Papillary thyroid carcinoma (PTC) is the most common thyroid cancer, and the gold standard for the diagnosis of PTC is conventional histology, which depends on the characteristic nuclear features (Prasad et al., 2005). However, the interpretation of nuclear features may be quite subjective, and interobserver disagreements among expert pathologists are well documented (Prasad et al., 2005; El Demellawy et al., 2008). In addition, morphologic similarities between benign and malignant lesions are frequent; follicular and papillary architectures may be seen in both benign and malignant lesions (Cheung et al., 2001; Prasad et al., 2005). Nowadays, the most controversial issue in thyroid pathology is deciding whether focally or poorly developed nuclear changes of PTC type justify the diagnosis of follicular variant of PTC (FVPTC) in an encapsulated tumor with a follicular architecture (Fonseca et al., 2006).
Because FVPTC is diagnosed almost solely on the basis of subjective nuclear criteria and no uniform diagnostic criteria exist, it is not surprising that disagreements in the diagnosis of FVPTC have underscored the interobserver variability in the evaluation of these lesions (Lloyd et al., 2004). This interobserver variation is particularly true for encapsulated follicular lesions with partial or incomplete features of PTC. Scognamiglio et al. (2006) and Williams (2000) have proposed the term well-differentiated tumors of uncertain malignant potential (WDT-UMP) for such lesions in which the cytologic features are not developed enough to ensure an unequivocal diagnosis of PTC. These tumors have been suggested as possible precursors to invasive PTC. However, the nature of these lesions and their relationship to PTC remains uncertain (Fusco et al., 2002; Scognamiglio et al., 2006).
In an attempt to resolve these diagnostic difficulties in thyroid pathology and to aid in the diagnosis and differential diagnosis of PTC to reach the most precise diagnosis, many biomarkers using immunohistochemical and molecular studies have been evaluated for their potential in the accurate diagnosis of PTC, including HBME-1, CK19, galectin-3, fibronectin-1, CITED-1, CD56, BRAF and Ras mutations, microRNA overexpression, or RET/PTC translocation (Al Brahim and Asa, 2006; Elsheikh et al., 2008).
HBME-1 is a monoclonal antibody generated against a suspension of epithelial malignant mesothelioma cells. It reacts with an unknown antigen present in the microvillus surface of normal and neoplastic mesothelial cells (Brown et al., 1997). CK 19, a cytoskeleton intermediate filament protein, has been found to be a phenotypic marker for PTC, showing diffuse strong staining in the majority of PTCs, whereas it is usually absent or focally expressed in benign thyroid lesions (Choi et al., 2005).
The present study was designed to investigate the potential diagnostic utility of anti-HBME-1 and anti-CK19 antibodies singly or in combination with regard to the diagnosis and differentiation of PTCs from their benign mimics, particularly when dealing WDT-UMP.
Material and methods
The materials for this study included fifty-two cases of surgically removed thyroid lesions, which were received at the Pathology Department at Ain-Shams University Hospital and Specialized Ain Shams University Hospital during the period from July 2007 to July 2009. In the present work, 52 cases of different surgically removed thyroid lesions were re-evaluated histopathologically and classified accordingly into 25 cases of PTC, 16 cases of benign thyroid lesions including six cases of follicular adenoma, five cases of hyperplastic nodule, five cases of benign papillary thyroid hyperplasia, and 11 cases of WDT-UMP. PTC and benign thyroid lesions were examined and re-evaluated according to the current WHO version, 2004. We studied the clinicopathological data, and evaluated the expression of HBME-1 and CK19 in all the 52 studied cases.
The 25 cases of PTC were classified into the following histopathological variants: classic variant (eight cases), FVPTC (eight cases), papillary microcarcinoma (four cases), encapsulated PTC (three cases), tall cell variant (one case), and Columnar cell variant (one case).
