What Are the Clinicopathological Correlates of Oncocytic Thyroid Carcinomas?

• Oncocytic follicular cell–derived thyroid carcinomas as a group can include many different entities:
  • Oncocytic papillary thyroid carcinomas (PTC)
  • Oncocytic encapsulated follicular subtype of PTC
  • Oncocytic poorly differentiated carcinoma
  • Oncocytic medullary thyroid carcinoma
• The term “oncocytic carcinoma of the thyroid”:
  • Is used in the new World Health Organization (WHO) to refer to:
    • Invasive malignant follicular cell neoplasms:
      • Composed of at least 75% oncocytic cells:
        • In which the nuclear features of PTC and high-grade features are absent
  • This term replaces Hürthle cell carcinoma:
    • A misnomer given that Hürthle actually described parafollicular C cells
  • Oncocytic cells:
    • Have abundant granular eosinophilic cytoplasm:
      • Secondary to a marked accumulation of dysfunctional mitochondria
  • Oncocytic carcinoma of the thyroid (OCA):
    • Represents the malignant counterpart of oncocytic adenoma
    • Accounts for approaching 2% to 5% of differentiated thyroid carcinomas in the USA
    • Can occur anywhere in the thyroid
    • Usually presents as a slowly enlarging painless solitary thyroid nodule
    • Thyroid ultrasound cannot distinguish between oncocytic adenoma and OCA:
      • Though larger tumors have a higher rate of malignancy
    • There are no known risk factors for developing OCA
    • The mean age at diagnosis is approaching 60 years:
      • Which is roughly 10 years later than the mean age of diagnosis for patient with follicular thyroid carcinoma
    • OCA, although more common in women (with a 1.6 to 1 female-to-male ratio):
      • Has a lower female-to-male ratio than is seen with follicular thyroid carcinoma
    • Histologically:
      • OCAs are encapsulated tumors with capsular and / or vascular invasion and at least 75% oncocytic cells (Figures)
    • OCAs are subclassified into:
      • Minimally invasive:
        • Those with capsular invasion only
      • Encapsulated angioinvasive
      • Widely invasive:
        • Those with gross invasion through the gland
    • When evaluating OCA, it is important not only to document extent of invasion, but also to evaluate for progression to oncocytic poorly differentiated thyroid carcinoma:
      • Thus, all tumors should be assessed for increased mitotic activity (3 or more mitoses per 10 high-power fields / ~ 2 mm2) and tumor necrosis
    • OCA can metastasize to lymph nodes:
      • However, some authors have shown that most of the so-called lymph nodes metastasis of OCA represent tumor plugs in veins in the neck and not lymph nodes involved by tumor
      • The important clue is the almost perfect roundness of these tumor plugs compared to oval or somewhat irregular outline for nodal metastases
    • OCA (like follicular thyroid carcinoma) usually spreads to distant sites via blood vessels:
      • Distant metastasis at presentation are seen in 15% to 27% of patients with OCA:
        • In up to 40% of tumors with extensive vascular invasion
  • Prognostic parameters for OCA include:
    • Patient age, tumor size, vascular invasion, extrathyroidal extension, and the presence of distant metastases:
    • Distant metastases at diagnosis are the most important prognostic factor for OCA
  • For OCA, the 5-year overall survival has been reported to be 85%:
    • But only 24% among patients with distant metastases at diagnosis compared to 91% for patients with M0 disease at diagnosis
  • Although it is not clear that OCA is more aggressive than follicular thyroid carcinoma after adjusting for variables such as patient age, gender, and tumor stage:
    • Due to decreased efficacy of radioactive iodine with OCA compared to follicular thyroid carcinoma:
      • Treating OCA is currently more difficult once there is disease recurrence
  • Benign and malignant oncocytic thyroid tumors:
    • Have both been shown to harbor homoplasmic or highly heteroplasmic (> 70%) mitochondrial DNA mutations in complex I subunit genes of the electron transport chain
    • Additionally, OCAs demonstrate widespread chromosome losses that result in near-genome-wide haploidization with or without subsequent genome endoreduplication:
      • Chromosomal changes have been found to be associated with extent of invasion:
        • Most OCAs with capsular invasion only or focal vascular invasion have been shown to be diploid
        • Whereas tumors with extensive vascular invasion and widely invasive tumors:
          • Are usually polysomic and nearly always demonstrate chromosome 7 amplification
          • Additionally, the near-haploid state has been shown to be maintained in metastases, implying selection during tumor evolution
        • OCAs have also been shown to have recurrent DNA mutations, including RAS mutations (though at a lower rate than is seen with follicular thyroid carcinoma), EIF1AX, TERT, TP53, NF1, and CDKN1A, among others

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