Introduction

Papillary thyroid carcinoma (PTC) is the most common type of thyroid malignancy, accounting for nearly 80–85% of all thyroid cancers. It originates from the follicular epithelial cells of the thyroid gland and is generally considered a well-differentiated carcinoma with an excellent prognosis. PTC is more prevalent in women than men, with the highest incidence occurring between the ages of 30 and 50 years. Its clinical significance lies in its indolent course, high curability, and low mortality rate, although recurrence is not uncommon.

Epidemiology

Thyroid cancer represents the most frequent endocrine malignancy, and PTC is its most dominant histological subtype. The global incidence of thyroid cancer has been increasing over the past few decades, partly due to the widespread use of high-resolution imaging techniques that enable detection of small, subclinical thyroid nodules. The incidence is higher in women, with a female-to-male ratio of approximately 3:1. Exposure to ionizing radiation, family history of thyroid cancer, and certain genetic mutations (such as BRAF V600E) have been associated with increased risk.

Pathophysiology and Molecular Genetics

PTC arises from thyroid follicular cells, which normally produce thyroglobulin and thyroid hormones. The carcinogenesis of PTC involves several molecular pathways:

  1. BRAF mutations – The BRAF V600E mutation is the most common genetic alteration, present in nearly 40–60% of PTC cases. It activates the MAPK signaling pathway, promoting uncontrolled cell proliferation.
  2. RET/PTC rearrangements – RET gene rearrangements lead to constitutive activation of tyrosine kinase signaling.
  3. RAS mutations – Though more commonly associated with follicular thyroid carcinoma, RAS mutations are occasionally found in PTC.
  4. TERT promoter mutations – These mutations are linked to aggressive tumor behavior and poor prognosis.

Histologically, PTC is characterized by papillary structures with fibrovascular cores, nuclear features such as “Orphan Annie eye” nuclei, nuclear grooves, and psammoma bodies.

Clinical Features

Most patients with papillary thyroid carcinoma present with an asymptomatic thyroid nodule detected during a routine physical examination or imaging study. The clinical features include:

  • Thyroid nodule: A painless, firm mass in the thyroid region.
  • Cervical lymphadenopathy: PTC frequently metastasizes to cervical lymph nodes.
  • Hoarseness or voice changes: Suggestive of recurrent laryngeal nerve involvement.
  • Dysphagia or dyspnea: Rare but possible in cases of large tumors compressing nearby structures.

Despite lymphatic spread, distant metastases are uncommon and usually involve lungs and bones.

Diagnosis

The diagnostic workup for suspected papillary thyroid carcinoma includes:

  1. Clinical evaluation and history – Assessing risk factors such as radiation exposure and family history.
  2. Neck ultrasonography – The primary imaging modality for evaluating thyroid nodules. Suspicious features include hypoechogenicity, microcalcifications, irregular margins, and increased nodular vascularity.
  3. Fine-needle aspiration biopsy (FNAB) – The gold standard for diagnosis, classified according to the Bethesda system. FNAB has high sensitivity and specificity for detecting malignancy.
  4. Serum thyroid function tests – Usually normal in PTC.
  5. Molecular testing – Genetic analysis for BRAF, RET/PTC, and RAS mutations can aid in diagnosis and prognosis.
  6. Cross-sectional imaging (CT/MRI) – Considered when there is suspicion of extrathyroidal extension or bulky nodal disease.

Management

The management of PTC is highly individualized, depending on tumor size, extent of disease, and risk stratification.

  1. Surgical treatment
    • Thyroidectomy: Total thyroidectomy is the standard treatment for tumors >1 cm or with high-risk features (extrathyroidal extension, nodal involvement, distant metastases).
    • Lobectomy: May be sufficient for low-risk, unifocal tumors ≤1 cm without nodal involvement.
    • Neck dissection: Indicated when cervical lymph node metastases are present.

  2. Radioactive iodine (RAI) ablation
    • Used post-thyroidectomy to ablate residual thyroid tissue and treat microscopic disease.
    • Most beneficial in high-risk patients; low-risk patients may not require RAI therapy.
  3. Thyroid hormone suppression therapy
    • Levothyroxine is administered to suppress thyroid-stimulating hormone (TSH), reducing the risk of recurrence.
  4. Targeted therapies
    • In advanced or RAI-refractory disease, tyrosine kinase inhibitors (e.g., sorafenib, lenvatinib) are used.
    • Immunotherapy and selective BRAF inhibitors are emerging as potential therapies.

Prognosis

Papillary thyroid carcinoma has an excellent prognosis, with a 10-year survival rate exceeding 90%. Factors influencing prognosis include:

  • Age: Younger patients have better outcomes.
  • Tumor size: Larger tumors are associated with increased recurrence risk.
  • Extrathyroidal extension: Predicts worse prognosis.
  • Genetic mutations: BRAF V600E and TERT mutations are linked to aggressive disease.

Despite favorable survival rates, up to 20–30% of patients experience recurrence, emphasizing the need for long-term follow-up.

Follow-up and Surveillance

Post-treatment monitoring includes:

  • Serum thyroglobulin levels – A tumor marker for detecting recurrence.
  • Neck ultrasound – Routine imaging to evaluate residual thyroid tissue or nodal recurrence.
  • Diagnostic whole-body iodine scanning – In selected cases, particularly in high-risk patients.

Conclusion

Papillary thyroid carcinoma is the most common thyroid malignancy, characterized by slow growth, excellent prognosis, and high survival rates. Advances in molecular genetics and targeted therapies have improved the understanding and management of this disease. Early diagnosis, appropriate surgical intervention, and individualized postoperative management remain crucial for optimal outcomes. Ongoing research into genetic mutations and novel therapeutic approaches promises to further enhance treatment strategies for patients with PTC.

References

  1. Cabanillas, M. E., McFadden, D. G., & Durante, C. (2016). Thyroid cancer. The Lancet, 388(10061), 2783–2795.
  2. Haugen, B. R., et al. (2016). 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer. Thyroid, 26(1), 1–133.
  3. Nikiforov, Y. E., & Nikiforova, M. N. (2011). Molecular genetics and diagnosis of thyroid cancer. Nature Reviews Endocrinology, 7(10), 569–580.
  4. Sherman, S. I. (2003). Thyroid carcinoma. The Lancet, 361(9356), 501–511.
  5. Lim, H., et al. (2017). Clinical and molecular features of papillary thyroid carcinoma. Endocrine-Related Cancer, 24(5), R91–R105.
  6. Schlumberger, M., & Leboulleux, S. (2021). Current practice in patients with differentiated thyroid cancer. Nature Reviews Endocrinology, 17(3), 176–188.

 

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