Paraffin-embedded tissue sections were stained with anti-HBME-1 and CK19 antibodies using the Biotin streptavidin immuno-peroxidase technique. Paraffin-embedded tissue sections, 4–5 µm thick, were deparaffinized and dehydrated with xylene and graded ethanol. The endogenous peroxidase activity was blocked with 3% hydrogen peroxide in methanol at room temperature for 3 min. For antigen retrieval, the sections were treated in a microwave for 5 min at 700 W in ready-to-use retrieval citrate buffer, pH 6 (Biogenex, California, USA; Cat No. HK 087–5K), and then the sections were left to cool for 20 min. Slides were subsequently incubated with an antibody against monoclonal mouse antihuman HBME-1 IgM antibody (Dako, Clone HBME-1, Code No. N1594, 7 ml of ready to use) for 1 h at room temperature, and monoclonal mouse anti-human CK19 IgG antibody (Biogenex, 6 ml of ready to use). After PBS rinsing, the sections were incubated with the biotinylated antimouse secondary antibody (Biogenex, Cat. No. AM3 10-5M) and were subsequently treated with the biotin–avidin peroxidase system. Diaminobenzidine was used as the final chromogen, and Harris hematoxylin was used as the counter stain.
Negative control slides were processed in the same immunostaining procedure but negative control sera were used instead of the primary antibody. Sections from malignant mesothelioma cases served as positive control slides for HBME-1. Sections from colonic adenocarcinoma were served as positive control slides for CK19.
Interpretation of immunostaining slides
HBME-1-stained and CK19-stained thyroid lesion slides were examined and assessed for the following:
The pattern of HBME-1 and CK19 immunoreactivity
HBME-1 was expressed in the cell membrane with apical or luminal accentuation; this pattern of expression may or may not be associated with cytoplasmic immunostaining (Park et al., 2007; Hofman et al., 2009). CK19 expression was cytoplasmic with membranous accentuation (Park et al., 2007).
The scoring of HBME-1 and CK19 immunoreactivity
Positive reactions for HBME-1 and CK19 were characterized by an immunoreactivity of at least 10% of the lesion. The immunoreactivities of HBME-1 and CK19 were scored on the basis of the extent of distribution of immunoreactive cells according to Park et al. (2007) as follows: 0, no staining or staining in less than 10% of the cells; 1+, staining in 10–25% of the cells; 2+, staining in 25–50% of the cells; 3+, staining in 50–75% of the cells; 4+, staining in more than 75% of the cells. A staining of 0 was defined as negative. A staining of 1+ or 2+ was defined as focal positive, and a staining of 3+ or 4+ was defined as diffuse positive.
Analysis of data was carried out by an IBM-PC compatible computer with SPSS (statistical program for social science, version 15, Chicago, Illinois, USA), using the χ2-test, and the Fisher exact test. A level of P<0.05 was considered the cut-off value for significance. One way analysis of variance was used to evaluate the equality of several group means. The diagnostic indices [sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy] were calculated for markers after classification into four categories: (a) true positive, (b) true negative, (c) false positive and, (d) false negative. The sensitivity (true positive rate) and the specificity (true negative rate) for each marker were calculated. The PPV is the percentage of the true positive to all positive cases by the examined test. The NPV is the percentage of the true negative to all negative cases by the examined test.
Papillary thyroid carcinoma
The age in this group ranged from 18 to 71 years, with a mean of 38.5 years. Seventeen out of the 25 patients were women (68%) and eight patients were men (32%).
The tumor size ranged from 0.6 to 7 cm, with a mean of 2.98 cm. Nine patients out of the 25 (36%) had a multifocal disease. Extrathyroid extension was detected in one case (4%). Three cases (12%) showed lymph node metastases. Capsular invasion was detected in seven cases (28%). Vascular invasion was present in one case (4%).
Benign thyroid lesions
The age in this group ranged from 20 to 58 years, with a mean of 39.8 years. Twelve patients (75%) were women, and four patients (25%) were men. The tumor size ranged from 0.8 to 8 cm, with a mean of 3 cm.
Well-differentiated tumors of uncertain malignant potential
The age in this group ranged from 15 to 63 years, with a mean of 33.5 years. Nine patients (81.8%) were women, and two patients (18.2%) were men. The tumor size ranged from 0.5 to 8 cm, with a mean of 2.9 cm. Questionable capsular invasion was detected in four out of 11 cases (36%).
There was no statistically significant difference between PTC, benign thyroid lesions, and WDT-UMP with regard to the distribution in men and women, the tumor size, and the multifocality of the lesions (P>0.05). There was a statistically significant difference between PTC, benign thyroid lesions, and WDT-UMP with regard to the mean age (P<0.01). Patients in the WDT-UMP group reported a younger age than the other two groups, but there was no statistically significant difference between the PTC and the benign thyroid lesion groups (P>0.05).
