Usefulness of HBME-1, cytokeratin 19 and galectin-3 immunostaining in the diagnosis of thyroid malignancy

Aims : To investigate the usefulness of immunohistochemical expression and immunolocalization of a panel of thyroid malignancy markers including HBME-1, cytokeratin (CK) 19 and galectin-3.
Methods and results : We evaluated 170 thyroid lesions including 148 neoplastic lesions [84 papillary carcinomas (PC), 38 follicular carcinomas (FC), 18 follicular adenomas, one hyalinizing trabecular tumour, five medullary carcinomas, two anaplastic carcinomas] and 22 non-neoplastic lesions (12 adenomatous nodules and 10 Hashimoto's thyroiditis). HBME-1, galectin-3 and CK19 were expressed in 94%, 72.6%, 72.6% of PCs and in 63%, 21%, 21% of FCs. The three markers were mostly negative in all normal tissues. Although the most helpful marker in terms of sensitivity and specificity for the follicular variant of PC and for FC diagnosis was HBME-1, when we consider the differentiation between cases of follicular variant of papillary carcinoma (FVPC) and FC or adenoma, in terms of percentage of positive cells, galectin-3 and CK19 were more relevant.
Conclusions : HBME-1 is the most sensitive marker for thyroid malignancy but the three markers may be useful in specific cases. This panel of markers is useful to differentiate the follicular patterned lesions, with special reference to the FVPC.     

Diagnostic value of galectin-3, HBME-1, cytokeratin 19, high molecular weight cytokeratin, cyclin D1 and p27(kip1) in the differential diagnosis of thyroid nodules

The distinction between benign and malignant thyroid tumors is critical for the management of patients with thyroid nodules. We applied immunohistochemical staining for galectin-3, HBME-1, cytokeratin 19 (CK19), high molecular weight cytokeratin (HMWCK), cyclin D1 and p27(kip1) in 295 thyroid lesions to determine their diagnostic accuracy. The expression of all markers was significantly associated with differentiated thyroid carcinoma (DTC).The sensitivity for the diagnosis of DTC was 94.7% with galectin-3, 91.3% with HBME-1, and 90.3% with CK19. The specificities of these markers were 95.5%, 69.7%, and 83.1%, respectively. Combining these markers, co-expression of galectin-3 and CK19 or galectin-3 and HBME-1 was seen in 93.2% of carcinomas but in none of the benign nodules. Comparing follicular variant of papillary carcinoma (FVPC) with follicular carcinoma (FC), the expression of galectin-3, CK19, and HMWCK was significantly higher in FVPC. When comparing FC with FA, the expression of galectin-3 and HBME-1 was significantly higher in FC. These results suggest that 1) galectin-3 is a useful marker in the distinction between benign and malignant thyroid tumors, 2) the combined use of HBME-1 and CK19 can increase the diagnostic accuracy, and 3) the use of CK19 and HMWCK can aid in the differential diagnosis between PC and FC.     

细胞角蛋白19、galectin-3、HBME-1在甲状腺病变上的表达及鉴别诊断意义

目的 研究细胞角蛋白(CK)19、galectin(Gal)-3、HBME-1在甲状腺不同病变表达的特点及鉴别诊断中的应用价值。方法 应用免疫组织化学EnVision法检测了21例结节性甲状腺肿(结甲)、14例毒性甲状腺肿(甲亢)、15例甲状腺滤泡性腺瘤(腺瘤)、13例滤泡性癌、13例滤泡型乳头状癌及48例经典型乳头状癌中单克隆抗体CK19、Gal-3、HBME-1的表达。结果 甲状腺病变中3种标记表达均位于细胞质;CK19、Gal-3、HBME-1的表达在甲状腺良性病变(结甲、甲亢、腺瘤)大多为弱阳性或阴性,而滤泡性癌阳性明显增加、乳头状癌(滤泡型及经典型)大多为中、强阳性,3种标记在甲状腺不同病变的阳性表达率结甲为52．4％(11／21)、9．5％(2／21)、19．0％(4／21),甲亢为50．0％(7／14)、7．1％(1／14)、7．1％(1／14),腺瘤为60％(9／15)、13．3％(2／15)、13．3％(2／15),滤泡性癌为76．9％(10／13)、61．5％(8／13)、53．8％(7／13),滤泡型乳头状癌为：100％(13／13)、84．6％(11／13)、92．3％(12／13),经典型乳头状癌为100％(48／48)、93．8％(45／48)、95．8％(46／48);在甲状腺良性病变(结甲、甲亢、腺瘤)与恶性病变(滤泡性癌、乳头状癌)间3种标记差异均有显著性(P均=0．000);同时3种标记在滤泡样病变即腺瘤、滤泡性癌和滤泡型乳头状癌间亦有显著差异(CK19：P=0．038,Gal-3：P=0．001,HBME-1：P=0．000)。结甲有9例,甲亢有7例,腺瘤有6例3种标记均不表达,滤泡性癌仅有1例,而乳头状癌(滤泡型及经典型)没有病例3种标记均不表达,同一病例有2种以上阳性表达在结甲、甲亢、腺瘤、滤泡性癌、滤泡型乳头状癌和经典型乳头状癌中分别为14．2％(3／21)、21．4％(3／14)、20．0％(3／15)、69．2％(9／13)、92．3％(12／13)、100．0%(48／48),在甲状腺良性病变与恶性病变间以及滤泡样病变间差异亦有显著性(P=0．000)。结论 CK19、Gal-3、HBME-1的检测尤其是联合检测对甲状腺病变的诊断、鉴别诊断具有较高的实用价值。     

