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Table of Contents
Year : 2013  |  Volume : 1  |  Issue : 1  |  Page : 8-16

Osteopontin cytoplasmic immunoexpression is a predictor of poor disease-free survival in thyroid cancer

1 Department of Pathology, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia; Department of Pathology, Faculty of Medicine, Minia University, El Minia, Egypt
2 Department of Medicine, Faculty of Medicine, King Abdulaziz University, Jeddah, Saudi Arabia
3 Department of Surgery, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
4 Department of Pathology, Faculty of Medicine, King Abdulaziz University; Department of Pathology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia

Date of Web Publication24-Jan-2018

Correspondence Address:
Wafaey Gomaa
Department of Pathology, King Abdulaziz University, P.O. Box 80205, Jeddah 21589

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Source of Support: None, Conflict of Interest: None

DOI: 10.1016/j.jmau.2013.07.001

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Background: Osteopontin (OPN) is expressed in various malignancies and may play an important role in tumorigenesis, tumour invasion, and metastasis in various malignancies including thyroid cancers. The objective of this study was to investigate the relationship between OPN immunoexpression and clinicopathological characteristics in thyroid lesions.
Material and methods: Paraffin blocks belonging to 160 patients with thyroid neoplasms were retrieved from the archive of the Department of Pathology at King Abdulaziz University, and King Faisal Specialist Hospital, Jeddah, Saudi Arabia. Immunohistochemistry was performed using anti-OPN antibody. Statistical tests were used to determine the relation of OPN immunoexpression to clinicopathological characteristics and survival.
Results: Immunostaining results showed that OPN was localised in the cytoplasm and nucleus with higher cytoplasmic expression. Cytoplasmic and nuclear OPN was higher in thyroid cancer than other lesions. Microcarcinoma variant of papillary thyroid carcinoma showed a lower OPN cytoplasmic level than other variants. OPN cytoplasmic expression was not associated with most of the clinicopathological parameters tests. However, OPN cytoplasmic overexpression was associated poor survival outcome (p < 0.001).
Conclusion: Upregulation of cytoplasmic OPN was associated with poor survival outcome and was an independent predictor of margin involvement and recurrence. Nuclear OPN expression was lower than cytoplasmic and was associated with extrathyroid extension of thyroid cancer. OPN plays a role in thyroid carcinoma and incoming research has to be focused on the mechanistic association with invasion and metastasis.

Keywords: Thyroid, Normal, Thyroiditis, Goitre, Adenoma, Carcinoma, Survival, Osteopontin, Immunohistochemistry

How to cite this article:
Gomaa W, Al-Ahwal M, Hamour O, Al-Maghrabi J. Osteopontin cytoplasmic immunoexpression is a predictor of poor disease-free survival in thyroid cancer. J Microsc Ultrastruct 2013;1:8-16

How to cite this URL:
Gomaa W, Al-Ahwal M, Hamour O, Al-Maghrabi J. Osteopontin cytoplasmic immunoexpression is a predictor of poor disease-free survival in thyroid cancer. J Microsc Ultrastruct [serial online] 2013 [cited 2021 Dec 2];1:8-16. Available from: https://www.jmau.org/text.asp?2013/1/1/8/223900

  1. Introduction Top

Thyroid gland tumours are the most common neoplasms of endocrine glands and head and neck region [1],[2]. The incidence of thyroid malignancy is rapidly increasing [3]. Three different types of thyroid cancer have been histologically identified: differentiated thyroid cancer (DTC) derived from thyroid follicular epithelial cells, medullary thyroid cancer (MTC); and anaplastic thyroid cancer (ATC). DTC represent about 90% of thyroid cancers of which papillary thyroid carcinoma (PTC) is the most frequent (75%), followed by follicular thyroid carcinoma (FTC) (10%), Hurthle cell carcinoma (HCC) (5%), and poorly differentiated thyroid carcinoma (1–6%). On the other hand, MTC represents approximately 10% thyroid tumours and ATC nearly 1% [4],[5]. Tumours derived from thyroid follicular epithelium represent a model of malignant transformation [6]. The transformation involves non-neoplastic lesions, benign lesions and malignant tumours including PTC, FTC and ATC [7],[8].

In Saudi Arabia, thyroid cancer (TC) is the fourth most common type of malignancy representing 6.4% of all reported cancers. PTC constitutes a large volume of thyroid cancers followed by FTC. The median age at diagnosis was 44 years among males (range 4–86 years) and 37 years among females (range 8–99 years). The male to female ratio was 1:4. [9].

Osteopontin (OPN) is a secreted and calcium binding phosphorylated glycoprotein and expressed constitutively in a limited number of normal tissues, stress-responsive physiological conditions, and abnormally elevated in some pathological conditions [10]. OPN is considered as cytokine that regulates cell pathways in the immune system [10],[11]. OPN was also expressed in various malignancies and may play important role in tumorigenesis, tumour invasion, and metastasis in various malignancies [12],[13],[14],[15],[16],[17],[18],[19],[20],[21],[22]. In addition, in some malignancies OPN expression was associated with poor prognosis [15]. There are few studies regarding the expression of OPN in thyroid cancer [2],[3],[17],[23],[24],[25],[26]. Some of these studies reported OPN expression as a part of a multi-organ study while others focused in OPN expression in relation to tumour characteristics.

The volume of publications on the subject of OPN in cancer diagnosis is substantially large, however the literature is inconclusive. In addition, there is a growing body regarding OPN expression in thyroid carcinoma especially PTC. However, its role in prognostication has not been fully studied. To increase our understanding of OPN role in thyroid cancer, OPN immunoexpression in a subset of thyroid neoplasms was studied as regards relation to tumour differentiation, invasion, metastasis, recurrence and disease-free survival.

