Anaplastic Thyroid Cancer

Etiology

The etiology of anaplastic thyroid cancer is unknown. Apart from its association with differentiated thyroid cancers in about 20% of cases, anaplastic thyroid cancer has no clear causative factors. Evidence supports the theory that some anaplastic cancers may arise from preexisting differentiated thyroid cancers by dedifferentiation.[4][5]

Epidemiology

Anaplastic thyroid cancer is a rare form of thyroid cancer, accounting for between 1% and 10% of all thyroid cancers globally and 1.7% of cases in the United States.[6] Given the rarity and high mortality rate of this cancer, the precise incidence remains uncertain. Despite its infrequency, anaplastic thyroid cancer is responsible for up to 50% of all deaths related to thyroid cancers. Anaplastic thyroid cancer typically occurs in older individuals with a mean age of 65 and, like other thyroid cancers, is more prevalent in women than in men.[6][7]

Pathophysiology

Anaplastic thyroid cancer is associated with differentiated thyroid cancers, with roughly 20% of patients having a history of differentiated thyroid cancer.[8] In addition, up to a third of patients have coexisting differentiated thyroid cancer, usually papillary thyroid cancer, when they are diagnosed. The molecular pathogenesis is similar to well-differentiated thyroid cancers, and our understanding of these molecular drivers continues to improve with ongoing research.

Mutations in the TERT promoter region and TP53 are common, with TERT promoter mutations associated with RAS and BRAF mutations. Other targetable mutations may be seen, including NTRK and ALK rearrangements.[9] Thyroid-specific rearrangements RET/PTC and PAX8/PPARγ are rarely found in poorly differentiated or undifferentiated thyroid cancer, suggesting that these genetic alterations do not predispose cells to dedifferentiation.[10]

Histopathology

Macroscopic Histology Examination

Histopathologic findings associated with anaplastic thyroid cancer lesions include:

• Bulky mass (mean: 6 cm)
• Homogeneous and variegated appearance
• Light tan and fleshy with zones of necrosis and hemorrhage on cut sections
• Infiltrating, often into adjacent soft tissues and organs [11]

Microscopic Histology Examination

The highly variable microscopic appearances of anaplastic thyroid cancer are broadly categorized into the following 3 patterns (see Image. Anaplastic Thyroid Cancer), which can occur alone or in any combination:

• Sarcomatoid: The sarcomatoid form is malignant spindle cells with features commonly seen in high-grade pleomorphic sarcoma.
• Giant cell: The giant cell comprises highly pleomorphic malignant cells, some containing multiple nuclei.
• Epithelial: The epithelial form manifests squamoid or squamous cohesive tumor nests with abundant eosinophilic cytoplasm; occasional keratinization can be present.

Necrosis, an elevated mitotic rate, and an infiltrative growth pattern are common in all 3 forms. Vascular invasion is also often present.

Immunohistochemistry

Immunohistochemistry helps to distinguish anaplastic carcinoma from other undifferentiated malignancies using a cluster of differentiation 45 and other lymphoid markers along with melanocytic markers to exclude lymphoma and melanoma, respectively. Common thyroid-lineage markers (eg, thyroid transcription factor-1 and thyroglobulin) are usually absent, whereas the paired box gene, also a thyroid-lineage marker, is retained in approximately half of all cases. Positive cytokeratin expression supports the epithelial nature of anaplastic thyroid cancer, but negative immunostaining for cytokeratin does not exclude the diagnosis.[12]

History and Physical

Anaplastic thyroid cancer almost invariably presents with a rapidly growing anterior neck mass, which may be causing compressive or invasive symptoms. The trachea, esophagus, and vocal cords may be involved, resulting in dysphagia, dyspnea, hoarseness, and recurrent aspiration. Additionally, 20% of patients have a history of differentiated thyroid cancer or chronic multinodular goiter.

A physical examination typically identifies a firm mass fixed to the trachea. Unlike other less invasive thyroid cancers, anaplastic thyroid cancer often invades surrounding structures, resulting in an immobile mass with swallowing on examination. While the mass is typically solid, larger lesions may have regions of fluctuance due to tumor necrosis or hemorrhage. Cervical lymph nodes should be examined as these nodes are involved in up to 40% of anaplastic thyroid cancer cases. A laryngoscopy is also important to identify and document recurrent laryngeal nerve injury.[13][14][15]

Evaluation

Diagnostic Imaging Studies 

Anaplastic thyroid cancer evaluation should begin with a neck ultrasound. Findings associated with malignancy include solid masses, marked hypodensity, irregular margins, internal calcifications, wider-than-tall nodules, and cervical lymph node involvement. These features are scored using the thyroid imaging reporting and data system, predicting the probability of a malignant thyroid lesion. However, no specific findings on sonography have been established that can reliably differentiate anaplastic thyroid cancer from other thyroid malignancies.[16]

Since all anaplastic thyroid cancers are considered stage IV tumors and up to 50% will have metastatic disease at the time of presentation, all patients should be staged with a fluorodeoxyglucose F18 positron emission tomography (PET) scan or computed tomography (CT) scan of the brain, neck, chest, abdomen, and pelvis. See Image. Hypermetabolic Thyroid Mass, Positron Emission Tomography-Computed Tomography Scan (PET-CT). The lungs are the most common site of metastasis, followed by the intrathoracic and cervical lymph nodes.[17] Local invasion and the tumor's relationship to surrounding structures may be better defined with magnetic resonance imaging (MRI).[18][19][20] 

