47 Diagnostic utility of molecular and imaging biomarkers 2 Nuclear protein Ki-67 is expressed in nearly all cell cycle phases in proliferating cells. It is associated with poor prognosis in PTC [222]. The percentage of cells with Ki-67 expression is considered the tissues’ proliferative index. At a cut-off of ≥1% Ki-67 was 85% sensitive and 71% specific for thyroid carcinoma in Bethesda IV nodules. A combination of HBME-1, CK-19 and Ki-67 immunomarkers was 91% accurate to diagnose malignancy [218]. Ki-67 expression is likely only distinctive for follicular type carcinoma; expression in PTC is generally low [218, 222, 223]. Glycoprotein human trophoblast cell surface marker (TROP-2) is overexpressed on the cell surface of different epithelial carcinoma (e.g. breast, colon) and associated with tumour aggressiveness and poor prognosis. In indeterminate thyroid cytology, it was only assessed in one small subseries of Bethesda III samples, correctly diagnosing the three included carcinoma and all but one of the nine benign nodules [224]. Emerin staining emphasizes features of the nuclear membrane often seen in PTC, such as irregularities and invaginations. Consequently, the stain could facilitate the morphological diagnosis of PTC and especially the more difficult-to-diagnose FVPTC [214, 225]. In 53 Thy3 nodules assessed by Asioli et al., positive emerin staining was highly specific for PTC (including FVPTC), but misdiagnosed all FTCs [214]. Another immunomarker associated with PTC is keratan sulphate, an abnormal glycosaminoglycan complex. It was 98% specific in indeterminate cytology, but correctly predicted PTC only; its sensitivity was poor at 48% [212]. The expression of thyroid peroxidase (TPO) is related to benign follicular neoplasms. A negative TPO stain was 80% sensitive and 86% specific for thyroid malignancy [212]. Finally, CD57 (Leu7) expression is associated with epithelial and nonepithelial malignancies, including thyroid carcinoma. Cytological staining was only investigated in a small series of indeterminate cytology, but seemed specific for PTC. In the same series, GLUT-1 was not a useful ICC marker – there were no positive stains [226]. Combined use of immunocytochemistry markers Some research groups have suggested that evident single-marker galectin-3 positivity is sufficient to refer a patient for total thyroidectomy [202, 208, 215]. The ATA guidelines did not adopt these suggestions, and many other researchers advocate that a panel of ICC markers should be applied to strengthen the suspicion of malignancy [17, 203, 212, 217]. Several panels were investigated in literature. Zhang et al. assessed a triple stain of galectin-3, HBME-1 and p27. P27 is a cyclindependent kinase inhibitor related to cell life span in normal thyroid cells. Downregulated in malignancy, positive P27 stain is related to benign histopathology. In a set of Bethesda III cytology samples, positive p27 staining with negative galectin-3 and HBME-1 staining was 100% predictive of a benign nodule and occurred in 38% of samples. Loss of p27 staining in combination with positive galectin-3 and/or HBME-1 staining was 100% sensitive and 86% specific [203]. Another study investigated galectin-3 and HBME-1 in combination with a RET proto-oncogene stain, which reflects abnormal intracellular RET proto-oncogene activity and presence of the RET/PTC rearrangement. Unfortunately, RET staining was inaccurate in indeterminate thyroid nodules [219].
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