The Current Understanding of the Molecular Pathogenesis of Papillary Thyroid Cancer

Abstract

The thyroid is a vital endocrine organ that regulates metabolism, heart rate, respiration, digestion, body temperature, brain development, skin and bone maintenance, and reproduction and fertility. Thyroid cancer (TC) is the most common endocrine malignancy, with an estimate of 44,020 new cases in 2025. Incidence has been increasing, most notably at 4-5% per year in young adults. Papillary thyroid cancer (PTC), the most common TC subtype, accounts for approximately 80% of newly diagnosed TC cases. Furthermore, 2290 deaths are expected from the disease in 2025, with survival at over 98% with treatment. However, as PTC occurs most frequently in young women, recurrences are frequent and the 10-year disease-specific survival rate for advanced PTC is less than 50%. This narrative review aims to describe the current understanding of the thyroid gland, the incidence and subtypes of thyroid cancer, and specifically the diagnosis, prognosis, treatment, and recurrence of PTC. This is supplemented by the role of molecular pathways and biomarkers in PTC.

Keywords: biomarkers; papillary thyroid cancer; recurrence; thyroid.

Figure 1

Follicular cell-derived thyroid cancers. Ranked by rate, PTC is the most prevalent follicular cell-derived thyroid cancer, followed by FTC and then undifferentiated (ATC). Prevalence also coincides with morphology changes and has an inverse correlation with prognosis. Histology images (magnification 200×) reprinted with permission from Ref: [18].

Figure 2

Thyroid cancer incidence rate by age at diagnosis among sexes, 2016–2020. Adapted from SEER (2024) [21].

Figure 3

Clinical presentation of PTC. PTC is characterized by a high rate of lymph node metastasis (50%). Less frequently, extrathyroidal extension may occur (ETE; 30%). Distant metastases are rare (1–13%) but when present will largely spread to the lung (50%), bone (20%), or brain (20%).

Figure 4

Extrathyroidal extension (ETE) in PTC. (A) Sagittal thyroid computed tomography scan shows that mass blocking most of the upper endoluminal trachea. Ref: [61] (B) Gross ETE into strap muscle (left) or adjacent organs (right) is considered AJCC pT3b and pT4a, respectively. Magnification: 40×. Reprinted with permission from Ref: [42] (C) Comparison of recurrence-free survival in PTC patients with different ETE classifications before propensity score matching. ETE, extrathyroidal extension. Reprinted with permission from Ref: [62].

Figure 5

The molecular pathogenesis of papillary thyroid cancer. PTC driver mutations result in constitutive activation in the MAPK and PI3K/Akt/mTOR pathways, affecting cell proliferation and differentiation. Red lines represent inhibition.

Figure 6

Thyroid cancer progression driven by MAPK and PI3k/Akt pathways. Genetic alterations leading to MAPK pathway activation primarily drives PTC development while PI3K-Akt primarily drives follicular thyroid adenoma and FTC. Accumulations of genetic alterations can strengthen both pathways’ signaling, with the potential to convert to the more aggressive poorly differentiated or undifferentiated TC. The increasing number of vertical arrows and color intensity of the ovals symbolize the increasing genetic alterations and signaling of the two pathways as thyroid tumorigenesis progresses.