Risk of Clinically Significant Thyroid Cancer Is Low During Long-Term Population-Based Follow-up of Thyroid Nodules

• Background
  • Fine-needle aspiration (FNA) using the recently revised Bethesda System for Reporting Thyroid Cytopathology accurately discriminates benign from malignant thyroid nodules:
    • However, the risk of malignancy in each Bethesda category has been studied using inconsistent methods, and most studies focus on nodules with corresponding surgical histology, which introduces selection bias
  • The present study sought to determine the real-world risk of malignancy in each Bethesda category using data from a large retrospective cohort of thyroid nodules with a mixture of surgical and long-term population-based clinical follow-up
• Methods
  • All thyroid FNAs from the University of California, San Francisco (UCSF) Pathology database (collected between January 1, 1997, and December 31, 2004) were reviewed and recoded using the 2017 Bethesda system reporting standard
  • If multiple nodules were biopsied and had different results, the highest-grade Bethesda category was used
  • Corresponding patients were matched to the UCSF cancer registry, along with the California Cancer Registry (CCR; a statewide, population-based registry)
  • Patients who were not detected in either registry were considered to be free of malignancy
  • Exclusion criteria included a prior diagnosis of thyroid cancer, prior thyroid surgery, or development of a cancer in the lobe con- tralateral to the biopsy site
  • The date of the original FNA was the time origin, and the interval time to repeat FNA, surgery, or final follow-up on July 10, 2015 (date of matching to the CCR), was recorded
  • Kaplan–Meier survival curves and Cox proportional hazards models were used to estimate incidence rates of malignancy for each category and the instantaneous risk of malignancy, respectively
• Results
  • A total of 2233 patients with 2758 FNA reports were available:
    • 26 were excluded, for a final count of 2207
  • The median age was 48 years (range, 7 to 92) and 1880 (85.2%) were female
  • Of the 2207 test results:
    • 236 (10.7%) were determined to be nondi- agnostic
    • 1575 (71.4%) benign
    • 57 (2.58%) atypia of undetermined significance (AUS)
    • 78 (3.53%) follicular lesion of undetermined significance (FLUS)
    • 107 (4.85%) follicular neoplasm or Hürthle-cell neoplasm
    • 20 (0.9%) suspicious for malignancy
    • 134 (6.07%) malignant
  • Median follow-up after the initial FNA was 13.9 years (range, 10.5 to 18.4):
    • 279 (12.6%) patients were diagnosed with thyroid malignancy during that period
  • Compared to the benign reference group, hazard ratios were:
    • 2.09 (95% CI, 1.2–3.7) for a nondiagnostic read
    • 8.8 (95% CI, 5.7–13.6) for AUS / FLUS
    • 10.9 (95% CI, 7.0–17.0) for follicular neoplasm
    • 49.1 (95% CI, 27.1–88.9) for suspicious for malignancy
    • 201 (95% CI, 138–293) for a malignant read
  • When AUS and FLUS were split into separate categories:
    • AUS had a higher hazard ratio (13.0; 95% CI, 7.7–22.0)
  • Malignancy rates per 1000 person-years were:
    • 4.82 (95% CI, 3.0–7.9) for a nondiagnostic read
    • 2.42 (95% CI, 1.9–3.2) for a benign read
    • 22.4 (95% CI, 16.0–31.6) for AUS / FLUS
    • 29.1 (95% CI, 20.4–41.3) for follicular neoplasm
    • 183 (95% CI, 108–310) for suspicious for malignancy, and 980 (CI) for a malignant read
  • A total of 52 (3.2%) of 1575 were false-negative results:
    • 29 (1.7%) of which were papillary thyroid microcarcinomas
  • A total of 15 patients died from thyroid cancer:
    • None of them had an initial benign FNA
• Conclusions
  • FNA and the Bethesda System for Reporting Thyroid Cytopathology are highly accurate in detecting thyroid malignancy
  • Long-term combined clinical and histopathologic follow-up reveal a low false-negative rate, low rates of malignancy in nondiagnostic specimens, and extremely low rates of mortality, especially in benign and nondiagnostic categories
• Thyroid nodules are common:
  • 5% to 15% of them are malignant:
    • The majority of which are well-differentiated thyroid cancers with a good prognosis
• The Bethesda system has standardized reporting of thyroid nodule cytopathology:
  • Thereby facilitating efficient and precise communication, research, and articulation of evidence-based management guidelines:
    • However, even the most robust classification systems meet with variable adoption and implementation in the real-world clinical setting, and generalizability depends on validation in diverse popula- tions of patients and care systems
• The present study sought to address two limitations in estimating risk of malignancy in validation studies:
  • Use of surgical histopathology as the gold standard:
    • Which leads to a higher estimated risk of malignancy in lower-risk nodules since they are less likely to undergo surgery
    • Inconsistent statistical handling of “indeterminate” categories:
      • Which have a wide range of preva- lence across institutions
• Strengths of the study include:
  • A long duration of follow-up of a robust number of patients and use of an institutional and comprehensive population-based cancer registry to detect and provide a narrative summary of malignant cases and patient mortality
• Limitations of the study include:
  • Its retrospective, single-institution design (which improves standardization at the cost of generalizability) and the assumption that patients without registry data did not develop malignancy, which misses patients who moved away or did not follow up, thereby underestimating the risk of malignancy
  • It is worth noting that even a median follow-up of 13.9 years is relatively short when dealing with an indolent disease, especially in light of long-term data showing minimal growth of biopsy-proven small papillary thyroid carcinomas
• Given the marked indolence of most thyroid cancers, coupled with a high and rising incidence of small and incidental cancers:
  • Perhaps the most important task for clinicians is to avoid missing patients harboring clinically significant malignancy
• The most notable aspect of this study is:
  • The confirmation that the false-negative rate for benign FNA was low, at 3.2%:
    • More than half of which were innocent papillary microcarcinomas), and that no patients with a false-negative FNA died of thyroid cancer
  • While risk of malignancy of nondiagnostic specimens was roughly double that of benign ones:
    • It was still relatively low, and the long-term outcomes for patients were similar
  • It is not surprising that thyroid cancer– related mortality was low (0.7%) across all categories during the follow-up period
  • Lastly, it was interesting that the AUS category had a higher risk of malignancy than FLUS:
    • When they were separated on the basis of nuclear (AUS) and architectural (FLUS) atypia:
      • While the Bethesda system designates AUS/ FLUS as a single category:
        • The current study corroborates others showing that subcategorization, while controversial, is worthy of discussion
        • Additional studies with large data sets and long-term follow-up are needed
  • Ultimately, while thoughtful management and longitudinal surveillance of patients with thyroid nodules requires integration of cytopathology with clinical and sonographic risk assessment:
    • It is reassuring to see confirmation that most patients with thyroid cancer do well, and that our standard-of- care approach of using FNA and Bethesda system reporting standards is accurate and rarely misses malignancy

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