Biopsy Confirmation

To histologically identify a thyroid lesion, fine-needle aspiration or core needle thyroid biopsies should be performed without delay. Findings suggestive of anaplastic thyroid cancer include increased cellularity with cells and clusters with epithelioid to spindle cells, severe pleomorphism with very aberrant nuclei, high mitotic rate, and significant necrosis. Lymphocytic infiltration and acute inflammation may also be seen. In addition, perineural and vascular invasion, as well as extrathyroidal extension, frequently occur. Given the degree of abnormality, distinguishing anaplastic thyroid cancer from other high-grade tumors, including lymphomas and melanoma, may be difficult.[21]

Diagnostic Molecular Testing

BRAF status, microsatellite instability, NTRK, RET, ALK mutations, and tumor mutational burden should be assessed. In particular, BRAF mutations should be evaluated, as these mutations can change the determined treatment approaches.[22] 

Laryngoscopy and Bronchoscopy

Laryngoscopy with an evaluation of the vocal cords should be performed in all patients, as recurrent laryngeal nerve invasion is prevalent at presentation. If a high suspicion of airway involvement exists, a bronchoscopy should be performed. Patients with airway involvement often require a tracheostomy for airway protection.[23] 

Treatment / Management

Surgical resection is the treatment of choice for localized anaplastic thyroid cancer. Chemotherapy and radiation are used as adjuncts or as definitive therapy in patients with metastatic disease.[3] Most cases of anaplastic thyroid cancer are unresectable at presentation.

Differential Diagnosis

The differential diagnosis for anaplastic thyroid cancer includes:

• Metastatic disease to the thyroid, including metastatic clear-cell renal carcinoma
• Primary thyroid lymphoma
• Primary thyroid sarcoma
• Poorly differentiated thyroid carcinoma
• Squamous cell thyroid carcinoma
• Medullary carcinoma [24]

Surgical Oncology

When anaplastic thyroid cancer is localized to the thyroid gland, without invasion of critical structures (eg, the trachea), complete surgical resection offers the best chance of cure. A total thyroidectomy with a therapeutic lymph node dissection is currently recommended. Adjacent structures may need to be resected en bloc if they are involved and can be sacrificed, as the ultimate goal is to obtain a negative margin. BRAF/V600E mutant anaplastic thyroid cancer can be treated with neoadjuvant dabrafenib/trametenib, especially if the tumor is borderline resectable.[11][25] Routine tracheostomy should be avoided and performed only in cases of true airway compromise.[23] 

Radiation Oncology

Radiation therapy can be used in adjuvant settings and in patients with nonresectable or metastatic diseases. External beam radiation therapy (EBRT) is recommended after resection and, when combined with concurrent chemotherapy, improves overall survival. As anaplastic thyroid cancer is so aggressive and is seldom resected with negative margins, radiation with concurrent EBRT should be started as soon as possible. Using newer techniques, eg, intensity-modulated radiation therapy, improves targeting.[23] In patients with locally advanced disease, higher doses of EBRT can delay local spread and some of its devastating consequences, including airway compromise. 

Medical Oncology

Cytotoxic chemotherapy alone is of limited benefit. Taxanes, doxorubicin, and cisplatin have been used with variable success. Paclitaxel, doxorubicin, and carboplatin are often used as radiosensitizing agents in administering concurrent chemoradiation. Identifying molecular targets has heralded a new therapy era, with treatments targeting specific mutations.[23] These include the following molecular targets and the respective agents:

• BRAF/V600E mutations: Dabrafenib/trametenib
• NTRK gene fusions: Larotrectinib, entrectinib, repotrectinib
• RET gene fusions: Pralsetinib, selpercatinib

Anaplastic thyroid cancer with high tumor mutational burden may respond to programmed cell death protein 1/programmed cell death ligand 1 inhibitors, including pembrolizumab and nivolumab. Neoadjuvant dabrafenib/trametinib is now a category 2B National Comprehensive Cancer Network recommendation for patients with resectable and borderline resectable tumors.[26] 

Staging

Thyroid carcinoma staging is according to the 8th edition of the American Joint Committee on Cancer (AJCC) classification. According to the International Union Against Cancer—TNM staging (primary tumor, regional lymph node involvement, and distant metastases) and AJCC system, all anaplastic thyroid cancers are considered stage IV.[3] Stage IVA and IVB patients have intrathyroidal tumors (stage IVA) and extrathyroidal tumors (stage IVB) and no distant metastatic disease, whereas stage IVC patients have distant metastasis.[23]

Prognosis

Anaplastic thyroid cancer is lethal. Historic survival estimates from Surveillance, Epidemiology, and End Results database studies report that 35% of patients have a median overall survival between 4 and 6 months.[2] More recent data incorporating patients who have received multimodality therapy, including targeted therapy, is more promising, with a median overall survival of 9.5 months. However, patients with BRAF mutant disease who received targeted therapy had a 94% survival rate at 1 year.[2] These data suggest that refinements in targeted therapy will continue to prolong survival.

Prognostic Factors

The favorable prognostic indicators of anaplastic thyroid cancer include:

• Younger age (aged 60 or younger)
• An absence of cervical or distant metastases
• Small tumors (≤5 to 7 cm)
• Unilateral tumors
• An absence of local invasion of the surrounding tissue or nodal involvement
• An incidental finding of anaplastic thyroid cancer within a thyroidectomy specimen [27][28][29][30]

Complications

Local invasion occurs in almost 70% of patients, including the muscles (65%), trachea (46%), esophagus (44%), laryngeal nerves (27%), and larynx (13%). Additionally, lymph node metastases are a feature in almost 40% of patients.[31] The progression of anaplastic thyroid cancer is rapid, and most patients die from local airway obstruction or complications of pulmonary metastases within 1 year.[11] Metastases occur in up to 75% of patients. They most frequently involve the lungs (80%), the brain (5% to13%), and bones (6% to 15%).