Tag: surgeon

Diagnostic Thyroid Testing: Serum Thyroglobulin

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Thyroglobulin (Tg):
    • Is a large glycoprotein that is stored as colloid:
      • The primary storage form of thyroid hormone, in the lumen of thyroid follicles
    • It is continuously secreted into circulation from the thyroid gland:
      • Thereby reflecting the mass of normal and malignant thyroid tissue
  • Higher serum concentrations result from:
    • TSH stimulation and / or injury of thyroid tissue:
      • However, for the individual with an intact thyroid gland:
        • Its clinical value for evaluating thyroid dysfunction or goiter is limited in the era of modern serum thyroid function testing and imaging
        • However, the demonstration of a suppressed serum Tg level in such a patient can be useful in differentiating factitious thyrotoxicosis (from exogenous thyroid hormone ingestion) from excessive endogenous thyroid hormone release of any etiology:
          • In this situation, when thyrotoxicosis is due to ingestion of exogenous thyroid hormone:
            • Normal thyroid hormone production is suppressed and serum Tg levels are decreased
          • In contrast, if excess thyroid hormone is produced from the thyroid:
            • Serum Tg levels are elevated
  • In current clinical practice:
    • The primary use of serum Tg concentrations is as a tumor marker in patients with differentiated thyroid cancer:
      • That is obtained to detect persistent and / or recurrent disease after a total thyroidectomy and radioactive iodine (131I) ablation
  • Most Tg assays have only first-generation functional sensitivity between 0.5 and 1 ng/mL:
    • But the second generation Tg assays are rapidly becoming the standard and have an improved functional sensitivity of 0.05 to 0.1 ng/mL
  • The Tg assay can be made more sensitive to detect persistent or recurrent tumor:
    • After stimulation by TSH:
      • Either endogenously by withholding thyroxine treatment in an athyreotic patient or with administration of recombinant human TSH (rhTSH):
        • The latter of which results in an approximate tenfold increase in basal serum Tg concentrations
  • Detection of persistent and / or recurrent disease in thyroid cancer depends on the performance of Tg immunometric assays:
    • Which currently have suboptimal sensitivity and high interassay variability
  • Virtually all immunometric methods:
    • Will report an undetectable Tg level in euthyroid Tg Ab positive controls:
      • Approximately 25% of patients with differentiated thyroid cancer have a positive serum TgAb titer:
        • Thus when a suspicious lymph node or neck mass is detected in an individual who has undergone a total thyroidectomy:
          • An unmeasurable basal or rhTSH-stimulated Tg in the setting of a positive serum TgAb level:
            • Does not necessarily exclude thyroid cancer recurrence
        • It is reasonable in this relatively uncommon situation to measure Tg instead by Tg Ab-resistant radioimmunoassay (RIA) or liquid chromatography tandem mass spectrometry:
          • Which are available at some specialty endocrine laboratories.
  • When the serum Tg Ab titer is positive:
    • It may also be used as a surrogate marker of tumor persistence / recurrence
  • In one study, a > 50% decrease of Tg Ab levels within the first year after a total thyroidectomy:
    • Was associated with the absence of tumor recurrence / persistence in all patients studied
    • Tumor recurrence / persistence was present in 37% of patients who had any rise of serum Tg Ab within the same period
  • Thus thyroid cancer patients with rising Tg antibody levels:
    • Are at high risk for disease persistence / recurrence and should be evaluated promptly
    • In addition, the sensitivities and absolute values reported by different methods of measuring Tg and TgAb are highly variable:
      • It is essential to always use the same Tg and TgAb method when following an individual over time for tumor persistence/recurrence
  • Finally, the presence of interfering heterophile antibodies (antibodies against the animal-derived antibodies used in the immunometric assay):
    • May rarely result in abnormally high or low serum Tg levels
    • The most common interfering antibodies are HAMAs:
      • Clinically, this should be suspected when an elevated serum Tg level is inappropriate for the clinical situation and does not increase with rhTSH stimulation
      • When heterophile antibody is suspected, the clinician should repeat the test using a commercially available heterophile-blocking tube (HBT) or measure Tg with an RIA assay

The combination of BRAF600E mutation and TERT promotor mutations increases risk of recurrence and death in papillary thyroid cancer

Rodrigo Arrangoiz MS, MD, FACS, FSSO
  • Most patients with papillary thyroid cancer (PTC) have an excellent prognosis:
    • But predicting which patients do not do well has been an ongoing area of interest
  • Ideally, identifying those at higher risk of cancer recurrence:
    • Would potentially allow the more aggressive therapies to be utilized when appropriate for patients with high risk papillary thyroid cancer
  • A lot of work has identified molecular markers, which are mutations in cancer-related genes that can help in the diagnosis of thyroid cancer on thyroid biopsy specimens
  • Two specific molecular markers, BRAFv600E and TERT promotor mutations:
    • Have been associated with aggressive tumor behavior and worse outcomes in papillary thyroid cancer
  • The BRAFv600E mutation is quite common in papillary thyroid cancer:
    • So using this mutation alone to predict outcome has been challenging, though it has been associated with poor prognosis
  • The TERT promoter mutation alone was not shown to cause adverse outcomes in some previous studies, though other studies suggested it was associated with a more aggressive clinical picture
  • A study by Moon S et al. aimed to determine the prognosis of papillary thyroid cancer in patients with either of these mutations alone or in combination by a review of the current studies:
    • Moon S et al. Effects of coexistent BRAFV600E and TERT promoter mutations on poor clinical outcomes in papillary thyroid cancer: a meta-analysis
  • Summary of the Study:
    • A literature review was done to identify studies that included BRAFV600Eand TERT promoter mutations in thyroid cancer
    • A total of 13 studies were identified
    • Data was extracted and reviewed for clinical information to include the number of males and females, age at diagnosis, cancer stage, spread to lymph nodes, extrathyroidal extention, spread outside of the neck, cancer recurrence and death
    • A total of 4347 patients with papillary thyroid cancer were evaluated in the study and 283 patients had both BRAFv600E and TERT promoter mutations
    • A BRAFv600E mutation alone:
      • Was related to advanced age at time of diagnosis, advanced cancer stage, extrathyroidal extension of tumor, and spread to lymph nodes, compared with no mutation
    • A TERT promoter mutation alone:
      • Was associated with older age at diagnoses, spread to lymph node and spread outside of the neck
    • The combination of BRAFv600E and TERT promoter mutations together when compared with no mutations:
      • Was associated with older age at diagnosis, male gender, advanced cancer staging, extrathyroidal extension, spread to lymph node and spread outside of the neck
    • Overall, the combination of BRAF600E and TERT mutations:
      • Was associated with high recurrence rate when compared with no mutations
    • Further, it was noted that the combination of mutations also had a higher risk of death than no mutations or BRAFv600E alone, although few patients were in this group
  • What are the implications to this study:
    • This study shows that molecular marker analysis can be used to identify patients that have more aggressive thyroid cancer
    • The combination of BRAFv600E and TERT promotor mutations worsens the prognosis for papillary thyroid cancer
    • Additionally, a limited data set suggested higher risk of death with the combination of BRAF600E and TERT promoter mutations
    • As we improve our understanding of the molecular changes in thyroid cancer, we will improve our ability to identify patients that have a more aggressive thyroid cancer
    • Ultimately this knowledge will lead to improved treatment options
    • Future studies must aim to determine if identifying these mutations at the time of diagnosis can lead to improved outcomes for patients at higher risk
#Arrangoiz #ThyroidSurgeon