Thyroid cytopathology: how far can we go?
In our journal, Cytopathology, it is rather unusual to publish almost an entire issue devoted to a specific topic. Nevertheless, in this June issue, with its six articles on thyroid fine needle aspiration (FNA), it is very much the case. Thyroid FNAs are widely recommended by the national health ministries in most European and non-European developed countries, as well as in the USA, because of the high estimated prevalence of thyroid nodules worldwide, ranging from 20% to 76%,1 correlated with the high diagnostic accuracy of thyroid cytology: sensitivity ranging from 65% to 98%, usually more than 90%; specificity ranging from 58% to 100%.2,3 Therefore, many teams of endocrinologists, radiologists, internists and cytopathologists have developed this test and wish to publish their results, which explains the large number of articles on thyroid cytology. Thyroid FNA cannot be considered as a recent technique, as it was first implemented in the 1950s.4 Although numbers of thyroid FNAs remained low for many years, during the last two decades the numbers have increased strongly in parallel with the development of preventative medicine and events such as Chernobyl. The diagnosis has historically been exclusively based on morphology, which remains pivotal to this technique, offering, as mentioned above, a quite satisfactory diagnostic global accuracy. As thyroid cancers, mostly papillary carcinoma, represent 5–12% of thyroid nodules,5 which are, in the great majority, benign, thyroid FNA may, to some extent, be considered as a screening test aiming to detect malignant cases and to avoid surgery for most of the benign nodules. Regardless of the skill of those who perform FNA in providing representative samples, and the expertise of the cytopathologists, 20–25% of nodules remain ‘unclassified’, neither benign nor malignant, and represent a group of so-called ‘indeterminate’ nodules for which partial or total thyroidectomies, or repeat FNAs, are required so that malignant cases do not go undetected. This unsatisfactory situation has not been solved and, although poor samples are responsible for many cases with indeterminate or suspicious diagnoses, three recent major changes have taken place. The first is represented by a standardized terminology; the other two by immunocytochemistry © 2014 John Wiley & Sons Ltd Cytopathology 2014, 25, 143–145
(ICC) and molecular testing, both often linked to liquid-based cytology (LBC) or cell block techniques. The six articles published in this issue illustrate these new techniques.6–11 Considering that standardized cytology terminology could lead the way to better diagnosis, this long remained as something unusual and thus rather ignored in practice; perhaps the Papanicolaou classification for cervical smears, followed by the Bethesda terminology in 1991, were the first examples.12 The Bethesda system for reporting thyroid cytopathology (TBSRTC) was published in 2009–2010.5 There are some others: the Societ a Italiana di Anatomia Patologica e Citologia Diagnostica (SIAPEC) classification, here represented by the study of Pagni et al.,7 and the UK terminology used by Poller and Glaysher9 and Johnson et al.10 TBSRTC was debated and then recommended during the European Congress of Cytology in Lisbon in 2009,13 and has been adopted by many European countries, including Croatia, Finland, France, Greece, Portugal and Turkey. These three terminologies are widely applied in the world and are all applicable: the Italian and UK classifications are five tiered, with subdivisions of their respective indeterminate categories, and TBSRTC is six tiered; all recognize benign, malignant, non-diagnostic categories, and some other categories named differently, representing the ‘indeterminate’ cases, and are more or less transposable. TBSRTC is the only classification with a published atlas, which includes explanations for the choice of a six-tier terminology, definitions for each category, many cytological images and an estimated percentage and risk of malignancy for each category. TBSRTC does not resolve the ‘borderline diagnoses’, but offers tools to help gain an acceptable interobserver reproducibility and therefore a more homogeneous management for patients. As TBSRTC is, for the first time, suitable for the comparison of observations obtained by different teams in the world,8,14–18 two major results have arisen: (1) in the most recent studies, the percentage and risk of malignancy for each category confirm those proposed by the TBSRTC, as well as its reproducibility; (2) in cases of discrepancy, a cause may be determined. For example, discrepancies may be caused by an epidemiological context, as reported
