure serum calcitonin and CEA, then obtain plasma fractionated metanephrines and serum calcium to rule out coexisting pheochromocytoma and primary hyperparathyroidism before any surgical intervention. Operating on a patient with an undiagnosed pheochromocytoma can precipitate a fatal hypertensive crisis. All patients with medullary carcinoma require RET germline testing, regardless of family history.

4. Management and Treatment

Subtype	Primary Treatment	Adjuvant Therapy	Long-term Surveillance
Papillary (low-risk, <1 cm)	Lobectomy	Usually none	Ultrasound, TSH, thyroglobulin
Papillary (>4 cm or high-risk)	Total thyroidectomy with central neck dissection	Radioactive iodine ablation	Thyroglobulin, anti-Tg antibodies, ultrasound
Follicular	Total thyroidectomy	Radioactive iodine ablation	Thyroglobulin, ultrasound, chest imaging
Medullary	Total thyroidectomy with central neck dissection (and lateral if indicated)	External beam radiation if locally advanced; tyrosine kinase inhibitors (vandetanib, cabozantinib, selpercatinib) for advanced disease	Calcitonin, CEA
Anaplastic	Multimodal: surgery if resectable, external beam radiation, chemotherapy, targeted therapy if BRAF V600E positive (dabrafenib + trametinib)	Tracheostomy may be required	Palliative focus
Lymphoma	Chemotherapy (R-CHOP) with or without radiation	Surgery typically not first-line	Imaging surveillance

Surgery is the foundation of treatment for nearly all thyroid cancers. The choice between lobectomy and total thyroidectomy depends on tumor size, histology, extrathyroidal extension, and nodal status. Recent guidelines permit lobectomy for unifocal differentiated tumors smaller than 1 cm without high-risk features. For tumors larger than 4 cm, those with extrathyroidal extension, or any medullary or anaplastic cancer, total thyroidectomy is mandatory. Central compartment neck dissection is added when clinically positive nodes are present and is routine for all medullary cancers.

After total thyroidectomy for differentiated thyroid cancer, radioactive iodine ablation is administered to destroy any remaining thyroid tissue and microscopic disease. This requires the residual tissue to be TSH-stimulated, achieved either by withdrawing levothyroxine for several weeks or by administering recombinant TSH. Doses range from 30 mCi for low-risk remnant ablation to 100-200 mCi for known metastatic disease. Pregnancy and breastfeeding are absolute contraindications to RAI; women must avoid conception for six to twelve months afterward.

Levothyroxine is then prescribed at a dose sufficient to suppress TSH, because TSH stimulates growth of any residual differentiated cancer cells. The target TSH depends on risk: less than 0.1 mU/L for high-risk patients, 0.1 to 0.5 mU/L for intermediate risk, and within the low-normal range for low-risk patients. Excessive suppression carries cardiac and skeletal risks, so the dose is individualized.

Medullary carcinoma does not respond to radioactive iodine because parafollicular C cells do not concentrate iodine. Treatment relies entirely on complete surgical resection. For locally advanced or metastatic disease, multikinase inhibitors such as vandetanib and cabozantinib improve progression-free survival, while selpercatinib and pralsetinib target RET-mutated tumors selectively with better tolerance. Postoperative surveillance uses calcitonin and CEA; rising calcitonin signals recurrence.

Anaplastic carcinoma demands urgent multimodal therapy. Airway protection comes first, sometimes requiring tracheostomy. Resectable disease is debulked, followed by external beam radiation and chemotherapy. For tumors harboring the BRAF V600E mutation (about 25 percent), dabrafenib plus trametinib has produced meaningful responses. Despite these advances, prognosis remains poor.

The next best step logic in vignettes typically follows this sequence: TSH first, then ultrasound, then FNA (if TSH normal) or radioiodine scan (if TSH suppressed), then surgery for malignant or indeterminate cytology, then RAI ablation and TSH suppression for differentiated cancer.

5. Differential Diagnosis and Distractors

Differential Diagnosis	Why It Looks Similar	Key Discriminator
Benign thyroid adenoma (follicular adenoma)	Solitary nodule on exam	FNA cytology may overlap, but absence of capsular or vascular invasion on excisional biopsy confirms benign nature
Multinodular goiter	Neck mass that moves with swallowing	Multiple nodules rather than solitary; usually euthyroid or hyperthyroid; dominant nodule still requires ultrasound and possible FNA
Subacute (de Quervain) thyroiditis	Tender thyroid enlargement	Painful, tender gland with viral prodrome, elevated ESR, low radioiodine uptake; thyroid cancer is painless
Hashimoto thyroiditis	Diffuse goiter with hypothyroidism	Anti-TPO and anti-thyroglobulin antibodies positive; gland is diffusely enlarged and rubbery rather than nodular; predisposes to lymphoma
Graves disease	Diffuse goiter, possibly with bruit	Hyperthyroid symptoms, ophthalmopathy, pretibial myxedema; diffuse uptake on radioiodine scan
Thyroglossal duct cyst	Midline neck mass	Moves with tongue protrusion, located along midline above thyroid, usually in children
Cervical lymphadenopathy from infection	Neck swelling	Tender, mobile nodes with systemic infectious symptoms; resolves with treatment
Parathyroid adenoma	Neck mass on imaging	Hypercalcemia and elevated PTH; sestamibi scan localization
Riedel thyroiditis	Hard, fixed neck mass	IgG4-related fibrosing disease; biopsy shows fibrosis without malignant cells
Primary thyroid lymphoma	Rapidly enlarging neck mass in an older patient	Almost always arises in a background of Hashimoto thyroiditis; biopsy shows lymphoid infiltrate; treated with chemotherapy, not surgery

6. Traps and High-Yield Pearls

The most common way examinees miss thyroid cancer questions is by skipping the TSH step and ordering biopsy or imaging first. Always anchor on the algorithm: TSH first, then ultrasound, then either FNA or radioiodine scan depending on whether TSH is normal or suppressed. A second classic pitfall is ordering an FNA on a follicular lesion and expecting a definitive answer; remember that follicular carcinoma diagnosis requires demonstration of capsular or vascular invasion, which mandates lobectomy. A third trap is forgetting to screen for pheochromocytoma before operating on medullary thyroid carcinoma; missing this step in the vignette is a frequent reason for losing the question.

Watch for the buzzwords. "Painless neck mass with cervical lymphadenopathy in a young woman" points to papillary cancer; "history of childhood radiation" is the strongest single risk factor mentioned in vignettes. "Pathologic fracture or lung metastases from a thyroid primary" points to follicular cancer because of its hematogenous spread. "Mucosal neuromas, marfanoid habitus, and a thyroid mass" is MEN 2B with medullary cancer. "Rapidly enlarging fixed neck mass with hoarseness in an elderly patient" is anaplastic carcinoma. "Hashimoto thyroiditis with sudden gland enlargement" is thyroid lymphoma, not anaplastic carcinoma, and is treated with chemotherapy rather than surgery.

The core competency being tested across these scenarios is twofold: first, sequencing the diagnostic workup correctly based on the TSH result, and second, matching the histologic and clinical pattern to the correct subtype so that management (surgery alone, surgery plus RAI, surgery plus genetic testing, or palliative multimodal therapy) follows logically. Mastering the cell of origin (follicular versus parafollicular C cells), the driver mutation, the spread pattern, and the tumor marker for each subtype lets you answer almost any question on this topic by deduction rather than recall.

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