Anaplastic Thyroid Carcinoma

Anaplastic thyroid carcinoma is an undifferentiated, highly aggressive thyroid malignancy. It makes up under 2% of thyroid cancers but about 40% of thyroid cancer deaths. Median age is 65 to 70 years, with a slight female predominance, and it usually arises in patients with a long-standing goiter or a prior differentiated thyroid carcinoma (dedifferentiation). Iodine deficiency and radiation exposure are risk factors.

Molecular features: BRAF V600E in about 40 to 45%, TP53 in over 70%, TERT promoter mutations, RAS mutations, and NTRK or RET fusions in a small share. All tumors are stage IV by definition: IVA (intrathyroidal), IVB (extrathyroidal extension or nodal disease) and IVC (distant metastasis, present in about 40 to 50% at diagnosis, mainly in lung, bone and brain).

Median survival is 3 to 6 months, and 1-year survival is about 20%. Better outcomes are seen after complete resection with radiotherapy and chemotherapy, and in BRAF V600E-mutant tumors treated with targeted therapy. Complications: airway obstruction, tracheal and esophageal invasion, vocal cord paralysis, venous thrombosis, hypercalcemia, leukocytosis and hemorrhage.

• A rapidly enlarging, hard, fixed neck mass over weeks
• Hoarseness, dysphagia, stridor, dyspnea and neck pain
• Compressive symptoms such as facial swelling from venous obstruction
• Constitutional symptoms and fever (tumor necrosis)
• Red flags: any airway compromise, stridor, hemoptysis, rapid growth, vocal cord palsy and a history of long-standing goiter with sudden change

1. Core needle biopsy or open biopsy (fine-needle aspiration is often inadequate). Histology: pleomorphic spindle, giant or epithelioid cells with necrosis and mitoses.
2. Immunohistochemistry: cytokeratin positive, PAX8 weak or absent, thyroglobulin and TTF-1 negative, with Ki-67 usually over 30%.
3. Rapid molecular testing (within days): BRAF V600E, NTRK and RET fusions, and PD-L1 expression. These results affect the treatment decision.
4. Imaging: CT of the neck and chest with contrast (invasion of trachea, esophagus and vessels), and PET-CT or CT of the abdomen and brain MRI for staging.
5. Laryngoscopy for vocal cord function and airway, and bronchoscopy for tracheal invasion.
6. Blood tests: complete blood count (leukocytosis), calcium and coagulation tests.

Differentials: thyroid lymphoma, poorly differentiated thyroid carcinoma, medullary carcinoma, metastasis to the thyroid, Riedel thyroiditis, sarcoma and squamous cell carcinoma from adjacent tissue.

Management begins immediately with a multidisciplinary team and an early conversation about goals.

1. Airway: assess urgently. Tracheostomy only when there is impending obstruction and a goal of long-term survival. A tracheal stent for obstruction by intraluminal tumor.
2. BRAF V600E-mutant tumors: dabrafenib 150 mg orally twice daily with trametinib 2 mg orally once daily, started as soon as the mutation is known, and before surgery in selected resectable tumors (neoadjuvant for 4 to 6 weeks, then surgery). Response is often rapid (within 1 to 2 weeks). Monitor fever (hold and treat), left ventricular ejection fraction, rash, hyperglycemia, ocular toxicity and hemorrhage.
3. Resectable disease (stage IVA or IVB): total thyroidectomy with complete (R0) resection when feasible, central and lateral neck dissection, preserving vital structures. Cefazolin 2 g IV before incision (3 g if over 120 kg), and enoxaparin 40 mg SC daily from 12 hours after surgery.
4. Radiotherapy: 60 to 70 Gy in 30 to 35 fractions as hyperfractionated or intensity-modulated radiotherapy, started within 3 to 4 weeks of surgery, with concurrent weekly paclitaxel 50 mg/m2 IV and carboplatin AUC 2 IV (or doxorubicin 10 mg/m2 IV weekly).
5. Metastatic or unresectable disease without a BRAF mutation: pembrolizumab 200 mg IV every 3 weeks when PD-L1 is positive (monitor thyroid function, liver tests and glucose), paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks, or lenvatinib 24 mg orally once daily (use with caution when the tumor invades the trachea or esophagus because of fistula and hemorrhage, and monitor blood pressure and proteinuria). Larotrectinib 100 mg orally twice daily for NTRK fusion and selpercatinib 160 mg orally twice daily for RET fusion.
6. Supportive care:
   • Percutaneous endoscopic gastrostomy for dysphagia.
   • Dexamethasone 4 to 8 mg orally or IV daily for airway edema.
   • Hypercalcemia: zoledronic acid 4 mg IV once with saline hydration.
   • Morphine immediate-release 5 to 10 mg orally every 4 hours as needed for pain or dyspnea, with laxatives.
   • Palliative radiotherapy 30 Gy in 10 fractions to symptomatic sites.
7. Early palliative care with psychological and family support, and advance care planning.

Follow-up: clinical review and imaging every 4 to 8 weeks during active treatment. Counsel patient and family clearly about prognosis and the expected course.