Minimal Extrathyroidal Extension Does Not Predict Initial Treatment Response, but Is a Better Prognostic Factor when Combined with Tumor S

• Background:
  • Minimal extrathyroidal extension (ETE):
    • Was recently removed from the TNM cancer staging system of the American Joint Committee on Cancer (AJCC):
      • Leaving only gross extra-thyroidal extension as part of the tumor staging:
        • This was done because only gross ETE impacts mortality, which is the primary focus of the TNM cancer staging system
  • Despite this change, minimal ETE remains clinically relevant:
    • As it is part of the 2015 American Thyroid Association (ATA) guidelines for thyroid nodules and thyroid cancer:
      • Minimal ETE:
        • Is associated with an intermediate risk for recurrence of papillary thyroid carcinoma (PTC)
        • Has been shown to be an independent risk factor for its recurrence
  • The decision to treat patients with radioactive iodine (RAI) ablation following thyroid surgery:
  • Is primarily based on the person’s risk of future disease recurrence:
    • The current ATA guidelines for differentiated thyroid cancer generally recommend RAI ablation in patients with:
      • Minimal ETE because of the associated risk of recurrent disease:
        • Despite having no impact on disease-related mortality
  • This study, Clin Thyroidol 2021;33:493–496:
    • Was done to assess the role of minimal ETE as a predictor of initial treatment response in PTC tumors and to evaluate the impact of RAI ablation in patients with minimal ETE
• Methods:
  • This study was an analysis of the Italian Thyroid Cancer Observatory (ITCO):
    • A web-based database started in 2013, which includes 49 thyroid cancer centers that prospectively collected data on more than 9000 patients with thyroid cancer
  • Inclusion criteria for the present study were:
    • Histologic diagnosis of PTC and associated variants
    • pN0 and pNX PTC tumors
    • Availability of all information on the initial treatment and pathologic characteristics of the tumor required for ATA recurrence risk assessment
    • Availability of the results for the 1-year follow-up visit needed to classify the treatment response
  • Of the 7746 case records available for review,:
    • 2237 subjects met all inclusion criteria and were included in this study
  • Initial treatment was classified as thyroid lobectomy or total thyroidectomy and if RAI ablation was given following total thyroidectomy
  • Tumors diagnosed as tall-cell, columnar-cell, hobnail-cell, solid / trabecular, or diffuse sclerosing PTC variants:
    • Were classified as tumors with “aggressive PTC histology.”
  • Risk of recurrence was classified based on the 2015 ATA guidelines for thyroid nodules and differentiated thyroid cancer, and response to initial treatment was classified based on imaging and serum thyroglobulin and thyroglobulin antibody levels at the 1-year follow-up visit
• Results:
  • There were 2237 subjects included in the analysis, including:
    • 1723 (77%) females and 514 (23%) males, with a median age of 51 years
  • Total thyroidectomy was performed in 2127 (95.1%) of patients, and 110 (4.9%) underwent near-total thyroidectomy
  • Central neck dissection was performed in 457 (20.4%), and the median tumor size was 10 mm
  • The cohort included 250 (11.2%) patients who were diagnosed with histologically aggressive variants
  • Minimal ETE was documented in 470 patients (21%), and 1153 patients (51.5%) received RAI ablation, with a median dose of 70 mCi 131I
  • Per the ATA risk stratification system:
    • 1632 (73%) were classified as low risk of recurrence and 605 (27%) as intermediate risk of recurrence
  • At the 1-year follow-up:
    • 1831 patients (81.9%) had an excellent response
    • 296 (13.2%) had an indeterminate response
    • 55 (2.5%) had a biochemical incomplete response
    • 55 (2.5%) had a structural incomplete response
  • There was no difference in initial therapy response rates between patients with and without minimal ETE (P = 0.54)
  • Treatment response was then evaluated as a binary variable (either excellent or incomplete response; indeterminate response was excluded) and multivariate analysis showed:
    • No significant difference with:
      • Minimal ETE (OR, 1.16; P = 0.65)
      • Tumor size > 2 cm (OR, 1.45; P = 0.34)
      • Aggressive PTC histology (OR, 0.55; P = 0.15)
      • Age at diagnosis (OR, 0.90; P = 0.32)
  • Combinations of minimal ETE, tumor size, and aggressive histology were evaluated, and the only combination with a significant finding was:
    • Minimal ETE and tumor size (OR, 5.27, 95% CI 1.39–19.91; P = 0.014)
  • Among the 470 patients with minimal ETE:
    • 370 had received RAI ablation:
      • Subjects who received RAI were more likely to have an excellent response at the 1-year evaluation than subjects who received surgery alone:
        • 84% vs. 77%; P = 0.005
  • To minimize selection bias, propensity-score matching based on known covariates and risk factors was performed:
    • After matching, the difference between subjects was no longer significant (84% vs. 77%; P = 0.06)
• Conclusions:
  • Minimal ETE is not an independent prognostic marker in predicting the initial response to therapy in patients with PTC who do not have lymph node metastases
  • However, the combination of minimal ETE and tumor size >2 cm:
    • Is an independent prognostic factor for worse outcomes and could be helpful in PTC patients with low to intermediate risk of recurrent disease
• This study failed to show the clinical significance of minimal ETE in patients with PTC and negative lymph nodes:
  • Which is contradictory to previous studies that show an increased risk of disease recurrence in patients with minimal ETE
  • This brings into question the general recommendation of whether or not to treat patients with minimal ETE with RAI ablation following thyroid surgery
  • Interestingly, this study strongly showed that a combination of minimal ETE and tumor > 2 cm:
    • Had a significant impact on disease status at 1-year follow-up, with an odds ratio of 5.27
  • ETE is a key surgical pathology finding, as it has been shown to be an independent risk factor for PTC recurrence
  • Gross ETE has a more pronounced impact on recurrence:
    • Yet minimal ETE also impacts recurrence
  • Because of this, some authorities recommend that patients with minimal ETE undergo RAI ablation following total thyroidectomy
  • Although this study suggests that patients with minimal ETE without lymph node metastasis may not benefit from RAI:
    • There was a trend toward benefit after propensity-score matching with a P value of 0.06:
      • Further studies with longer follow-up are needed
  • Given these findings, I would certainly continue to generally advocate for RAI ablation in patients with minimal ETE and a tumor size >2 cm:
    • But for patients with tumors less than 2 cm:
      • A more nuanced decision will be needed
  • A major strength of this study is the large size of the patient cohort, with over 2000 subjects included in the analysis
  • These patients also had negative lymph nodes, another strength in trying to isolate the effects of minimal ETE in a lower-risk cohort
  • The major limitation is the short duration of the study follow-up, which was only 1 year
  • While initial response to treatment is important, long-term outcomes are clinically more relevant, and as the authors state, this analysis is underway
  • Finally, despite propensity-score matching, there will still be inherent selection bias with this type of study design, as RAI treatment decisions were individually recommended by the treating physician and more detailed data are unavailable
  • Despite this, this study advances our understanding of minimal ETE and has the possibility to change the care of patients with DTC who have this histologic finding

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