Tumor Volume Doubling Time as a Disease Predictor for Tumor Growth and Lymph Node Metastasis in Papillary Thyroid Microcarcinoma

• Background:
  • Papillary thyroid micro-carcinomas (PTMCs):
    • Are well-differentiated tumors with an indolent nature and excellent outcome
  • The American Thyroid Association (ATA) guidelines:
    • Have endorsed active surveillance as a safe alternative to surgery for the management of PTMC
  • Data from the Kuma Hospital, Japan:
    • Have reported 5- and 10-year cumulative rates of:
      • Tumor enlargement:
        • Defined as a maximal tumor diameter increase of greater than 3 mm:
          • At 4.9% and 8.0%, respectively
      • Lymph node (LN) metastasis rates were:
        • 1.7% and 3.8%
    • Based on these findings, clinicians have used an:
      • Increase of greater than 3 mm in maximal tumor diameter or the presence of new cervical LN metastasis:
        • As a threshold for surgical intervention
      • However, there are limited data on clinical features that can reliably differentiate which PTMC patients will go on to develop clinically significant disease progression:
        • This would allow better risk stratification and tailoring of PTMC management
• Methods:
  • Clin Thyroidol 2021;33:490–492:
    • Is multicenter, retrospective cohort study of patients with PTMCs undergoing active surveillance from three tertiary medical centers in Korea
  • All patients had uni-focal tumors measuring less than 10 mm, cytologically diagnosed as suspicious for malignancy or confirmed malignant
  • Physical exam and ultrasound follow-up were done every 6 to 12 months
  • Fine-needle aspiration and thyroglobulin needle washout:
    • Was performed on new suspicious LNs found during active surveillance
  • Exclusion criteria included:
    • Undergoing surgery instead of active surveillance and a follow-up duration of less than 3 years
  • The primary outcome of the study was disease progression during active surveillance:
    • Which was defined as:
      • An increase in maximal tumor diameter greater than 3 mm
      • Tumor volume (TV) increase of greater than 50%
      • Tumor volume doubling time (TVDT) < 5 years
      • Development of cervical LN metastasis
  • A Cox proportion-al-hazards model was used to evaluate risk factors for disease progression
• Results:
  • The 326 patients included had a median follow-up of 4.9 years (IQR, 3.4–6.3)
  • Disease progression was confirmed in 26 patients (8.0%; 95% CI, 5.0–10.9):
    • 17 of whom (5.2%; 95% CI, 2.7–7.6) had a maximal tumor diameter increase of greater 3 mm after a median of 4.0 years of follow-up
      • Nine of whom (2.8%; 95% CI, 1.0–4.5) developed new LN metastasis after a median of 2.2 years of follow-up:
      • Lateral neck metastasis developed in two of the 9 patients who developed new LN metastasis
      • Seven had central neck LN metastasis
    • All patients with LN metastasis had an increase of tumor diameter greater than 3 mm
    • TV greater 50% was seen in:
      • 94 patients, with 3 (3.2%) developing new LN metastasis
        • The rate of new LN metastasis in TVDT less than 5 years:
          • Was 7.4%
  • Univariate and multi-variate analyses showed that TVDT less than 5 years was:
    • An independent risk factor for LN metastasis:
      • HR, 6.51; 95% CI, 1.73–24.50; P = 0.002
• Conclusions:
  • TVDT less than 5 years:
    • Was an independent risk factor:
      • For PTMC tumor growth and development of new LN metastasis
• Active surveillance for PTMC in appropriately selected patients is a safe and viable treatment method
• The development of cervical LN metastasis:
  • Is an important clinical outcome that:
    • Requires conversion from an active surveillance approach to a surgical one
• In this study Clin Thyroidol 2021;33:490–492:
  • The authors investigate several tumor kinetic parameters as markers to predict disease progression in PTMC
  • The authors concluded that TVDT less than 5 years:
    • May be a useful predictor for identifying patients who may be at risk for developing clinically significant disease progression
  • However, the application of these results in practice may require a better understanding of estimates of prediction
  • Using the study’s data about the association between TVDT and LN metastasis:
    • We can calculate that the accuracy of TVDT less than 5 years to predict LN metastasis:
      • Is low – sensitivity 56% / specificity 80%:
        • Which corresponds to a positive predictive value of 8%:
          • Of 100 patients followed with active surveillance for PTMC who experience TVDT < 5 years, only 8 will have LN metastasis
      • In practice, this means that for most patients who experience TVDT < 5 years:
        • The probability of finding LN metastasis is still low
  • Nevertheless, this information about the association of tumor kinetics with disease progression could help:
    • Recalibrate expectations, follow-up times, and informed decision-making with patients:
      • For instance, a patient considered ideal for active surveillance may be considered not ideal or appropriate if TVDT < 5 years occurs during the initial years of follow-up
  • This and other studies highlight the need for future research on the role of tumor kinetic parameters in active surveillance risk stratification
• References:
  • Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumber M, 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 26:1–131.
  • Jin M, Kim HI, Ha J, Min JJ, Kim WG, Lim DJ, Kim TY, Chung JH, Shong YK, Kim TH, Kim WB 2021 Tumor volume doubling time in active surveillance of papillary thyroid microcarcinoma: A multicenter cohort study in Korea. Thyroid. Epub 2021 Aug 3.
  • Ito Y, Uruno T, Nakano L, Takamura Y, Miya A, Kobayashi K, Yokozawa T, Matsukuza F, Kuma S, Kuma K, Miyauchi A 2003 An observation trial without surgical treatment in patients with papillary microcarcinoma of the thyroid. Thyroid 13:381–387.
  • Tuttle RM, Fagin JA, Minkowitz G, Wong RJ, Roman B, Patel S, Untch B, Ganly I, Shaha AR, Shah JP, et al. 2017 Natural history and tumor volume kinetics of papillary thyroid cancers during active surveillance. JAMA Otolaryngol Head Neck Surg 143:1015–1020.
  • Brito JP, Ito Y, Miyauchi A, Tuttle RM 2016 A clinical framework to facilitate risk stratification when considering an active surveillance alternative to immediate biopsy and surgery in papillary microcarcinoma. Thyroid 26:144–149.

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