70 chapter 2 Recent discussions in thyroid histopathology Histopathology is classically based on microscopic assessment of tumour phenotype, aided by immunohistochemistry. However, this ‘gold standard test’ is also subject to advancing insights regarding tumour phenotype, increasingly aided by knowledge regarding tumour genotype. Mutation-negative malignancies resulting from indeterminate cytology were frequently identified as encapsulated follicular variants of papillary thyroid carcinoma without histologic features of aggressive behaviour [60, 61, 69, 97, 118]. Also, several studies defined a separate intermediate histopathological category called ‘(follicular) tumour of uncertain malignant potential’ for encapsulated, well-differentiated follicular tumours with questionable PTC-type nuclear changes [109, 202, 215, 309]. These examples illustrate one of the important ongoing discussions in thyroid histopathology. In 2016, Nikiforov et al. proposed an official downscaling of the classification of proven noninvasive encapsulated FVPTCs, renaming them ‘noninvasive follicular neoplasm with papillary-like nuclear features’ (NIFTP). The behaviour of these neoplasms is benign unlike other thyroid carcinoma subtypes, showing no evidence of recurrent disease after a median 13-year followup. About one in four of the neoplasms in the retrospective cohort were mutated, most frequently carrying RAS (NRAS) or PAX8/PPARγ alterations. Presence of a mutation likely predisposes the NIFTP to progress into an invasive encapsulated FVPTC, justifying surgical resection. Treatment of NIFTP should most likely be limited to hemithyroidectomy, waiving totalizing thyroidectomy and radioiodine ablation [24]. Although revolutionizing, this new nomenclature complicates mutationbased preoperative decision-making [60, 69, 118]. The justification to skip two-stage surgery and perform a total thyroidectomy at once for mutation-positive nodules is the driving force of the 7-gene mutation panel and similar tests, but would be overkill for the subgroup of NIFTP [69]. Nonetheless, most of the undesirable possible overtreatment for NIFTP is likely resolved if RASmutated indeterminate nodules are treated with hemi- instead of total thyroidectomy, as previously suggested. No comprehensive diagnostic test is currently available to diagnose mutation-positive NIFTP preoperatively, as follicular tumour invasiveness and encapsulation cannot be distinguished on cytology. Hürthle cell cytology The Achilles heel of many diagnostics investigated in this review is cytology suspicious for a Hürthle cell neoplasm (Bethesda IV SHCN/HCN). Hürthle cells are oxyphilic cells with abundant cytoplasm and an enlarged nucleus with a prominent nucleolus. They are found in benign thyroid diseases such as Hashimoto’s thyroiditis, but also occur in the notorious Hürthle cell adenoma and carcinoma, the oncocytic variant of follicular adenoma and carcinoma [44, 223]. Although Hürthle cell carcinomas (FTC-OV) are rare, their aberrant clinical course and association with invasive
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