267 Non-invasive imaging biomarkers 3 Introduction After stratification by ultrasonography (US), the next step in analysis of a thyroid nodule in a nonhyperthyroid patient is by obtaining cytology. Usually this is performed by fine-needle aspiration cytology (FNAC) as this procedure is simple, safe, inexpensive and has a high accuracy. The FNAC specimens are categorised into six diagnostic categories according to the Bethesda System for the Reporting of Thyroid Cytology (See Chapter 1, Table 1) [18]. Around 20% of thyroid nodules are cytologically indeterminate, including both atypia of undetermined significance or follicular nodules of undetermined significance (Bethesda III, AUS/FLUS) with a malignancy rate of 6-18% and cytology suspicious for a follicular neoplasm (Bethesda IV, FN/SFN) or Hürthle cell neoplasm (Bethesda IV, HCN/SHCN) together having a malignancy rate of 10-40% [18, 49]. Nodules that are suspicious for malignancy upon FNAC (Bethesda V, SUSP) encounter a malignancy rate of 45-60% and can also be considered cytologically indeterminate [18]. Indeterminate thyroid cytology corresponds to histopathological follicular adenoma (FA), Hürthle cell adenoma (HCA), non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), (encapsulated) follicular variant of papillary thyroid carcinoma ((E)FVPTC), follicular thyroid carcinoma (FTC), and Hürthle cell carcinoma (HCC), but can also be seen in papillary thyroid carcinoma (PTC). Unlike histology, cytology does not provide insight into tissue structure: it does not show the capsular and/or vascular invasion that distinguishes an FTC from a benign FA. In FVPTC, the growth pattern is follicular and clearly identifying nuclear features of PTC can usually not be distinguished cytologically. As an alternative to FNAC, the use of core needle histological biopsy has recently received increased interest [360]. Although lower nondiagnostic (Bethesda I) or indeterminate rates are published, core needle histological biopsy requires more advanced training for radiologists and histopathologists. Furthermore, this procedure is more painful for patients and has more complications including haematomas and voice changes, and therefore it has not been well-adopted. The American Thyroid Association (ATA) specified recommendations for the clinical management of the different cytological categories [17]. Repeat FNAC for a Bethesda III nodule may oftentimes result in a Bethesda II result. For nodules that remain Bethesda III after repeat FNAC, or those with Bethesda IV or V cytology, diagnostic hemithyroidectomy is often performed [17]. As the joint malignancy rate in indeterminate nodules is approximately 25%, approximately 75% of these diagnostic surgeries result in a benign histopathological diagnosis. For these benign nodules, the diagnostic surgery can be considered unbeneficial from an oncological perspective, increasing health care consumption expenses and exposing patients to unnecessary surgical risks. In case of malignant histopathology, a completion thyroidectomy might be indicated, putting the patient at a higher risk of two-stage
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