Papillary thyroid carcinoma
HBME-1: Twenty-three out of the 25 cases (92%) showed positive immunostaining. Twenty-one out of these 23 cases (84%) showed diffuse positive immunostaining (Fig. 1) and two cases (8%) showed focal positive immunostaining, whereas the remaining two out of the 25 cases (8%) showed negative immunostaining (Table 1).
CK19: Twenty-four out of the 25 cases of PTC (96%) showed positive immunoreactivity, with 22 out of these 24 cases (88%) showing diffuse immunoreactivity (Fig. 2) and two cases (8%) showing focal immunoreactivity, whereas the remaining one (4%) showed negative immunoreactivity (Table 1).
No statistically significant difference was found between different histopathological variants of PTC with regard to the distribution of CK19 or HBME-1 immunostaining (P>0.05). Regarding the coexpression of HBME-1 and CK19 in 25 cases of PTC, 22 cases (88%) showed coexpression. Nineteen of them (76%) showed diffuse immunoreactivity for both markers and three cases (12%) showed diffuse immunoreactivity for one marker and focal immunoreactivity for the other.
Benign thyroid lesions
Negative HBME-1 immunoreactivity was detected in all the 16 cases of benign thyroid lesions (100%). Among the 16 cases of benign thyroid lesions examined, 11 out of the 16 cases (68.8%) showed no immunoreactivity for CK19, whereas the remaining five cases (31.2%) showed positive immunoreactivity. Two out of these five immunoreactive cases (12.4%) showed focal immunostaining.
The calculated diagnostic indices listed in (Table 2) indicated that HBME-1 showed a higher specificity, PPV, and diagnostic accuracy than CK19, whereas CK19 showed a slightly higher sensitivity and NPV. The combined expression of HBME-1 and CK19 markedly enhanced the specificity, PPV, and diagnostic accuracy of CK19, but the sensitivity of CK19 was still higher than the coexpression of HBME-1 and CK19. The diagnostic indices of the coexpression were very close to those of HBME-1 alone.
HBME-1 immunoreactivity showed a significant difference between PTC with papillary configuration and benign papillary thyroid hyperplasia. HBME-1 was noted is all the 15 cases of PTC with classic papillary architecture (100%), of which 13 cases showed diffuse strong immunoreactivity. However, negative HBME-1 expression was detected in all the five cases of benign papillary hyperplasia (100%). The sensitivity, specificity, and diagnostic accuracy of HBME-1 were all 100%. Also, CK19 immunoreactivity in our study showed a significant difference between PTC with papillary configuration and benign papillary thyroid hyperplasia. The sensitivity was 93%, the specificity was 80%, and the diagnostic accuracy was 90%.
Diffuse HBME-1 immunostaining was detected in six out of eight FVPTC cases (75%), whereas negative immunostaining was detected in all the 11 cases of the benign follicular-patterned nodules (100%). However, CK19 immunostaining was noted in all the FVPTC cases (100%), of which six cases showed diffuse strong positivity. CK19 immunoreactivity was detected in four out of 11 cases of the benign follicular-patterned nodules (36%), with two cases showing diffuse strong immunostaining. HBME-1 specificity (100%) and diagnostic accuracy (89%) were higher than those of CK19 (64% and 79%) in differentiating between FVPTC and follicular-patterned nodules, whereas CK19 revealed a higher sensitivity, and NPV reached 100%. The coexpression of both markers was similar to those of HBME-1.
Well-differentiated tumors uncertain malignant potential
HBME-1: Three cases (27.2%) showed moderate focal immunoreactivity (Fig. 3) and five cases (45.5%) showed strong diffuse immunoreactivity (Fig. 4), whereas the remaining three cases (27.3%) were negative. There was a statistically significant difference between PTC and WDT-UMP cases with regard to the distribution of HBME-1 (P<0.05). There was a statistically significant difference between PTC and benign cases with regard to the distribution of HBME-1 (P<0.0001), and between WDT-UMP and benign cases (P<0.0001).
CK19: Three cases (27.3%) showed strong diffuse immunoreactivity (Fig. 5) and two cases (18.2%) showed moderate focal immunoreactivity, whereas six cases (54.5%) were negative. Regarding the coexpression of HBME-1 and CK19 in WDT-UMP, three out of 11 cases (27.2%) showed coexpression.
