430 chapter 9 Dear Sir, According to Virgil’s ancient myth, the legendary lyrist Orpheus of Thrace decided to descend to the Underworld to see his wife Euridice after a snake bite had caused her untimely death. Singing his grief with his lyre, he convinced Hades and Persephone to ascend into the world of the living together with Euridice. The sole condition was that she would follow him without him looking back as they walked. Unable to hear her footsteps, Orpheus feared the Gods had fooled him. At the verge of the underworld´s exit, just before bright daylight would have embodied Euridice’s shade, Orpheus lost faith and turned around, only to see Euridice vanish, now eternally trapped in Hades' reign. Thyroid nodules are increasingly diagnosed, mainly due to the increased use of medical imaging. To rule out malignancy, cytologic analysis of fine-needle aspiration biopsy (FNAB) material is the primary modality for initial evaluation [17]. In 2007, the National Cancer Institute convened a conference to define consistent thyroid cytology terminology, including the risk of malignancy (RoM). This resulted in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC), which has since been widely adopted [18]. More recently, nodules diagnosed as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and follicular tumour of uncertain malignant potential (FTUMP) were defined as benign yet potentially premalignant lesions, for which surgery is considered justified. Additionally, ultrasound-based risk-stratification systems such as Thyroid Imaging Reporting and Data System (TI-RADS) are finding their way into the clinic, aiding to the decision which nodules need to be biopsied and guiding the location of the sampling [17]. TBSRTC stratifies FNAB-samples to five categories of increasing RoM, after excluding nondiagnostic or unsatisfactory FNAB (Bethesda I, RoM 5-10%) which require a repeat US-guided biopsy. At the lower end of the spectrum, benign lesions (Bethesda II, RoM 0-3%), require only clinical and sonographic follow-up. At the higher end, lesions suspicious for malignancy (Bethesda V, RoM 5075%) or malignant (Bethesda VI, RoM 97-99%), require near-total thyroidectomy or lobectomy. For the intermediate, rather heterogeneous group of nodules with indeterminate cytology, the TBSRTC does not provide clear answers. This includes cytology with atypia or follicular lesion, both of undetermined significance (Bethesda III, RoM 10-30%), and cytology (suspicious for a) follicular or Hürthle cell neoplasm (Bethesda IV, RoM 25-40%). Bethesda III and IV nodules require repeat FNAB (Bethesda III only), molecular diagnostics and/or diagnostic lobectomy [18]. In a recent large series, the nodules that were selected for biopsy by TI-RADS showed an indeterminate outcome in 14%, in unselected nodules even 20% [650]. Thus, thyroid nodules with indeterminate cytology are posing a frequent and difficult dilemma for clinical decision making. Different pre-operative approaches including ex vivo analysis of cytology and in vivo clinical imaging have been investigated to further stratify these nodules and to prevent
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