HBME-1 and CK19 are highly discriminatory in the cytological diagnosis of papillary thyroid carcinoma

The cytologic diagnosis of papillary thyroid carcinoma is straightforward in most instances. However, there are some mimics including goitrous nodules and Hurthle cell neoplasms. Many studies have shown the combination of HBME-1 and CK19 expression to be useful in reaching a correct histologic diagnosis on tissue sections. We aim to assess the value of these markers in the setting of cell blocks prepared from needle aspiration specimens. We performed immunohistochemical staining of HBME-1 and CK19 on cell block material from 22 thyroid nodules that also had follow-up histology. Both CK19 and HBME-1 were strongly positive in all nine cases of papillary thyroid carcinoma, the latter showing distinct luminal accentuation. In the non-papillary carcinomas, none showed positivity for both HBME-1 and CK19. Two of six Hurthle cell neoplasms were positive for CK19, however all were negative for HBME-1. One of nine goitrous nodules was strongly positive for HBME-1 with luminal/membranous staining, but this were negative for CK19. The sensitivity, specificity and positive predictive value of HBME-1 in distinguishing between papillary thyroid carcinoma and goitrous nodules/Hurthle cell neoplasms were found to be 100%, 92.9% and 0.9, respectively; and that of HBME-1 and CK19 combination was 100%, 100% and 1. We thus conclude that the combination of positive HBME-1 (luminal/membranous) and CK 19 (cytoplasmic) staining on cell blocks of thyroid cytologic specimens is highly discriminatory in the diagnostic workup for papillary thyroid carcinoma.     

Immunohistochemical expression of HBME-1 and galectin-3 in the differential diagnosis of follicular-derived thyroid nodules

BackgroundThyroid nodules are common among adults with only a small percentage being malignant and histologically mimic benign nodules. Accurate diagnosis of these thyroid nodules is critical for the proper clinical management. The determination of malignancy in follicular patterned thyroid lesions is based on postoperative histological findings. Therefore, affected patients are referred for surgery, although only 10% will have a final diagnosis of malignancy. The aim of this study was to investigate the ability of two immunohistochemical (IHC) markers; galectin-3 and Hector Battifora mesothelial-1 (HBME-1) individually or in combination, to distinguish between benign (non-neoplastic and neoplastic) and malignant (follicular and papillary carcinomas) thyroid lesions removed by surgical resection.MethodsWe investigated the immunoexpression of galectin-3 and HBME-1 in 50 cases of benign and malignant thyroid nodules. The benign group included 13 cases of thyroid nodular goiter (NG) and 9 cases of follicular adenoma (FA). The malignant group included 5 cases of follicular thyroid carcinomas (FC), 18 cases of classic papillary thyroid carcinoma and 5 cases of follicular variant papillary carcinoma (FVPC).ResultsThe staining results showed that malignant tumors expressed galectin-3 and HBME-1 significantly more than benign nodules. The sensitivity of these markers for the distinction between benign and malignant lesions ranged from 89.3% to 92.9%. Co-expression of galectin-3 and HBME-1 was seen in 82.1% of carcinomas, but in none of the benign nodules. Immunoexpression was usually diffuse in malignant tumors, and focal in the benign lesions.ConclusionOur findings indicate that these immunohistochemical markers are significantly more expressed in malignant tumors compared to benign lesions and may be of additional diagnostic value when combined with routine histology. Galectin-3 has higher sensitivity and specificity of immunoexpression in thyroid malignancy than HBME-1, and the combined use of galectin-3 and HBME-1 can increase the specificity of immunoexpression in malignant tumors.     

