The Question of an Optimal TSH Goal After Lobectomy for Papillary Thyroid Cance

• The American Thyroid Association (ATA) guidelines recommend that:
  • Thyroid lobectomy is sufficient:
    • In low-risk patients with differentiated thyroid cancer (DTC):
      • However, the corresponding optimal serum TSH level, and thus whether replacement therapy with levothyroxine (LT4) might be advised, in low-risk patients after lobectomy is still a controversial issue
• In this study Clin Thyroidol 2022;34:67–70, Xu and coworkers:
  • Examined the association between post-surgical TSH levels in patients with papillary thyroid carcinoma (PTC):
    • Who were given LT4 therapy after lobectomy and their risk of structural recurrence
• Methods:
  • This study included adult patients (ages 18 to 75) who underwent thyroid lobectomy for PTC:
    • At the National Cancer Institute and Hospital at the Chinese Academy of Medical Sciences from January 2000 to December 2014
  • Patients without advanced tumors or preoperative evidence of distant metastasis, high-risk aggressive variants, and positive surgical margins were included
  • Staging was assigned according to the American Joint Committee on Cancer staging system (8th edition)
  • The post-surgical risk stratification was assessed according to the 2015 ATA differentiated thyroid cancer guidelines
  • All included patients received thyroid hormone replacement therapy as LT4:
    • Targeting an optimal serum TSH range of 0.5 to 1 mU/L
  • Serum TSH concentrations were determined by electrochemiluminescence immunoassay with a functional sensitivity of at least 0.01 mU/L and a reference range of 0.5 to 4.0 mU/L
  • Physical examination, neck ultrasonography, computed tomography or chest radiography, and serum thyroid tests (TSH, thyroglobulin, and antithyroglobulin antibodies) were assessed every 6 months during the first 5 years and every 12 months thereafter
  • Recurrence-free survival was estimated from the time of surgery for PTC until there was evidence of a structural recurrence
  • The association of mean TSH and structural recurrence was assessed using univar-iate and multivariate Cox regression models with restricted cubic spline
• Results:
  • The study sample included 2297 patients (median age, 42 years; 76.2% women)
  • The mean (±SD) tumor size was 1.23 ±0.98 cm, with 59.2% of patients having a tumor < 1 cm
  • Central neck dissection was performed in 70.9% and lateral neck dissection in 22.6%, respectively
  • At the initial evaluation, 41.2% patients had low-risk of recurrence, 42.4% had intermediate-risk, and 16.4% high-risk of recurrence, according to the 2015 ATA risk stratification guidelines
  • The mean post-surgical TSH level in the cohort was 1.456 ± 2.224 mIU/L
  • Serum TSH values were 0.5 mU/L in 29.1%, in the lower half of the reference range (0.5 to < 2) in 50.6%, in the upper half of the reference range (2.1 to ≤4) in 15%, and above the reference range (>4) in 5.3%
  • During a median follow-up period of 70 months:
    • 167 (7.3%) patients had structural recurrences and 26 died (11 from PTC)
  • Local or regional recurrences developed in 84.4% of patients (37 local, 66 regional, and 38 both), whereas distant metastases developed in 26 (isolated in 12 cases and combined with local or regional recurrences in 14)
  • Recurrences were detected in the:
    • Residual lobe (n = 71)
    • Thyroid bed (n = 6)
    • Central neck (n = 60)
    • Lateral neck (n = 90)
  • Recurrence-free survival rates at 5 and 10 years were 94.7% and 84.7%, respectively
  • 81.4% of the recurrences occurred in patients in the intermediate-to-high-risk group
  • No associations were observed between mean TSH levels and recurrence-free survival in the combined cohort of low-risk and intermediate-to-high-risk groups
  • The only recurrence-free survival difference observed in the stratified univariate analysis was between patients with mean TSH levels in the lower half of the reference range (0.6–2 mU/L, n = 659) versus those above the reference range (>4 mU/L, n = 68) in the intermediate-to-high-risk group (10-year recurrence-free survival by Kaplan–Meier analysis, 84.4% vs. 69.4%, log-rank P = 0.011)
• Conclusions:
  • In this retrospective cohort study, no associations were observed between the mean postoperative serum TSH levels and tumor recurrence among PTC patients who underwent thyroid lobectomy
  • The recurrence-free survival rates were similar between patients whose TSH levels were within the reference range and those with suppressed TSH levels
• Optimal management of DTC includes:
  • The avoidance of overdiagnosis and overtreatment in patients with a low risk of disease recurrence
• Papillary micro-carcinoma represents a very-low-risk tumor and one for which the ATA supports the possibility of active surveillance as a management option
• Furthermore, the ATA recommends thyroid lobectomy for differentiated thyroid cancer:
  • Greater than 1 cm and less than 4 cm with unifocal and intrathyroidal carcinoma without extra-thyroidal extension and clinical evidence of any lymph-node metastases (cN0), in the absence of prior head and neck radiation, familial thyroid carcinoma or clinically detectable cervical node metastases
