Lingering Questions about Active Surveillance for Papillary Thyroid Microcarcinomas

• Clin Thyroidol 2021;33:128–130.
• Background
  • Autopsy studies have shown that up to one third of adults who die of other causes:
    • Have latent or unsuspected papillary thyroid microcarcinomas (PTMC):
      • That is, papillary thyroid cancers (PTCs) of sizes ≤ 1 cm and frequently quite minute
  • For PTMCs detected during life (by ultrasound and / or fine-needle aspiration [FNA]):
    • The 2015 American Thyroid Association guidelines for the management of thyroid nodules and cancer recommend:
      • Thyroid lobectomy as a definitive treatment:
        • Provided there is no evidence of extrathyroidal extension (ETE), lymph node (LN) or distant metastases, or history of high risk
  • However, the guidelines also support the non‐ surgical alternative of active surveillance (AS) in such settings
  • Unease with AS arises from the fact that a small minority of PTMCs are associated with advanced features such as:
    • LN or distant metastases, lymphovascular invasion (LVI), or ETE:
      • Features that may be difficult to detect prior to surgical extirpation and histopathologic evaluation
  • The aim of this study was to investigate the incidence of and interrelation between such advanced pathologic features in a large database of PTMC cases, which make up about 30% of all diagnosed PTCs
• Methods
  • This retrospective cohort study used the National Cancer Database (NCDB; 2010 to 2014) and analyzed adult patients with a primary diagnosis of PTMC who had undergone thyroid surgery
  • Independent factors assessed were age, gender, race, Deyo–Charlson comorbidity score, type of thyroidectomy, LN dissection (or not), radioactive iodine therapy (or not), and hospital PTMC volume
  • The association between each of these independent factors and the risk of advanced pathologic features was tested, and a multivariable logistic-regression model incorporated the factors that showed a significant association
  • Further, the association of each factor with overall survival was assessed using log-rank and Kaplan–Meier tests.
• Results
  • The study cohort consisted of 30,180 patients, of whom 5628 (18.65%) had at least one advanced pathologic feature (LN metastasis, ETE, LVI, or distant metastasis)
  • The median follow-up was 38.93 months
  • The 5-year overall survival (OS) was 98.45%, which was similar to the OS of patients without advanced pathologic features (98.40%)
  • Most patients (82%) had no comorbidities
  • The majority of patients (82.64%) underwent total thyroidectomy, half (52.22%) underwent concomitant neck dissection, and a quarter (25.42%) received adjuvant radioactive iodine therapy.
  • Patients with advanced pathologic features:
    • Were more likely to be young (less than 55 years old)
    • Male
    • White
    • Treated in high-PTMC-volume hospitals (P<0.05 or stronger)
  • With regard to the association of pathologic features with OS:
    • Both central and lateral LN metastases, as well as gross ETE and distant metastases:
      • Were associated with decreased OS,
      • Whereas microscopic ETE and LVI were not
  • The presence of central or lateral LN metastasis or gross ETE:
    • Was also associated with distant metastasis
• Conclusions
  • Since AS does not yield the opportunity for histopathologic evaluation of PTMC and related LNs:
    • Advanced pathologic features may go undetected and untreated in some patients (18.65% of patients in this cohort)
  • The authors propose that for PTMC, thyroid lobectomy offers both therapeutic and diag‐ nostic advantages for such patients and likely results in improved survival
• Large cancers grow from smaller ones, and even knowing that one has a small (or “micro”) cancer is different from having a microscopic cancer found in one’s thyroid after death
• The current study recommends diagnostic and therapeutic thyroid lobectomy for seemingly isolated PTMCs:
  • Owing to the limited ability to detect features, through clinical and radiographic examination, that have been associated with worse prognosis
• Even more limited is the ability to predict future behavior of small cancers:
  • Are they truly indolent tumors?
  • Or are they potentially aggressive cancers that were just caught early?
  • In this NCDB cohort of over 30,000 patients with PTMC who underwent surgery:
    • So-called advanced features were identified in 18.65% of patients:
      • 8% had central LN metastases
      • 4% had lateral LN metastases
      • 6.7% had ETE
      • 4% had LVI
      • 0.4% had distant metastases
  • Yet the high (98.5%) 5-year survival rate was the same for patients with no versus those with any advanced pathologic features (although median follow-up in this study was just over 3 years)
  • The NCDB does not provide data on recurrence (or persistence) rate
• Preoperative findings that led to surgery for these patients is unknown, but these findings likely contributed to selection bias
• The time frame of the study (2010 to 2014) overlapped with the 7th edition of the AJCC staging system and 2009 ATA guidelines for the management of thyroid nodules and cancer, which promoted total thyroidectomy (rather than lobectomy) and suggested prophylactic central neck dissection for patients with PTC
• Newer (2015) ATA guidelines and the 2017 8th edition AJCC staging system have helped to deescalate therapy through evidence-based deemphasis of certain features as “aggressive”
• Time will tell how much further we have to go to achieve deescalation and deferred intervention (AS) or whether the pendulum will swing back, as suggested here
• We remain hampered by the lack of biologic predictors, such as genetic markers, that portend bad behavior, independent of tumor size at the time of detection
• This limitation is further aggravated by operator dependence and variable quality of neck ultrasonography
• Perhaps the most impactful observation was that younger patients were more likely to harbor advanced pathologic features:
  • A finding that parallels the observation that under AS, PTMC is most likely to progress in younger patients
• One caveat is that while refraining from FNA biopsy of suspicious but subcentimeter thyroid nodules:
  • Remember that a small percentage of such nodules may harbor medullary, rather than papillary carcinoma
  • A serum calcitonin test in such patients might go far in detecting and preventing progression of a truly more aggressive cancer
  • The current ATA guidelines for the management of medullary thyroid cancers advise that routine measurement of serum calcitonin concentrations for patients with thyroid nodules should be decided on an individual basis

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