12 chapter 1 Introduction Incidence and risk of malignancy of thyroid nodules The growing use of progressively sensitive imaging techniques has resulted in an increased detection of thyroid nodules. Whereas the prevalence of palpable thyroid nodules is merely 1% in males and 5% in females in iodine-sufficient countries, the lifetime prevalence of thyroid nodules detected during ultrasound examination or on autopsy studies ranges between 34% to 66%. Less than 10% of these nodules are malignant; most are benign, asymptomatic, and do not require treatment [1-5]. Yet, the increased detection of thyroid nodules has resulted in a rise in thyroid surgeries and higher incidence of differentiated thyroid carcinoma [6-10]. In the United States, a tripling of the incidence of thyroid carcinoma was observed from 4.5 to 14.4 per 100.000 between 1974 and 2013 [11]. In the Netherlands, the incidence of thyroid carcinoma more than doubled from 1.65 to 3.34 per 100.000 (Revised European Standardized Rate) in males and from 3.51 to 6.73 per 100.00 in females between 1990 and 2022 [9]. The clinical relevance of this raised thyroid cancer incidence is questionable, as these were oftentimes indolent papillary thyroid microcarcinoma (i.e., subclinical disease) [5-7, 10-12]. Moreover, despite the increased diagnosis and treatment, the mortality rates for papillary thyroid carcinoma have not decreased [10-12]. These epidemiological observations feed ongoing discussions about the overdiagnosis and overtreatment of thyroid nodules and endorse the need for cost-effective, risk-adapted and de-escalating management strategies [7, 12-15]. The Bethesda System for Reporting Thyroid Cytopathology To aid the concise and unambiguous reporting of thyroid cytology using uniform terminology, the Bethesda System for Reporting Thyroid Cytopathology was developed and first published in 2009 [16]. Since then, the Bethesda System has been updated several times to meet recent developments in thyroid pathology, including the latest guidelines for the management of thyroid nodules, the latest WHO classification of endocrine tumours, the reclassification of the ‘malignant’ encapsulated follicular variant of papillary thyroid carcinoma to the benign diagnosis of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), and corrected estimates of the risk of malignancy per diagnostic category following the standardized introduction of the Bethesda System [17-24]. The most recent update of the Bethesda System was published in 2023 [23]. The Bethesda System incorporates six diagnostic categories with an increasing risk of malignancy (Table 1). In most literature as well as in the current thesis, Bethesda categories III (atypia of undetermined significance) and IV (follicular neoplasm) are defined as indeterminate cytology. These categories consist of follicular-patterned lesions that are difficult to diagnose on fine needle
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