GADD153在甲状腺滤泡样肿瘤中的表达及与CK19、Galectin-3和HBME-1的对比研究

目的 探讨GADD153在甲状腺滤泡样肿瘤中的表达及其鉴别诊断价值,并与CK19、Galectin-3(简称Gal-3)和HBME-1进行对比.方法 应用免疫组织化学EnVision法检测了34例甲状腺滤泡性腺瘤、46例甲状腺滤泡性癌及29例甲状腺滤泡型乳头状癌中GADD153、CK19、Gal-3和HBME-1的表达情况.结果 (1)GADD153的表达位于细胞核,在甲状腺滤泡性癌中的表达大多为中度阳性或强阳性,在滤泡性腺瘤和滤泡型乳头状癌中的表达多为阴性或弱阳性,阳性表达率分别为82.6％( 38/46)、32.4％( 11/34)、10.3％ (3/29),滤泡性癌明显高于滤泡性腺瘤和滤泡型乳头状癌,差异均有统计学意义(x2值分别为20.80和37.48;均P＜0.01).(2)CK19、Gal-3和HBME-1 三种标志物均表达于细胞质,其阳性表达率在滤泡性癌为54.3％( 25/46)、67.4％ (31/46)、58.7％( 27/46),在滤泡性腺瘤为50.0％( 17/34)、29.4％( 10/34)、32.4％( 11/34),在滤泡型乳头状癌为100％( 29/29)、93.1％ (27/29)、89.7％ (26/29),滤泡型乳头状癌与滤泡性腺瘤、滤泡性癌间比较,差异亦均有统计学意义(x2值分别为21.20和8.22;均P＜0.01).(3)根据CK19、Gal-3、HBME-1和GADD153四种标志物表达的强弱分为低表达组(记为0和1+)和高表达组(记为2+和3+),分别计算其在各组的敏感性和特异性.滤泡性腺瘤组敏感性分别为26.5％、8.8％、2.9％和11.8％,特异性为50.7％、52.0％、54.7％和58.7％;滤泡性癌组敏感性分别为19.6％、26.1％、23.9％和65.2％,特异性为41.3％、57.1％、62.0％和92.1％;滤泡型乳头状癌组敏感性分别为96.6％、82.8％、79.3％和3.4％,特异性为77.5％、81.3％、85.0％和57.5％.结论 GADD153对甲状腺滤泡性癌诊断的敏感性和特异性均较好,而CK19、Gal-3和HBME-1则能更好地提示甲状腺滤泡型乳头状癌.四者联合应用能更好地鉴别甲状腺滤泡性肿瘤.     

Diagnosis of necrotic and degenerate thyroid lesions: value of immunohistochemistry

Aims: Classification of necrotic or degenerate thyroid nodules can be difficult. The aim of this study was to investigate the value of cytokeratins, thyroid-specific markers (TTF-1 and thyroglobulin) and HBME-1 antibodies in such thyroid lesions. METHODS AND RESULTS: Twenty-eight necrotic or degenerate thyroid lesions, including four cervical cystic papillary carcinoma (CPC) metastases, were evaluated with immunohistochemistry for TTF-1, thyroglobulin, HBME-1, AE1&3, Cam5.2, MNF116 and cytokeratin (CK)19. There was loss of TTF-1 staining in all necrotic lesions, with positive staining in degenerate tumour cells of all four metastatic CPCs. Thyroglobulin was retained in 18 lesions. Dual CK19 and HBME-1 expression was seen only in six of seven necrotic papillary thyroid carcinomas and the four metastatic CPCs. Retained immunoreactivity for AE1&3 and Cam5.2 was seen in most necrotic papillary carcinomas (n = 11/11 and n = 10/11, respectively), poorly differentiated carcinomas (n = 2/3 and n = 3/3, respectively) and follicular-patterned areas of anaplastic carcinoma (n = 3/5 and n = 4/5, respectively). Cam5.2 showed spurious staining of macrophages in eight lesions. CONCLUSIONS: Thyroglobulin is useful in establishing the thyroid origin of a necrotic lesion. TTF-1 may be useful for highlighting degenerate tumour cells within metastatic CPCs. Retained expression of CK19 and HBME-1 is seen in necrotic papillary carcinomas. AE1&3 is the most specific and Cam5.2 the most sensitive of the CK cocktails in non-viable thyroid lesions.     

