What Do Hürthle Cells Mean in Thyroid Nodule Aspirates?

• Clin Thyroidol 2021;33:83–86.
• Background
  • Hürthle cells (also called “oncocytes”):
    • Are follicular thyroid cells with increased mitochondrial content:
      • Characterized by:
        • Polygonal shape
        • Abundant granular eosinophilic cytoplasm
        • Prominent nucleoli
  • Hürthle cell change:
    • Is thought to represent metaplastic change:
      • In response to cellular stress and microenvironmental factors
  • Hürthle cells are found in both benign and malignant thyroid conditions, yet they can present diagnostic challenges and confusion for both cytopathologists and clinicians
  • Cytopathologists have attempted to use the proportion of Hürthle cells, if any are found, to help classify the malignancy risk in fine-needle aspiration (FNA) samples:
    • A Hürthle-cell neoplasm is a subtype of follicular neoplasm in which the FNA consists exclusively or nearly exclusively of Hürthle cells; if surgery is performed, this difference may correspond to either a:
      • Benign Hürthle-cell adenoma or a malignant Hürthle-cell carcinoma
  • But what about all other thyroid FNAs containing fewer Hürthle cells?
    • The current study aimed to determine the risk of malignancy (ROM) across all Bethesda categories in FNAs containing Hürthle cells, subclassified according to degree of Hürthle-cell change (mild, moderate, or predominant)
    • Ultimately, this information could help inform clinicians about how to interpret cytology reports that show the presence of Hürthle cells
• Methods
  • This retrospective analysis studied all thyroid nodules that had undergone FNA with cytology reports that included:
    • The words Hürthle cell or oncocytes
    • Used the Bethesda System for Reporting Thyroid Cytopathology (BSRTC or “Bethesda,” or analogous/ Bethesda-inferred) categorization
    • Had undergone surgical resection at the Massachusetts General Hospital between 2000 and 2013
• Results
  • The proportion of the 300 study FNA samples in each Bethesda category (I to VI) were:
    • 4.7, 37.7, 11, 41.6, 4, and 1%, respectively
  • Of the subset of 203 samples stratified according to Hürthle-cell content:
    • 29% had mild
    • 6% moderate
    • 65% predominant Hürthle cells
  • The ROM for each Bethesda category (I to VI) based on final histopathologic diagnosis was:
    • 7%, 7%, 15%, 21%, 50%, and 100%
  • The ROM for each Hürthle-cell category based on final histopathologic diagnosis was:
    • Mild – 3%
    • Moderate – 15%
    • Predominant – 21.4%.
  • The ROM in the study cohort was calculated for the combination of Bethesda score and Hürthle-cell category and compared to the multiinstitutional control group (that was not stratified by Hürthle-cell content)
  • The ROM for the study group was found to be equal or lower for each Bethesda category, except for one:
    • Hürthle cell-predominant, Bethesda II (benign) FNAs:
      • Which had a higher rate of malignancy (27.3%) than the Bethesda II control group:
        • 9.3%, not stratified for Hürthle-cell content
  • From the entire study cohort of nodules, 16% were malignant on surgical pathology, but only half of these were Hürthle-cell carcinomas; the second half were other cancers (mostly papillary, but also follicular and medullary carcinomas)
• Conclusions
  • In this study, the presence of Hürthle cells did not generally increase the ROM for any given Bethesda category:
    • The one exception of increased ROM was the finding of Hürthle-cell predominance (>75%) from Bethesda II (benign) FNAs
• If cytopathologists find the interpretation of Hürthle cells within thyroid FNA samples to be challenging, no wonder clinicians are even more confounded:
  • The alias oncocyte (which conjures oncology) doesn’t help
• The connotation of poor prognosis of malignant Hürthle cell carcinomas is at least partly attribut- able to their lower avidity for radioactive iodine compared to other differentiated thyroid cancers
• Although Hürthle-cell carcinomas represent only 3% to 5% of all thyroid malignancies:
  • Hürthle cells are found in both nonneoplastic conditions (Hashimoto’s thyroiditis being the most common) and neoplasms (which include benign and malignant follicular and Hürthle-cell tumors and even papillary and medullary carcinomas)
• The current study aims to determine how Hürthle-cell presence in FNA samples relates to both Bethesda classification and the risk of malignancy
• The study began with FNA samples whose reports mentioned Hürthle cells:
  • So the ROM rates are understandably different from those predicted by the 2017 Bethesda system (both excluding and including noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP] as “malignant”) as well as from the multicenter control group, neither of which selected FNAs for Hürthle cells
  • The study further integrated Hürthle-cell content (mild, moderate, or predominant) with Bethesda classification, to reveal even more stratified ROM rates
  • The net results were that Hürthle cells did not increase ROM beyond that of the underlying Bethesda category, except in one group: Bethesda II with predominance of Hürthle cells
• This study and its extrapolation have limitations:
  • There is no mention of whether the cytopathologist was blinded to final results, nor that the study institution (and perhaps even some of the same samples) were part of the multiinstitutional control cohort
  • The diagnosis and reporting of Hürthle cells is variable among cytopathologists, and Hürthle cells may especially be underreported in otherwis unequivocally benign FNAs
  • On the other hand, only highly experienced cytopathologists would likely label Hürthle-cell–predominant (>75%) FNAs as benign (Bethesda II) as was the case in 11 patients in this cohort, three of whom proved to have malignant tumors according to surgical pathology (for a rate of 27.3%)
  • The study time frame largely preceded the development of the Bethesda system (2009) its revision (2017), although the authors describe their reporting system as “analogous” to the BSRTC prior to 2009
  • Yet they excluded 77 cases that lacked Bethesda assignments, though these cases are relevant
  • Surgical pathology specimens were not reviewed, so some may have been called “malignant” that would now be called “NIFTP” or “nonmalignant
  • The cohort was biased toward patients selected for surgery, and there may have been worrisome clinical or sonographic features that contributed to the decision to operate
  • Finally, although there were “Hürthle-cell–predominant” samples across all Bethesda categories, the majority were in the Bethesda IV group, and the majority of these (81.3%) were benign according to surgical pathology
  • If the Hürthle-cell–predominant benign (Bethesda II) FNAs had been called “Bethesda IV follicular” (Hürthle cell) neoplasms / suspicious for follicular neoplasms, as would likely occur in the community at large, the overall ROM calculations would have been altered but thus more similar to those of the Bethesda system alone
• In summary, the presence and proportion of Hürthle cells in FNA samples does not help the clinician interpret ROM beyond that predicted by the Bethesda system itself
• The mere mention of Hürthle cells does not increase malignancy risk from that predicted by Bethesda category
• The quest for understanding the significance of Hürthle cells continues

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