Immunohistochemical and Molecular Markers Associated with Differentiated Thyroid Carcinoma

Jun Woo Jung; June Young Choi; Kyu Eun Lee; Kwi Won Park

doi:10.11106/cet.2015.8.1.50

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Jung, Choi, Lee, and Park: Immunohistochemical and Molecular Markers Associated with Differentiated Thyroid Carcinoma

Review Article

Clin Exp Thyroidol 2015;8(1):50-60.

Published online: 4 May 2015

DOI: https://doi.org/10.11106/cet.2015.8.1.50

Immunohistochemical and Molecular Markers Associated with Differentiated Thyroid Carcinoma

Jun Woo Jung¹, June Young Choi¹, Kyu Eun Lee², Kwi Won Park²

Department of Surgery, Seoul National University Bundang Hospital, Seongnam, Korea

Department of Surgery, Seoul National University Hospital, Seoul, Korea

Correspondence: Kyu Eun Lee, MD, PhD, Department of Surgery, Seoul National University Hospital, Seoul National University College of Medicine, 101 Daehak-ro, Jongno-gu, Seoul 110-744, Korea Tel: 82-2-2072-2081, Fax: 82-2-766-3975, E-mail: kyu.eun.lee.md@gmail.com

Received 12 November 2014 Accepted 2 February 2015

This is an open-access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

In the last decade, conventional diagnosis of thyroid nodules largely depended on fine-needle aspiration (FNA) and ultrasound. However, FNA has a limited ability to distinguish between benign and malignant lesions, especially in cases with indeterminate cytology. Although the clinical course of differentiated thyroid carcinoma is believed to be favorable, delayed diagnosis can make its clinical management difficult. Many immunohistochemical (IHC) or molecular adjunctive markers have been tested to improve the diagnostic accuracy for thyroid nodules. The common IHC markers galectin-3, Hector Battifora mesothelial-1, and cytokeratin-19 are used alone or as part of panels for both FNA and analysis of surgical specimens. A novel IHC marker, podoplanin, was recently introduced as an adjunctive marker for thyroid cancer diagnosis and prognosis and is associated with the progression of papillary thyroid carcinoma (PTC). Several researchers have identified molecular markers to increase the diagnostic accuracy of thyroid lesions of undetermined significance. Four promising molecular markers have been proposed and thoroughly investigated: B-type Raf kinase (BRAF) and RAS, rearranged in transformation/PTC (RET/PTC), paired box gene 8 (Pax8)/peroxisome proliferator-activated receptor gamma (PPAR γ). BRAF mutations can be measured by immunohistochemistry using an antibody specific to the mutated protein. In this review, we focused on the limitations of current diagnostic tools and on determining the application of the above-mentioned markers to thyroid nodule diagnosis.

Keywords: Differentiated thyroid carcinoma, Immunohistochemistry, Molecular markers

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Fig. 1.

Galectin-3 immunostaining. (A) Galectin-3 is diffusely expressed in papillary thyroid carcinoma. It is localized in both the cytoplasm and nuclei (×400). (B) Focal expression of galectin-3 is detected in follicular thyroid carcinoma (×200). (C) Galectin-3 is not detected in follicular adenoma (×200).

Fig. 2.

HBME-1 immunostaining. (A) Papillary thyroid carcinoma exhibits a strong membranous staining (×200). (B) Follicular thyroid carcinoma exhibits a diffuse cytoplasmic staining (×200). (C) Follicular adenoma shows focal expression of HBME-1 (×200).

Fig. 3.

CK-19 immunostaining. (A) Papillary thyroid carcinoma exhibits a diffuse expression of CK-19 (×200). (B) Focal expression of CK19 is detected in follicular thyroid carcinoma (×200). (C) CK-19 is not detected in follicular adenoma (×200).

Fig. 4.

BRAF staining in papillary thyroid carcinoma. A diffuse expression can be distinctively observed in both the cytoplasm and nuclei (×200).