Expression of cytokeratin 19, HBME-1 and galectin-3 in neoplastic and nonneoplastic thyroid lesions

In this study, 105 cases of thyroid lesions were evaluated to assess the role of HBME-1, cytokeratin-19 (CK-19), galectin-3 in distinguishing benign from malignant thyroid lesions. Thirty-seven papillary, 10 follicular, 6 medullary, 1 mixed medullary follicular cell carcinoma, 3 poorly differentiated carcinoma, 18 adenomatous nodular hyperplasia, 30 follicular adenoma cases were included in the study. Immunohistochemical staining was performed with HBME-1, CK-19, galectin-3 on cross-sections derived from selected paraffin blocks. Benign and malignant lesions were compared in terms of intensity, percentage and type of staining with CK-19, HBME-1 and galectin-3, and a statistically significant difference (p < 0.05) was found. The percentage and intensity of staining was higher in malignant lesions. Especially, strong and diffuse expressions of CK19, HBME-1 and galectin-3 were observed in papillary carcinomas. Membranous (luminal) staining was seen more frequently in malignant lesions; cytoplasmic staining in benign lesions. It was concluded that these markers could assist in the diagnosis of thyroid lesions with cellular properties suspicious for the diagnosis of papillary carcinoma and without capsule and vessel invasion. They may be used especially in cases where the follicular variant of papillary carcinoma, follicular adenoma and follicular carcinoma are confused with each other and follicular adenoma cannot be differentiated from follicular carcinoma.     

Expression of HBME-1 and CD56 in follicular variant of papillary carcinoma in children: An immunohistochemical study and their diagnostic utility

Papillary thyroid carcinoma (PTC) is the most common differentiated thyroid cancer in children; and the follicular variant is the second most common variant after the classic subtype. The histological appearance of follicular variant of papillary thyroid cancer (FVPTC), can be mimicked by benign follicular nodules. Pediatric pathologists encountering such lesions with FVPTC-like appearance may err on diagnosing the benign lesions as malignant. In adult patients, several immunohistochemical markers have emerged recently as a useful adjunct to distinguish differentiated thyroid carcinomas from benign follicular lesions. We undertook an inter-institutional retrospective study to establish the diagnostic utility of immunohistochemical staining for HBME-1, Galectin-3 and CD56 in differentiating FVPTC from its benign mimics, follicular adenoma and adenomatoid nodules, in children. Our specific aim of the project was to define the sensitivity and specificity of the three antibodies in FVPTC. Based on institutional diagnoses, a total of 66 cases were obtained: 32 FVPTC and 34 benign follicular nodules that comprised of 23 follicular adenoma and 11 adenomatoid nodules. Five investigators, who were blinded to the original diagnoses, independently reviewed the slides following pre-determined criteria and semi-quantitatively scoring the immunohistochemical staining. The immunohistochemical staining revealed that a combination of positive HBME-1 and negative CD56 result gave 100% specificity and positive predictive value in distinguishing FVPTC from benign follicular nodules. However, the antibody combination suffered from a lower sensitivity (50%). We used a cutoff of 25% positivity of tumor cells in determining positivity of tumor cells to an antibody. In conclusion, our study found a very high specificity and strong positive predictive value for the combination of HBME-1 and CD56 immunohistochemical stains in distinguishing FVPTC from benign follicular lesions.     

Simultaneous immunohistochemical expression of HBME-1 and galectin-3 differentiates papillary carcinomas from hyperfunctioning lesions of the thyroid

AIMS: The histological diagnosis is critical for the postsurgical management and follow-up of thyroid malignancies. The differential diagnosis between papillary carcinoma and hyperfunctioning lesions, either with papillary hyperplasia or with a follicular architecture, can create real diagnostic difficulty. The aim of this study was to evaluate the expression of several antibodies considered to be markers of malignancy in malignant and hyperfunctioning thyroid neoplasms and to include the most effective of them in a diagnostic panel. METHODS AND RESULTS: One hundred resected thyroid nodules--58 hyperfunctioning benign lesions and 42 papillary carcinomas (14 follicular variant, 14 macrofollicular variant and 14 classic type)--were immunohistochemically studied for HBME-1, galectin-3, cytokeratin (CK) 19 and RET-proto-oncogene. HBME-1 and galectin-3 showed 92.8% and 89% sensitivity, respectively, and their coexpression was present in 36 out of 42 papillary carcinomas (85.7%) and absent in non-malignant lesions. Their association increased sensitivity to 94.7% and the diagnostic accuracy to 97.9% and involved the highest number of cases (95%) in comparison with two other panels including, respectively, three (HBME-1, galectin-3, CK19) and all four antibodies. CONCLUSION: An immunohistochemical panel consisting of HBME-1 and galectin-3 can make a correct distinction between malignant and hyperfunctioning thyroid neoplasms with high diagnostic accuracy.     

