A Possible Role for Serum Thyroglobulin to Predict Structural Recurrence of Papillary Thyroid Cancer After Thyroid Lobectomy

• Papillary thyroid cancer (PTC):
  • Is the most common subtype of differentiated thyroid cancer (DTC)
• In the 2015 DTC guidelines from the American Thyroid Association (ATA):
  • Thyroid lobectomy is recommended as a reliable therapeutic option for patients with low and intermediate risk intra-thyroidal DTC that is:
    • Less than 4 cm in size
    • No previous history of head and neck radiation
    • A strong family history of thyroid cancer
    • Ultrasound abnormalities in the contralateral lobe
• Lobectomy has been shown to have therapeutic efficacy:
  • Similar to that of total thyroidectomy (TT) with lesser postsurgical complications
• Serum thyroglobulin (Tg) and anti-thyroglobulin antibody (TgAb) levels:
  • Are used to monitor for persistent or recurrent disease after initial surgery:
    • But the precise postlobectomy Tg cutoffs are uncertain
• This study, Clin Thyroidol 2021;33:497–499:
  • Aimed to evaluate the prognostic value of postlobectomy serum Tg and TgAb titers with structural recurrence of PTC
• Methods:
  • This retrospective cohort study included patients with unilateral PTC who underwent lobectomy at a National Cancer Center in China between 2000 and 2014
  • Patients with preoperative evidence of distant metastasis, positive surgical margins, incomplete Tg or TgAb data, or serum thyrotropin (TSH) levels > 4 mIU/L during follow-up were excluded
  • Serum Tg / TgAb levels were measured semi-annually for the first 5 years and annually thereafter
  • TgAb titer positivity was defined as greater 60 IU/ml:
    • From which the cohort was stratified into TgAb-positive and TgAb-negative groups
  • The first, penultimate, and last Tg/TgAb levels were defined as those:
    • Measured in the initial period (6 to 12 months) after lobectomy, penultimate, and last follow-up, respectively
  • The primary end point was structural recurrence
  • The predictive classifier of recurrence was based on random forest analysis
  • Tg cutoff values were determined with receiver operating characteristic (ROC) curves
  • Recurrence-free survival (RFS) rates were analyzed with Kaplan–Meier curves and Cox proportional-hazards modeling was performed to examine the relationship between RFS and clinicopathologic variables
• Results:
  • Of 1451 patients enrolled:
    • 66 of 1050 (6.3%) in the TgAb-negative group and 26 of 401 (6.5%) in the TgAb-positive group:
      • Developed recurrence over a median follow-up of 72 months
  • In the TgAb-negative group:
    • According to the classifier:
      • The last Tg level
      • The difference between the last and penultimate Tg levels
      • The proportion of the last to the penultimate Tg:
        • Had the best predictive values
    • The optimal cutoff values of the first and last Tg levels were determined to be:
      • 5.3 ng/ml and 11.0 ng/ml, respectively, by ROC analysis
    • Patients whose last Tg levels were ≥ 11 ng/ml:
      • Had higher recurrence rates than those with levels < 11 ng/ml:
        • 23.5% vs. 4.4%:
          • P<0.001
    • The overall trend in serum Tg was relatively stable and rose sharply before recurrence but decreased in those without recurrence
    • Patients with elevated first Tg levels (≥ 5.3 mg/ml):
      • Had worse RFS in both the low-risk and the intermediate-to high-risk subgroups (P<0.05 for both)
    • A multivariate analysis including gender, age, primary tumor size, gross extra-thyroidal extension, N stage and elevated first Tg levels indicated that:
      • Patients with elevated first Tg levels had double the risk of recurrence compared with those with normal first Tg levels:
        • Hazard ratio, 2.052, 95% CI, 1.231–3.421; P = 0.006
  • In the TgAb-positive group:
    • There was no significant difference between first TgAb and last TgAb levels in patients with or without recurrence
    • The established classifier of serum TgAb:
      • Did not show a favorable association with recurrence (AUC, 0.72; 95% CI, 0.53–0.91)
• Conclusions:
  • Serum Tg has a predictive value for surveillance in patients with PTC after lobectomy
  • The proposed adverse threshold values of the:
    • Initial Tg levels in the first 6 to 12 months after lobectomy (greater than 5.3 ng/ml) and of the last Tg levels available in this cohort (greater than 11.0 ng/ml over a median of 72 months of follow-up):
      • Could identify patients at a higher risk of recurrence, despite the presence of an intact residual thyroid lobe
• The expected reference range of serum Tg:
  • Arising from a normal, fully intact thyroid gland is:
    • 20 to 60 ng/ml
• The predictive value of serum Tg levels for the recurrence of PTC after thyroid lobectomy has been uncertain
• A retrospective cohort study by Ritter et al:
  • Showed that basal or trend of serum Tg levels during follow up of the patients did not predict disease recurrence
• A historical cohort study by Park et al:
  • Also showed limited value of serial Tg measurements in predicting the recurrence of PTC after lobectomy, as serum Tg and Tg:TSH ratios:
    • Were found to be gradually increasing in both the groups with and those without disease recurrence
• However, other studies have shown that Tg values increasing over time:
  • Is significantly more likely in patients with disease recurrence
• A review paper that was cited in the 2015 ATA DTC guidelines:
  • Suggested that after thyroid lobectomy:
    • A stable, non-stimulated Tg cutoff value of less than 30 ng/ml:
      • Is a reasonable indicator for excellent response
    • Whereas non-stimulated Tg values greater than 30 ng/ml, an upward Tg trend over time, or increasing serum TgAb levels:
      • Would signify a biochemical incomplete response
• This study by Xu et al., Clin Thyroidol 2021;33:497–499:
  • Using a large sample size, an innovative approach (random forest, machine earning), and adjustment of confounders found that:
    • Serum Tg levels, but not TgAb, was a significant predictor of structural disease recurrence in patients who have undergone thyroid lobectomy for PTC
  • The optimal adverse cutoff values of the first Tg and last Tg values were determined to be:
    • 5.3 ng/ml and 11.0 ng/ml, respectively
  • The overall trend in serum Tg levels sharply increased before disease recur-rence:
    • But it decreased in patients without recurrence
  • Limitations of the study include different intervals between serial Tg and TgAb measurements, as well as nonadjusted TSH influences on Tg levels when patients with normal-range TSH levels (<4 mIU/L) were included
  • The findings of this study are useful in clinical practice:
    • As they increase our confidence that serum Tg data, including their absolute values and trends, can guide us in identifying patients at high risk for DTC recurrence after thyroid lobectomy
  • Larger population studies are needed to further clarify our insight on this emerging topic, particularly as a more conservative surgical approach toward low- and some intermediate-risk DTCs is being adopted

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