Anaplastic thyroid cancer (ATC) is a rare and aggressive form of thyroid malignancy that originates from the thyroid gland, a butterfly-shaped organ located at the base of the neck. This cancer accounts for a small percentage of all thyroid cancer diagnoses, typically 1% to 2%, yet it is recognized for its rapid growth and highly invasive nature. The cells of anaplastic thyroid cancer are described as undifferentiated, meaning they do not resemble normal thyroid cells and have lost their specialized functions. This lack of differentiation contributes to the cancer’s poor prognosis and challenging treatment landscape.
Genetic Alterations
The development of anaplastic thyroid cancer is linked to specific genetic changes within thyroid cells. These alterations accumulate, enabling cells to grow uncontrollably and acquire aggressive characteristics. Several key gene mutations are frequently identified in anaplastic thyroid cancer, driving its formation and progression.
The BRAF V600E mutation is common, found in 40% to 70% of anaplastic thyroid cancer cases. This mutation continuously activates a signaling pathway known as MAPK/ERK, which regulates cell proliferation, differentiation, and survival. The sustained activation of this pathway promotes unchecked cell division and contributes to the aggressive behavior of the cancer.
Mutations in the TERT promoter region are present in 40% to 70% of anaplastic thyroid cancers. These mutations reactivate the telomerase enzyme, which is typically inactive in most adult cells. Telomerase allows cancer cells to maintain telomeres, enabling them to divide indefinitely and avoid the natural cellular aging process. TERT promoter mutations often occur alongside BRAF or RAS mutations, increasing the cancer’s aggressiveness.
Mutations in the TP53 gene are frequently observed in anaplastic thyroid cancer, affecting 54% to 80% of patients. TP53 is a tumor suppressor gene that normally helps regulate cell growth and can trigger programmed cell death if DNA damage is detected. When TP53 is mutated or inactivated, cells lose this important control mechanism, allowing damaged cells to proliferate and resist death. This contributes to the uncontrolled growth and spread characteristic of anaplastic thyroid cancer.
Alterations in the PIK3CA gene are identified in 10% to 23% of anaplastic thyroid cancer cases. PIK3CA mutations activate the PI3K/Akt pathway, which plays a role in cell growth, metabolism, and survival. This pathway’s overactivation can further fuel the cancer’s progression and contribute to its resistance to therapies. These genetic changes collectively drive the aggressive nature of anaplastic thyroid cancer by disrupting normal cellular regulation.
Transformation from Pre-existing Thyroid Conditions
Anaplastic thyroid cancer often develops through dedifferentiation, where cells from pre-existing, less aggressive thyroid conditions lose their specialized features and become more primitive and aggressive. This transformation can occur from well-differentiated thyroid cancers, such as papillary or follicular thyroid cancer, or even from benign thyroid conditions. This progression signifies a loss of cellular identity, leading to highly proliferative and invasive cancer cells.
Papillary thyroid cancer (PTC) is the most common type of thyroid cancer and can serve as a precursor to anaplastic thyroid cancer. Over time, PTC cells can acquire additional genetic mutations, driving them toward a more aggressive, undifferentiated state. Similarly, follicular thyroid cancer (FTC), another differentiated type, also has the potential to transform into anaplastic thyroid cancer through a similar accumulation of genetic changes.
Anaplastic thyroid cancer can also arise from long-standing benign conditions like multinodular goiters, which are enlarged thyroid glands. While most goiters are not cancerous, the presence of chronic thyroid abnormalities can create an environment where cells are more susceptible to acquiring mutations that lead to dedifferentiation. The concept of dedifferentiation highlights how thyroid cells lose their normal structure and function, becoming highly abnormal and capable of rapid, uncontrolled growth.
Other Risk Indicators
While genetic alterations and transformation from existing conditions are direct drivers, other factors are associated with an increased likelihood of developing anaplastic thyroid cancer. These indicators do not directly cause the cancer but represent conditions or demographics where the disease is more frequently observed.
Age is a prominent risk indicator, with anaplastic thyroid cancer occurring more often in older individuals. The average age of diagnosis typically falls between 60 and 70 years. The incidence of this cancer increases significantly with advancing age, distinguishing it from other thyroid cancer types that often affect younger populations.
Anaplastic thyroid cancer is generally observed more frequently in women than in men. A history of radiation exposure to the head or neck region is another factor that may increase the risk. This includes therapeutic radiation treatments received for other medical conditions in the past.
A long-standing goiter, which is an enlargement of the thyroid gland, is also considered a risk indicator. While most goiters are benign, their prolonged existence can be associated with an elevated risk for anaplastic transformation.