by Mastorakis et al.,14 where the percentage of malignant thyroid nodules was much higher in Crete than in Athens (26.8% versus 12.2%), or, as reported by Yazgan et al.6 and Rossi et al.,19 where there was respectively a higher and lower risk of malignancy in H€ urthle cell lesions; or, in some instances, there may be interobserver variability in histological diagnosis, especially in follicular-patterned nodules, raising a question about the nature of follicular variant of papillary carcinoma, follicular carcinoma, follicular adenoma and well-differentiated tumour of uncertain malignant potential) (WDT-UMP). The lack, or very low numbers, of follicular carcinomas with surgical outcomes in some studies makes it necessary to have harmonized histological criteria for these types of lesions. Ancillary techniques represent not the next but the current step in thyroid FNAs. Lacoste-Collin et al.,11 using ICC for three antibodies [cytokeratin 19 (CK19), HBME-1 and Ki-67], increased the overall diagnostic accuracy of FNA to 91% in the follicular neoplasm/suspicious for follicular neoplasm (FN/ SFN) category of TBSRTC. This study supports previous studies, especially two recent ones applying a panel of CK19 and HBME-120 or HBME-1 and galactin-3.21 For both studies, negative ICC almost always predicted a benign nodule in the indeterminate categories. Therefore, as long as these findings are supported by follow-up studies, this technique could truly help to reduce the number of unnecessary surgical interventions. Furthermore, the use of antibodies such as calcitonin, thyroid transcription factor-1 (TTF-1), thyroglobulin and b-catenin, can also be very helpful in resolving some difficult diagnoses of medullary or anaplastic carcinoma versus metastases, or to give a prognostic assessment in poorly differentiated or anaplastic carcinoma. However, it is essential to keep in mind that ICC must be performed following previously tested and/ or validated techniques, including appropriate positive and negative controls. Molecular cytopathology is also a current step for thyroid FNA: BRAF V600 mutation is characteristic of papillary carcinoma and is found in about 45– 75% of these tumours, more often in the classical and tall cell than in the follicular variant. The specificity of this mutation is very high, but its sensitivity is lower. Several articles have been published recently reporting BRAF V600 positivity in indeterminate categories. The close correlation of this positive test with the final histological diagnosis
of papillary carcinoma is encouraging. Johnson et al.10 and Poller and Glaysher9 both conclude that this test is very helpful for indeterminate nodules, especially for the ‘suspicious of malignancy’ category, potentially allowing a total thyroidectomy and avoiding two-step surgery with a partial thyroidectomy and later surgical completion. In the literature, these techniques may be applied to LBC as well as conventional cytology slides, as a small quantity of DNA is sufficient. Currently, a BRAF mutation-specific antibody (clone VE1) has been developed and can be used with a classical ICC technique. Two articles have been published using this antibody on thyroid FNA with satisfactory results.22,23 Finally, other mutations may be found in papillary carcinoma as well as in follicular or medullary carcinoma, e.g. RAS, RET or PAX8/PPAR gamma mutations.24 Some molecular tests including several mutations are now commercially available and may be applied to cytological material if a precise procedure is followed.24,25 However, even if the detection of a BRAF mutation makes the diagnosis of papillary carcinoma quite certain, and other tests are markers for malignancy, many carcinomas remain negative. Therefore, considering the tests available now, if it were necessary to choose between ICC and molecular testing (the limitation being the quantity of cells), then, from my point of view, ICC would seem to be more relevant. Nevertheless, the association of these two techniques could widely enhance thyroid FNA sensitivity and specificity, and the BRAF antibody represents true progress. We must not forget that the most important point is to demonstrate that molecular cytology is feasible and realistic for thyroid cytology; it will find its place as soon as a targeted therapy or new markers become available. B. Cochand-Priollet Department of Pathology, Cochin Hospital, Paris, France E-mail: [email protected]
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© 2014 John Wiley & Sons Ltd Cytopathology 2014, 25, 143–145
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© 2014 John Wiley & Sons Ltd Cytopathology 2014, 25, 143–145
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