There was a statistically significant difference between PTC and WDT-UMP cases with regard to the distribution of CK 19 (P<0.05) and between PTC and benign cases (P<0.0001). However, no statistically significant difference was found between benign and WDT-UMP cases (P>0.05).
On the basis of the results of this study, a suggested protocol to identify the various degrees of risk potential for malignancy is as follows: (a) Definite malignancy can be supposed if both HBME-1 and CK19 are diffusely expressed, HBME-1 alone is diffusely expressed, or CK19 is diffusely expressed and HBME-1 is focally expressed. (b) A suspicion of malignancy can be suggested if CK19 is diffusely expressed and HBME-1 is negative. (c) WDT-UMP (borderline lesion) for strict follow-up can be suggested if HBME-1 and CK19 are focally expressed, or HBME-1 is focally expressed and CK19 is negative. (d) Benign diagnosis can be considered if both HBME-1 and CK19 are negative, or HBME-1 is negative and CK19 is focally expressed.
Thus, using this suggested protocol in evaluating the 11 cases of WDT-UMP (Table 3), six cases could be classified as malignant (54.5%), one case as suspicious of malignancy (9.1%), two as WDT-UMP (borderline) for strict follow-up (18.2%), and two cases as benign (18.2%).
HBME-1 and CK19 have been reported to be diagnostically useful in PTC by many authors; they show a higher expression in PTC than in benign thyroid lesions (Cheung et al., 2001; Prasad et al., 2005; Liu et al., 2008; Barut et al., 2009). However, the extent of immunoreactivity, and accordingly the sensitivity and specificity, have varied among studies. The reasons for such discrepancies reported by different authors are not clear. Possible explanations include variations in technical methods, the antibody clone used, and the interpretation of the results.
In this work, HBME-1 immunoreactivity showed a significant difference between PTC and benign thyroid lesions (P<0.0001). These results were in agreement with most of the studies that demonstrated diffuse strong immunoreactivity for HBME-1 in almost all cases of PTC, whereas immunoreactivity in benign cases was usually negative or showed only weak and focal immunoreactivity (Prasad et al., 2005; Torregrossa et al., 2007).
In this study, HBME-1 showed 92% sensitivity and 100% specificity. These figures were comparable to most of the studies that reported a sensitivity ranging from 85 to 100% (Prasad et al., 2005; Barroeta et al., 2006; Nasr et al., 2006) and a specificity ranging from 91 to 100% (Cheung et al., 2001; Prasad et al., 2005; Barroeta et al., 2006; Scognamiglio et al., 2006). However, a few studies reported less sensitivity and specificity. Cheung et al. (2001) reported a sensitivity of 55%, and Park et al. (2007) reported a specificity of 68.5%.
In this study, the diagnostic accuracy of HBME-1 immunoreactivity in differentiating PTC from benign thyroid lesions was 95%; similarly, Rossi et al. (2006) reported a diagnostic accuracy of 96%.
CK19 immunostaining showed a high sensitivity (96%) and a low specificity (69%) in the diagnosis of PTC. This finding was consistent with many studies, such as those by Barroeta et al. (2006), Scognamiglio et al. (2006), and El Demellawy et al. (2008), who reported a sensitivity ranging from 86 to 100% and a specificity ranging from 34 to 72%. However, in contrast to our result, studies by Prasad et al. (2005) and De Matos et al. (2005) revealed a relatively lower sensitivity of about 70%, whereas Cheung et al. (2001), Kösem et al. (2005), and Barut et al. (2009) reported a high specificity of 90, 94, and 97.5%; respectively. In this study, the diagnostic accuracy of CK19 immunoreactivity in the diagnosis of PTC was 82.5%, whereas Rossi et al. (2006) and Park et al. (2007) reported 92 and 88% diagnostic accuracies, respectively.
Several authors emphasized the importance of the distribution of CK19 staining as the most critical aspect of accurate interpretation, with most PTCs showing diffuse strong immunoreactivity (Scognamiglio et al., 2006). However, De Matos et al. (2005), Kösem et al. (2005), and Bukhari et al. (2009) detected negative or focal immunoreactivity of CK19 in benign cases.