• This approach has been associated with a favorable outcome and had no negative impact on overall survival according to a systematic literature review
• The advantages of lobectomy include:
  • Fewer surgical complications (less risk of hypocalcemia and recurrent laryngeal-nerve injury) and a lower risk of postoperative hypothyroidism:
    • A large meta-analasis of 32 studies reported an estimated risk of 12% for subclinical hypothyroidism and 4% for clinical hypothyroidism in patients who undergo lobectomy
• For patients with DTC, the ATA guidelines recommend a postoperative TSH level in the mid to lower reference range (0.5–2 mU/L):
  • Therefore, treatment with LT4 in this group is not necessary when the postoperative serum TSH remains below 2 mIU/L
• It should be noted that patients with high pre-operative TSH levels and positive for antithyroid peroxidase antibodies:
  • Might have an increased risk of developing hypothyroidism after lobectomy
• In addition, high postoperative TSH levels (after 1 year):
  • May identify patients with persistent postoperative hypothyroidism after lobectomy
• The disadvantage of lobectomy is:
  • The need for completion thyroidectomy in patients with:
    • A high risk for recurrence, worrisome histologic features, malignant new nodules in the contralateral lobe, or evidence of structural disease on imaging during follow-up
• In this large retrospective study by Xu et al. that included 2297 patients who underwent lobectomy for thyroid cancer, the surgical pathology revealed that 42.4% of patients had an intermediate risk and 16.4% a high risk for recurrence (defined by the 2015 ATA DTC guidelines), despite the preoperative exclusion of high-risk variants, distant metastases, and positive surgical margins
• The fact that a relatively large proportion of patients were at intermediate or high risk and yet did not undergo completion thyroidectomy could explain why structural recurrence developed in 7.3% and thyroid cancer–specific mortality was observed in 11 patients over a follow-up of 70 months
• However, despite the inclusion of these patients, serum TSH levels were not associated with recurrence risks, even in the adjusted model restricted to patients with intermediate or high risk for recurrent disease
• The risk of thyroid malignancy increases with serum TSH, and higher TSH values (even within the normal range), have been associated with a higher frequency of thyroid cancer in patients with nodular thyroid disease
• However, there are conflicting data in the literature concerning the potential role of postsurgical TSH levels regarding the prognosis of low-risk DTC patients
• In a retrospective, propensity score–matched cohort study by Park et al:
  • TSH suppression did not improve clinical outcomes, and serum TSH levels were not associated with recurrence in patients with low-risk DTC who underwent lobectomy
• In addition, no difference in the rate of recurrences was reported among patients with TSH values ranging from less than 0.5 to 4.5 mIU/L in a study by Lee et al:
  • Their analysis showed that there were no differences in recurrence when comparing those with and those without thyroid hormone replacement therapy
• These results suggest the necessity of large prospective studies with rigorous criteria to determine the optimal range of serum TSH levels in low-risk DTC patients, including those who undergo lobectomy:
  • These future studies should consider the risks and benefits of LT4 therapy with regard to thyroid cancer recurrence risks, survival and quality of life measures
  • The results of these studies could be of significant clinical and psychological importance when recommending the extent of surgery in patients with low-risk DTC
• References:
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, et al. 2016 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association guidelines task force on thyroid nodules and differentiated thyroid cancer. Thyroid 26:1–133
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  • Park S, Jeon MJ, Song E, Oh H-S, Kim M, Kwon H, et al. 2017 Clinical features of early and late postoperative hypothyroidism after lobectomy. J Clin Endocrinol Metab 102:1317–1324.7. Fiore E, Vitti P 2012 Serum TSH and risk of papillary thyroid cancer in nodular thyroid disease J Clin Endocrinol Metab 97:1134–1145.
  • Park JH, Lee YM, Lee YH, Hong SJ, Yoon JH 2018 The prognostic value of serum thyroid-stimulating hormone level post-lobectomy in low- and intermediate-risk papillary thyroid carcinoma. J Surg Oncol 118:390–396.
  • Park S, Kim WG, Han M, Jeon MJ, Kwon H, Kim M, et al. 2017 Thyrotropin suppressive therapy for low-risk small thyroid cancer: A propensity score-matched cohort study. Thyroid 27:1164–1170.
  • Lee MC, Kim MJ, Choi HS, Cho SW, Lee GH, Park YJ, Park DJ 2019 Postoperative thyroid-stimulating hormone levels did not affect recurrence after thyroid lobectomy in patients with papillary thyroid cancer. Endocrinol Metab (Seoul) 34:150–157.

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