Differentiated thyroid cancer (DTC)

DTC accounts for 90% of thyroid tumor pathology, including papillary and follicular carcinoma. Compared to other subtypes, differentiated thyroid cancer has a very favorable prognosis. However, the survival rate decreases in the presence of metastatic disease. (Figure 1).

Proper classification and stratification of patients with a diagnosis of thyroid cancer are crucial to determine the frequency and imaging modalities for monitoring.

Initial mortality risk is determined according to the 8th edition of the American Joint Committee on Cancer (AJCC/TNM) staging system, which provides a 10-year survival estimate based on stage (Figure 2-3). However, the AJCC/TNM system does not predict the risk of persistent/recurrent disease.

The American Thyroid Association (ATA) guidelines currently provide a framework for assessing the risk of persistent or recurrent disease based on information available after primary cancer treatment. (Table 1).

Existing static risk stratification systems (ATA 2015 and AJCC/TNM 8th edition) provide an initial framework for patient follow-up; however, their static nature necessitates dynamic risk re-stratification based on long-term response to therapy (medical and surgical). This dynamic approach integrates biochemical, clinical, and imaging data to personalize patient management and optimize outcomes. Response definitions are summarized in Table 2.

In the follow-up of thyroid cancer, the measurement of serum Tg levels and neck ultrasound (US) are primarily used. These are the two key parameters for assessing potential recurrence. (Case 1 – Image 1-2-3)

• Low-intermediate risk in DTC (thyroidectomy and radioiodine ablation): 

• • Excellent response: follow-up is performed through serum thyroglobulin measurement and neck ultrasound. The low recurrence rate of these tumors suggests follow-up every 12 months. If the first ultrasound shows no abnormalities, a new ultrasound can be scheduled, but not before 3-5 years after the primary treatment. After 5-10 years of follow-up with no evidence of disease, the risk of recurrence is very low, and it is safe to perform follow-up every two years with TSH and serum thyroglobulin levels.
  • Biochemical incomplete response: in these patients, monitoring should be performed every 6-12 months through the measurement of serum thyroglobulin and anti-thyroglobulin antibodies, ideally conducting these tests in a serial manner. In the case of a gradual increase in levels over time, a possible recurrence and/or persistence of the disease should be suspected, and it should be investigated with a neck ultrasound.
  • Indeterminate response: in patients with low or intermediate risk, the risk of recurrence is almost negligible. In these cases, serial levels of thyroglobulin and anti-thyroglobulin antibodies should be considered, also taking into account the initial risk stratification (low vs. intermediate) to define the follow-up duration and whether additional imaging studies beyond neck ultrasound are required.

• Low-intermediate risk in DTC (thyroid lobectomy): 

• • In these patients, follow-up is based on neck ultrasound. Additionally, a stepwise increase in thyroglobulin levels can be useful for the follow-up protocol.
• High risk in DTC: for these patients, the treatment involves total thyroidectomy followed by radioiodine ablation of the surgical bed. Periodic assessments (every 6-12 months) with serum thyroglobulin (Tg) and anti-thyroglobulin antibody (TgAb) assays, as well as neck US are recommended. In the presence of detectable serum Tg levels, particularly in the context of a short doubling time (<12 months) or the presence of TgAb (which may confound Tg assay interpretation), cross-sectional imaging (including contrast-enhanced computed tomography of the neck and chest) and 18F-FDG-PET/CT should be considered. Radioactive iodine whole-body scan (preferably with SPECT/CT) is also an option.

Due to the polymorphic nature of thyroid cancer and potential dedifferentiation over time, 18F-FDG PET/CT is considered in patients initially diagnosed with DTC who present with negative 131I scans and inexplicably elevated thyroglobulin levels.

Dedifferentiated thyroid cancer (dDTC), now referred to as RR-DTC, occurs in approximately 5% of cases, leading to increased risk of tumor growth, metastatic spread, and loss of radioiodine uptake. This phenomenon is associated with downregulation of the sodium-iodide symporter and a corresponding upregulation of glucose transporter 1 (GLUT-1), called “flip‐flop” phenomenon. This shift in tumor biology supports the use of 18F-FDG-PET/CT for patient follow-up. (Case 2- Image 4-5).

The BRAFV600E mutation, the most common mutation in thyroid cancer, is associated with adverse prognostic factors, including extrathyroidal invasion, lymph node metastasis, and dDTC. The BRAFV600E mutation often demonstrates significantly higher 18F-FDG uptake, which in some cases suggests the utility of 18F-FDG-PET/CT for monitoring. Further studies are needed to validate its routine use.

Medullary thyroid carcinoma (MTC).

MTC, a rare thyroid neoplasm originating from parafollicular C cells, accounts for 2-5% of all thyroid cancers. Most cases (75%) arise sporadically or in the context of hereditary syndromes such as multiple endocrine neoplasia type 2 (MEN 2) or familial medullary thyroid carcinoma (FMTC), resulting from mutations in the RET oncogene.

MTC does not express the sodium-iodine symporter and therefore does not absorb iodine.

The initial study and staging of a patient diagnosed with MTC, should include laboratory tests such as calcitonin and carcinoembryonic antigen (CEA), as well as imaging studies to assess for regional lymph node involvement or distant metastases (Table 3).

An important feature of MTC is its ability to accumulate amine precursors, such as L-DOPA. For this reason, PET with 18F-DOPA is superior to 18F-FDG in assessing the extent of residual disease, although 18F-FDG has better utility in distinguishing progressive disease (Case 3- Image 6-7 and 8).