Anaplastic thyroid carcinoma also known as undifferentiated carcinoma is a rare, highly aggressive malignant tumor accounting for 2% to 3% of all thyroid gland neoplasms. It is composed of undifferentiated thyroid follicular cells, requiring immunohistochemical or ultrastructural support to determine their epithelial origin. Anaplastic thyroid carcinoma continues to rank as one of the most deadly diseases worldwide and carries a very poor prognosis. In addition to considerable local invasion, anaplastic thyroid carcinoma often presents with metastatic spread to regional lymph nodes and distant sites.
The risk factors of anaplastic thyroid carcinoma remain unknown. However, areas of differentiated thyroid carcinomas in anaplastic thyroid carcinoma are not uncommon, suggesting high-grade/anaplastic evolution from these entities. TP53 gene inactivation plays a role in the progression from differentiated to undifferentiated carcinoma.
The cytogenetics are often complex and show progressive accumulation of chromosomal alterations (numerical and structural aberrations). The most common mutations are in TP53 (nuclear expression), while BRAF V600E, RAS, PIK3CA, and PTEN are also present in a range of 10% to 20% each.
The frequency of anaplastic thyroid carcinoma is higher in areas of endemic goiter. Anaplastic thyroid carcinoma is responsible for 1.7% of all thyroid cancers in the United States. However, geographical prevalence ranges from 1.3% to 9.8%. Patients are typically elderly (sixth to seventh decades of life); the female-to-male ratio is 2 to 1. According to the latest epidemiological data from Nagaiah et al., the incidence of anaplastic thyroid cancer is decreasing worldwide.
The highly variable microscopic appearances of anaplastic thyroid carcinoma are broadly categorized into three patterns, which can occur singly or in any combination:
Common to all three forms are necrosis, an elevated mitotic rate, and an infiltrative pattern of growth. Vascular invasion is also often present.
Immunohistochemistry helps to distinguish anaplastic carcinoma from other undifferentiated malignancies using CD45 and other lymphoid markers along with melanocytic markers to exclude lymphoma and melanoma, respectively.
Common thyroid-lineage markers such as TTF1 and thyroglobulin are usually absent, whereas PAX, also a thyroid-lineage marker, is retained in approximately half of all cases. Positive cytokeratin expression supports the epithelial nature of anaplastic thyroid carcinoma, but negative immunostaining for cytokeratin does not exclude the diagnosis.
The most common ultrasonographic findings of anaplastic thyroid carcinoma include:
Fine needle aspiration (FNA):
A fine-needle biopsy is a useful diagnostic modality. However, the diagnosis of anaplastic carcinoma must be established by surgical biopsy or at surgery.
Cytologic findings of anaplastic thyroid carcinoma include:
Intraoperative frozen section and pathology consultation:
Intraoperative consultation provides a rapid diagnosis to assist in determining the ongoing operative extent and approach.
Computed tomography scan:
Anaplastic thyroid carcinomas usually present as large isodense or slightly hyperdense masses relative to skeletal muscle. Calcification and necrosis are present, and often are extensive. Computed tomography scan is much more useful in defining the local extent of anaplastic thyroid carcinoma and detecting lymph node metastases.
Magnetic resonance imaging:
Magnetic resonance imaging can be useful to best assess tumor extension, particularly in the esophagus musculature, trachea and carotid vessel.
F-fluorodeoxyglucose positron emission tomography (FDG-PET):
Staging assessment with F-fluorodeoxyglucose positron emission tomography (FDG-PET) fused coincident computerized tomography scan (FDG-PET/CT) is uniquely valuable in anaplastic thyroid carcinoma due to its enhanced expression of glucose transporter (GLUT-1), resulting in increased glucose uptake.
The recommended treatment for anaplastic thyroid carcinoma is based on surgery when feasible and/or chemoradiation either concurrently or sequentially. Most cases of anaplastic thyroid carcinoma are unresectable at presentation because of the invasion of cervical structures. Surgery should aim to secure the patient’s airway.
Debulking surgery is the most common procedure in anaplastic thyroid carcinoma. It consists of removing gross tumor that is potentially threatening the airway, with the aim of preserving the larynx. However, a tracheostomy may be necessary in cases with airway compromise. While complete excision is often impossible due to local extension of disease, the quality of resection is a significant prognostic factor for survival.
Radiation therapy and chemotherapy:
External-beam irradiation is effective in improving local control. For patients with locally advanced unresectable disease, definitive radiation therapy and chemotherapy are the recommendations. Adjuvant radiation therapy should be performed in all cases, including completely resected small size incidental anaplastic thyroid carcinoma and anaplastic thyroid carcinoma with a differentiated component.
Anaplastic thyroid carcinoma is usually not responsive to I131 therapy. Radioiodine is only a recommendation upon identification of a differentiated iodine-positive component. New insights into the biological behavior, the genetic and molecular pathogenesis of anaplastic thyroid carcinoma might offer the possibility of novel targeted therapies.
Histological differential diagnosis:
Thyroid carcinomas staging is according to the 8th edition of the AJCC classification. According to the International Union Against Cancer (UICC)—TNM staging and AJCC system, all anaplastic thyroid carcinomas are considered stage IV. Stage IVA and IVB patients have intrathyroidal tumors (IVA) and extrathyroidal tumors (IVB) and no distant metastatic disease, whereas stage IVC patients have distant metastasis.
Anaplastic thyroid carcinoma is poorly responsive to any multimodality therapy. According to the Surveillance, Epidemiology and End Results (SEER) database from 1983 to 2002, the median survival of patients with anaplastic thyroid carcinoma was 4 months. Survival beyond 2 years is 12%.
Local invasion of the surrounding structures occurs in almost 70% of patients as observed in large series: muscles (65%), trachea (46%), esophagus (44%), laryngeal nerve (27%), and larynx (13%). Lymph node metastases are a feature in almost 40% of the patients.
The progression of anaplastic thyroid carcinoma is rapid, and most patients die from local airway obstruction or complications of pulmonary metastases within one year. Metastases occur in up to 75% of patients. They most frequently involve the lungs (80%), the brain (5 to 13%), and bones (6 to 15%).
To avoid the development of anaplastic carcinoma, longstanding goiters, as well as benign nodules, should be followed carefully and considered for resection if they grow or do not respond to medical therapy. Moreover, total thyroidectomy for malignant disease can prevent the development of anaplastic carcinoma.
Due to the aggressive nature of the disease, prompt diagnosis is critical in determining appropriate treatment options. Management of anaplastic thyroid carcinoma is complex and needs an interprofessional team approach involving a team that consists of an ENT surgeon, a surgical oncologist, a radiation oncologist, a pathologist, an endocrinologist, a radiologist, and a nuclear medicine specialist. The pharmacist reviews prescribed medications, provides education to the patient, and monitors compliance. Oncology pharmacists assist in planning chemotherapy and provide feedback to the team. Specialty trained otolaryngology and oncology nurses help coordinate care, educate patients and their families, schedule follow up, and inform the team of status changes. Palliative care and hospice nurses and doctors commonly are involved to improve end of life care. [Level 5]
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