p53, ki-67, galectin-3, HBME-1, 34βE12和CK19在甲状腺乳头状癌中的表达及临床病理意义

 摘要：目的：探讨p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌中的表达及临床病理意义。方法：采用免疫组化检测43例甲状腺乳头状癌、37例结节性甲状腺肿、33例甲状腺腺瘤和17例桥本甲状腺炎中p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19的表达。结果：p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌中的阳性表达例数分别为88.37%、79.07%、88.37%、93.02%、86.05%、95.35%;6种蛋白在甲状腺乳头状癌与结节性甲状腺肿、甲状腺腺瘤和桥本甲状腺炎中的阳性表达率相比较差异均有统计学意义（P<0.01）。结论：联合检测p53, ki-67, galectin-3, HBME-1, 34βE12和CK-19在甲状腺乳头状癌与良性病变的诊断和鉴别诊断中具有重要的价值。     

Caveolin-1 and 14-3-3 sigma expression in follicular variant of thyroid papillary carcinoma

There are two prominent types of thyroid carcinoma, papillary carcinoma (PC) and follicular carcinoma (FC) arising from thyroid follicular cells, which have different biological characteristics. The follicular variant of papillary carcinoma (FVPC) has a structure similar to FC, although it is classified as a subtype of PC. We have previously demonstrated that caveolin-1, a major component of caveolae and an inhibitor of growth signal transduction, and 14-3-3 sigma, a regulator of the cell cycle and signal transduction, are frequently expressed in pure PC, but not in FC. In this study, we investigated these expressions in FVPC and FC. Caveolin-1 and 14-3-3 sigma were expressed in 96.2% and 92.3% of FVPC, respectively. However, almost all FC, with only a few exceptions, were negative for these findings, indicating that these proteins were more frequently expressed in FVPC than in FC (p < 0.0001). These findings suggest that caveolin-1 and 14-3-3 sigma positively or negatively regulate the development of FVPC but not that of FC, reflecting the difference of biological characteristics of these two types of carcinoma.     

The use of immunohistochemistry in the differential diagnosis of thyroid gland tumors with follicular growth pattern

The aim of the study was to evaluate the expression of galectin-3 (gal3), cytokeratin 19 (CK19), neural cell adhesion molecule (NCAM), and E-cadherin (Ecad) in thyroid gland tumors with follicular growth pattern with particular focus on their use in differential diagnosis. A series of 139 cases - 87 follicular adenomas (FAs), 26 follicular carcinomas (FCs), and 26 cases of the follicular variant of papillary carcinoma (FVPC) was studied. Expression of gal3 was found in 29/87 (33%) of FAs, in 13/26 (50%) of FCs, and in 24/26 (92%) of FVPCs. Expression of CK19 was found in 11/87 (13%) of FAs, in 4/26 (15%) of FCs, and in 17/26 (65%) of FVPCs. Expression of NCAM was found in 60/87 (69%) of FAs, in 20/26 (77%) of FCs, and in 7/26 (27%) FVPCs. Expression of Ecad was found in 81/87 (93%) of FAs, in 22/26 (85%) of FCs, and in 17/26 (65%) of FVPCs. The sensitivity and specificity of gal3 for malignancy were 0.70 and 0.85, of CK19 0.48 and 0.98, of NCAM 0.28 and 0.47, and of Ecad 0.48 and 0.20, respectively. A significant difference (p < 0.05) in expression of all studied markers between FVPC versus FA and FC was found, in contrast to FA and FC. Therefore, the use of gal3 and CK19 in differential diagnosis of FVPC versus FA and FC can be recommended.     

