Papillary Thyroid Cancer Overview

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Papillary thyroid cancer (PTC) is the most prevalent thyroid cancer, accounting for approximately 80% of thyroid cancer cases.1 While PTC can occur at any age, it is most commonly diagnosed in the third to fifth decades of life. PTC affects women more frequently than men with estimated ratios of 2:1 to 4:1. The only well-established environmental factor related to the development of PTC is a history of radiation exposure, which was confirmed based on observations following the atomic bomb detonations at Hiroshima and Nagasaki, and the Chernobyl nuclear power station explosion. Additional risk factors that have been suggested include preexisting benign thyroid disease or family history of PTC.1

The diagnostic method of choice for PTC is fine needle aspiration and cytology.1 Prognostic factors suggestive of poor outcomes in PTC include male gender, older age at diagnosis, a large tumor size, and extrathyroidal growth. Overall, prognosis is very good for most patients. Nearly 90% of patients with PTC could be cancer-free with an aggressive treatment approach.1 First-line therapy for PTC is typically surgery, with the extent of surgery depending on the size of the tumor and the presence or absence of lymph node metastasis. For high-risk patients, oral radioiodine is usually recommended subsequent to surgery. Historically, PTC was associated with a low risk for recurrence, with survival estimates of 99% at 20 years postsurgery. However, more recent data suggest that more than 600 genes are associated with increased risk for PTC recurrence. Genes related to DNA repair, cell cycle regulation, and thyroid dedifferentiation are postulated to have a negative impact on survival.1

Uninhibited tyrosine kinase receptor activation is a primary mechanism of cancer development, and the function of RET tyrosine kinase receptor in MTC pathogenesis is well documented.1-3 Studies have demonstrated that nonoverlapping alterations within the MEK/ERK signaling pathways are prevalent, with mutant BRAF, RAS, and RET fusions contributing to approximately 80% of the known alterations in PTC cases.3 The reported frequency of RET mutations or fusions in PTC varies greatly, with estimates ranging from 5% to 40% of PTC cases.4 Carcinogenesis related to RET/PTC occurs through chromosomal rearrangements as a result of the C-terminal kinase domain of RET being linked to the promoter and N-terminal domains of unrelated genes.1 The resulting disruption in the signaling cascade results in the MAPK pathway becoming unrestrained and chronically activated. As many as 13 forms of RET/PTC rearrangements have been identified.1 RET/PTC1 and RET/PTC3 are the most common rearrangements, accounting for more than 90% of these cases.

Treatment with tyrosine kinase inhibitors represents a relatively new approach to treatment of patients with advanced PTC.5 The tyrosine kinase inhibitors, lenvatinib (Lenvima) and sorafenib (Nexavar), are approved for the treatment of patients with advanced thyroid cancer whose disease is refractory to radioiodine therapy.6,7 However, these drugs are relatively weak RET kinase inhibitors and their clinical efficacy has been attributed more to their antiangiogenesis effects via vascular endothelial growth factor receptor pathway inhibition. Emerging therapies, such as the small-molecule inhibitors selpercatinib (Retevmo) and pralsetinib (Gavreto), are potent RET-specific kinase inhibitors that have demonstrated positive outcomes in clinical trials among patients with advanced cancer driven by RET alterations.3 Selpercatinib was granted accelerated approval by the FDA for patients with advanced PTC whose disease is refractory to radioiodine therapy.8

In summary, PTC is a common thyroid cancer, accounting for the majority of thyroid cancer cases; however, prognosis is good for patients with early and aggressive treatment. While there are no curative therapeutic options for patients with advanced disease, our developing understanding of the RET pathway and the new and emerging therapies targeting this pathway may improve outcomes for these patients.


  1. Abdullah MI, Junit SM, Ng KL, et al. Papillary thyroid cancer: genetic alterations and molecular biomarker investigations. Int J Med Sci. 2019;16:450-460.
  2. Ceolin L, Duval MAS, Benini AF, et al. Medullary thyroid carcinoma beyond surgery: advances, challenges, and perspectives. Endocr Relat Cancer. 2019;26:R499-R518.
  3. Cabanillas ME, Ryder M, Jimnez C. Targeted therapy for advanced thyroid cancer: kinase inhibitors and beyond. Endocr Rev. 2019;40:1573-1604.
  4. Gainor JF, Shaw AT. Novel targets in non-small cell lung cancer: ROS1 and RET fusions. Oncologist. 2013;18:865-875.
  5. Schmidbauer B, Menhart K, Hellwig D, Grosse J. Differentiated thyroid cancer—treatment: state of the art. Int J Mol Sci. 2017;18:1292.
  6. Nexavar (sorafenib) tablets, for oral use [prescribing information]. Whippany, NJ: Bayer HealthCare; July 2020.
  7. Fala L. Lenvima (lenvatinib), a multireceptor tyrosine kinase inhibitor, approved by the FDA for the treatment of patients with differentiated thyroid cancer. Am Health Drug Benefits. 2015;8(Spec Feature):176-179.
  8. US Food and Drug Administration. FDA approves selpercatinib for lung and thyroid cancers with RET gene mutations or fusions. May 11, 2020. Accessed August 23, 2020.

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