Table 1.

Immunohistochemical detection of galectin-3 in thyroid surgical specimens^⋆

	Normal	CLT	NH	FA	PTC	FTC	PDTC	ATC
Fernandez et al.²³⁾	0 (0)	-	0 (0)	0 (0)	18/18 (100)	4/8 (50)	2/3 (67)	5/5 (100)
Herrmann et al.¹⁹⁾	-	-	0 (0)	3/8 (37)	22/34 (64)	2/3 (67)	-	-
Kovacs et al.²⁰⁾	-	7/7 (100)	-	4/19 (21)	19/20 (95)	7/10 (70)	-	-
Weber et al.⁷¹⁾	-	-	-	4/13 (31)	22/24 (92)	4/9 (44)	-	-
Prasad et al.³³⁾	0 (0)	-	16/29 (55)	2/21 (9)	63/67 (94)	4/6 (67)	-	4/4 (100)
Oestreicher-Kedem et al.⁷²	-	-	-	7/15 (47)	15/18 (83)	7/11 (64)	-	-
Cvejic et al.²¹⁾	-	-	-	-	169/202 (84)	-	-	-
Bartolazzi et al.²²⁾	0/75 (0)	2/4 (50)	0/50 (0)	5/132 (4)	195/201 (97)	54/57 (95)	13/20 (65)	18/20 (90)
Saggiorato et al.²⁹⁾	-	-	-	3/50 (6)	39/39 (100)	16/19 (84)	-	-
Park et al.⁹⁾	-	-	3/54 (6)	1/35 (29)	179/181 (99)	16/25 (64)	-	-

^⋆ Values are number/total number (percent). Hyphen indicate not determined in this study

ATC: anaplastic thyroid carcinoma, CLT: chronic lymphocytic thyroiditis, FA: follicular adenoma, FTC: follicular thyroid carcinoma, NH: nodular hyperplasia, PDTC: poorly differentiated thyroid carcinoma, PTC: papillary thyroid carcinoma

Table 2.

HBME-1 immunohistochemical detection in thyroid surgical specimens^⋆

	Normal	NH	FA	PTC	FTC	PDTC	ATC
Prasad et al.³³⁾	0/59 (0)	1/29 (3)	2/21 (10)	57/67 (85)	3/6 (50)	-	-
Cheung et al.²⁾	-	0/35 (0)	0/35 (0)	76/138 (55)	2/4 (50)	4/6 (67)	1/2 (50)
Mase et al.³¹⁾	-	8/62 (12)	17/62 (27)	35/36 (97.2)	33/39 (84.6)	-	0/2 (0)
Choi et al.³⁰⁾	-	-	-	65/67 (97)	30/30 (100)	11/12 (91.6)	2/10 (20)
Papotti et al.³²⁾	-	-	1/15 (6.6)	14/14 (100)	-	-	-
Saggiorato et al.	-	-	2/50 (4)	37/39 (94.8)	17/19 (89.5)	-	-
Nikiforova et al.⁷³⁾	-	-	3/23 (13)	-	11/33 (34)	-	-
Park et al.⁹⁾	-	11/54 (20.4)	17/35 (49)	166/181 (92)	22/25 (88)	-	-

^⋆ Values are number/total number (percent). Hyphen indicate not determined in this study

Table 3.

Molecular markers used in the preoperative evaluation of thyroid nodule FNA. From Rodrigues et al.⁸⁾

	Average SN	Average SP	Average PPV	Average NPV	Average AC
BRAF mutations	52.35	97.92	99.85	51.62	70.54
RAS Mutations	23.00	97.20	82.20	63.20	65.00
RET rearrangements	18.20	88.72	87.00	59.60	55.30
PAX8/PPAR γ rearrangements	20.00	100.00	100.00	46.00	60.00

AC: accuracy, NPV: negative predictive value, PPV: positive predictive value, SN: sensitivity, SP: specificity

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