In view of the low specificity of CK19 and the diffuse strong immunoreactivity detected in three benign thyroid lesions detected in this study, this work and those of Cameron and Berean (2003), Nasr et al. (2006), and Park et al. (2007) can indicate that diffuse strong CK19 immunoreactivity raises the suspicion of PTC, but CK19 cannot by itself be used to establish a diagnosis of PTC. Conversely, Sahoo et al. (2001) and Cameron and Berean (2003) stated that focal immunostaining of CK19 did not rule out a diagnosis of PTC if the diffuse diagnostic nuclear features of PTC were present.
In the present work, the specificity and the diagnostic accuracy of HBME-1 (100 and 95%) were almost similar to or slightly higher than those of the coexpression (100 and 93%). Those results were in disagreement with the results reported by Nga et al. (2008), who found a superior diagnostic accuracy of coexpression of HBME-1 and CK19 (100%) over each marker alone.
In this study, HBME-1 immunoreactivity showed higher diagnostic indices (100%) in differentiating PTC from benign papillary hyperplasia than that of CK19 (sensitivity 93%, specificity 80%, and diagnostic accuracy 90%). Similarly, Casey et al. (2003) found that HBME-1 was better than CK19 in differentiating PTC from benign papillary hyperplasia.
This work showed that HBME-1 had a higher specificity than CK19 (100 vs. 64%) in diagnosing and differentiating FVPTC from their benign mimics. In agreement with our results, Nasr et al. (2006) reported a higher specificity for HBME-1 than CK19 in differentiating FVPTC from follicular adenoma and hyperplastic nodule (100 vs. 62.5%). Also, HBME-1 showed a higher diagnostic accuracy than CK19 (89 vs. 79%). In parallel to our results, Liu et al. (2008) recorded a higher diagnostic accuracy for HBME-1 than CK19 in differentiating FVPTC from follicular adenoma (89 vs. 63%). However, CK19 attained a higher sensitivity than HBME-1 (100 vs. 75%). This finding may encourage the combined utility of HBME-1and CK19 as the two markers may be mutually supportive.
In the present study, the expressions of HBME-1 and CK19 immunoreactivities were evaluated in a group of 11 cases of WDT-UMP. The results showed HBME-1 immunoreactivity in 72.7%, which was more or less similar to those found by Papotti et al. (2005), Scognamiglio et al. (2006), and Hofman et al. (2009), who found HBME-1 immunoreactivity in 70, 64, and 56%; respectively, whereas CK19 immunoreactivity was detected in 45.5, 64, and 62%; respectively.
Our work reported statistically significant differences between PTC, WDT-UMP, and benign thyroid lesions with regard to the distribution of HBME-1 immunoreactivity, whereas a statistically significant difference was found between PTC and WDT-UMP and not between WDT-UMP and benign thyroid lesions with regard to the distribution of CK19 immunoreactivity.
This finding showed that WDT-UMP may represent a distinct group when compared with benign and malignant tumors, and this may reflect the biologically borderline nature of these tumors, which require a strict follow-up. In addition, Hofman et al. (2009) strongly believed that the terminology WDT-UMP should be quickly tested in different reference centers.
On the basis of our results, a protocol was suggested to identify various degrees of risk potential for malignancy as follows: definite malignancy can be supposed if both HBME-1 and CK19 are diffusely expressed, HBME-1 alone is diffusely expressed, or CK19 is diffusely expressed and HBME-1 is focally expressed; benign diagnosis if both or either HBME-1 and CK19 are negative or CK19 is focally positive; suspicious of malignancy if CK19 is diffusely expressed and HBME-1 is negative; and WDT-UMP if HBME-1 and CK19 are focally expressed or HBME-1 is focally expressed and CK19 is negative. According to our suggested protocol, of the 11 cases diagnosed histopathologically as WDT-UMP, two cases were classified as benign (18.2%), six cases as malignant (54%), one case as suspicious of malignancy (9.1%), and two cases as WDT-UMP (borderline) for strict follow up (18.2%).
Our suggested protocol to assess the role of HBME-1 and CK19 expression as a diagnostic tool, especially in equivocal cases, needs to be further applied on a large number of cases combined with follow-up data of the patients.
We conclude that the combined use of HBME-1 and CK19 is highly recommended for diagnosing and differentiating PTC cases from their benign mimics and WDT-UMP. The diagnostic indices of HBME-1 are generally better than those of CK19.
Conflicts of interest
There are no conflicts of interest.
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