Immunohistochemical separation of follicular variant of papillary thyroid carcinoma from follicular adenoma

The accurate diagnosis of differentiated thyroid tumors is very important for clinical management of patients. The histopathological distinction between some types of differentiated thyroid tumors can be very difficult even for experienced pathologists. We used immunohistochemical markers from published data obtained from DNA expression profiling, tissue microarray analysis, and immunohistochemistry to analyze a series of 157 thyroid tumors and 5 normal thyroids. These analyses showed that several antibodies were useful in distinguishing follicular adenomas from follicular variant of papillary thyroid carcinomas including HBME-1, CITED 1, galectin-3, cytokeratin 19, and S100A4 (p<0.0001). A combination of markers consisting of a panel of HBME-1, galectin-3, and CK19 or a panel of HBME-1, CITED1, and galectin-3 was usually most effective in distinguishing follicular adenoma from follicular variant of papillary thyroid carcinoma. Because individual tumors may not express some of these markers, the use of a panel of antibodies is recommended. These results indicate that some individual antibodies or a panel of antibodies combined with histopathological analysis can be useful in separating follicular adenoma (FA) from follicular variant of papillary thyroid carcinoma (FVPTC).     

Role of cd56 and e-cadherin expression in the differential diagnosis of papillary thyroid carcinoma and suspected follicular-patterned lesions of the thyroid: the prognostic importance of e-cadherin

Introduction: The pathological diagnosis of papillary thyroid carcinoma (PTC) is generally easy on routine sections stained with hematoxylin and eosin (H&E). However, the differentiation of the follicular variant of PTC (FVPTC) from other suspected follicular-patterned lesions of the thyroid is highly difficult. Among these, the lesions for which FVPTC cannot be excluded are classified as well-differentiated tumors of uncertain malignant potential (WDT-UMP). The most common immunohistochemical (IHC) markers used in the differential diagnosis include HBME-1, galectin-3, and CK19. However, none of these markers provide a 100% differential diagnosis. Objective: The present study compared the diagnostic value of CD56 and E-cadherin for the differentiation of FVPTC from the other benign follicular-patterned lesions, with HBME-1, galectin-3, and CK19. Using these markers, the controversial cases within the WDT-UMP group were reclassified. Additionally, the relationship between the reductions in E-cadherin expression with poor prognostic factors was investigated. Materials and methods: The IHC expressions of CD56, E-cadherin, HBME-1, galectin-3, and CK19 were evaluated in 181 thyroid lesions, including 101 PTCs (45 classical variant PTCs and 56 FVPTCs), 20 WDT-UMPs, 20 follicular adenomas (FAs), 20 hyperplastic nodules (HN), and 20 hyperplastic foci of lymphocytic thyroiditis. The results were statistically compared via SPSS. Results: The expressions of all of the markers were statistically significantly different in PTC and follicular-patterned lesions (P<0.05). It was found that the only marker with both sensitivity and specificity above 90% was CD56 negativity (sensitivity 91.1%, specificity 91.7%). The most sensitive and also the most specific double panel was CD56 negativity and galectin-3 positivity (sensitivity 96%, specificity 85%), and the most sensitive and specific triple panel was CD56 negativity, HBME-1 positivity, and galectin-3 positivity (97% and 70%, respectively).     

Immunohistochemical markers in diagnosis of papillary thyroid carcinoma: Utility of HBME1 combined with CK19 immunostaining.

Papillary thyroid carcinoma and its variants can be difficult to distinguish from cellular adenomatous nodules. Prior studies have advocated various antibodies to aid in the differential diagnosis, but there is little agreement on their utility. We undertook this study to evaluate immunohistochemical markers in the diagnosis and differential diagnosis of papillary thyroid carcinoma. Ten cases of papillary thyroid carcinoma were initially stained for HBME1, CK19, fibronectin1, Ki-67, Calretinin, p16, SFTPB and CITED1. Additionally, two previously untested antibodies to molecules that have been found to be upregulated in papillary thyroid carcinoma (CST6 and EPS8) were also evaluated. Of these, only HBME1, CK19 and fibronectin1 showed diagnostic utility. These three markers were then further evaluated in 51 papillary thyroid carcinomas and 57 benign thyroids. HBME1 was the most sensitive and specific marker, staining 49/51 papillary thyroid carcinomas and only 4/57 benign thyroids. CK19 was equally sensitive staining all 51 papillary thyroid carcinomas, but it was nonspecific staining 39 of 57 benign thyroids. A negative result, however, was helpful in excluding papillary thyroid carcinoma. Fibronectin1 was positive in 35/51 papillary thyroid carcinomas (69%) and 4/57 (7%) benign thyroids, but its utility was hampered by high background staining. These findings suggest that the combination of HBME1 and CK19 has the greatest diagnostic utility in the differentiation of papillary thyroid carcinoma from its benign mimics.