  2. Materials and methods Top

2.1. Patients

The study involved 160 thyroid neoplasms (in the period from 1997 to 2010). Paraffin blocks and patients’ data were retrieved from the archive of the Department of Pathology at King Abdulaziz University, and King Faisal Specialist Hospital & Research Centre, Jeddah, Saudi Arabia. From the surgical specimens of 160 patients, distinct samples were obtained including; 43 benign and 117 malignant. In 108 (67.5%) a background thyroid tissue was present. Data on tumour characteristics, prognostic factors, and follow up were obtained from surgical pathology reports and patients’ records. This data is presented in [Table 1] and [Table 2]. Staging was done according to the American Joint Committee on Cancer (AJCC) [27]. The female to male ratio for malignant cases (117) was 3:1 and age distribution was 79 (67.5%) under 45 years while 38 (32.5%) for 45 years or above. All patient samples and related data analyses were performed after approval by the Research Committee of the Biomedical Ethics Unit, Faculty of Medicine, King Abdulaziz University and the ethical review board of King Faisal Specialist Hospital and Research Centre.
Table 1: Patients' clinicopathological characteristics.

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Table 2: Histological subtyping of thyroid neoplasms included in the study.

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2.2. OPN immunostaining

Paraffin blocks of tumours were cut at 4 μm, and mounted on positive-charged slides (Leica Microsystems Plus Slides). Sections were deparaffinised in xylene and rehydrated in an automated immunostainer (BenchMark XT, Ventana® Medical Systems Inc., Tucson, AZ, USA). Pre-treatment was done using CC1 (prediluted cell conditioning solution) for 60 min. Anti-human rabbit anti-OPN polyclonal antibody (Spring™ Bioscience; Cat # E3281) was incubated at 37°c for 20 min. Ventana® I-view DAB detection kit was used according to kit manufacturer instructions. Subsequently, slides were washed, counterstained with Mayer's haematoxylin and mounted. Negative control (substitution of primary antibody with Trisbuffered saline) and positive control slides (normal breast tissue previously known to be positive to OPN) were included.

2.3. Interpretation of OPN immunostaining

The expression of OPN was examined in thyroid neoplasms and in background thyroid tissues. In order to evaluate OPN extent (%) of cytoplasmic and/or nuclear immunostaining; cells showing cytoplasmic, or nuclear staining were regarded as positive cells. All available cells in each section were counted at microscope magnification 200×. Positive cells for OPN immunostaining were counted. The mean values of positivity were calculated and expressed as percentage in relation to total cells for both cytoplasmic and nuclear immunostaining. Assessment of immunostaining intensity was performed in a semi-quantitatively. The fractions of percentage of positive cells for OPN were divided as follows; (1) 0–25%, (2) 26–50%, (3) 50–100%. For cytoplasmic immunostaining; 3 (heavy and intense brown immunostaining), 2 (brown immunostaining lighter than 3), 1 (brown immunostaining is weak), and 0 (no brown immunostaining). Nuclear staining intensity was scored as: 3 (no blue areas of the nuclei are seen through brown staining), 2 (scarcely blue nuclear staining is seen through brown staining), 1 (blue areas of nuclei are clearly seen through brown staining), and 0 (only blue nuclear staining is seen). A 6-scale scoring system to categorise OPN expression was used by combination of intensity and extent. For the statistical analysis, an OPN immunostaining score of 1–3 was considered as low expression, and an OPN immunostaining score of 4–6 was considered as high expression.

2.4. Statistical analysis

Differences between two groups of patients on one variable were tested by using Mann Whitney test. To test association procedure in three groups of patients on one independent variable the Kruskal Wallis test was used. Wilcoxon signed rank test is used to test differences between two related groups of paired continuous variables Binary logistic regression analysis was used to predict lymph node metastasis, recurrence, and distant metastasis in relation immunoexpression of OPN. Estimated odds ratio [exponential (B)], 95% confidence interval (CI) for exp(B), and significance denoted for each analysis. For purpose of binary logistic analysis clinical stage and pT were dichotomised as low (category 1&2), and high (category 3&4). The Kaplan–Meier procedure was used to calculate the survival probabilities and the Log Rank test was used to compare the difference between survivals. The endpoint for patients was death from tumour (disease-free). Disease-free survival (DFS) was calculated as the time from diagnosis to the appearance of recurrent disease (or date last seen disease-free). Statistical procedures were performed using SPSS® Release 16.0. Statistical significance was determined at p-value of ≤0.05 and was 2-sided.

  3. Results Top

3.1. OPN cytoplasmic immunoexpression

OPN immunoexpression was observed in the cytoplasm of ductal cells of normal breast (positive control). Strong positive staining in colloid as well as macrophages and lymphocytes was seen in nodular goitre, Hashimoto's thyroiditis, and in neoplastic lesions. Also, strong positive staining in Psammoma bodies of PTC. Cytoplasmic OPN immunoexpression was observed in follicular cells normal thyroid, background nodular goitre, Hashimoto's thyroiditis, and in thyroid neoplasms. Representative sections are shown in [Figure 1] and [Figure 2]. OPN cytoplasmic expression was significantly higher than nuclear expression in all lesions examined (details are shown in [Table 3]). In malignant tumours, cytoplasmic expression was significantly higher than in other lesions. Benign tumours showed significantly a higher expression than thyroiditis, goitre and normal thyroid. Thyroiditis and goitre showed a significantly higher cytoplasmic expression than in normal thyroid. On the other hand, there was no statistically significant difference in cytoplasmic expression between thyroiditis and goitre [Table 3] and [Table 4]. There was no statistically significant difference between cytoplasmic expression between PTC and other malignant subtypes (p = 0.203). For PTC subtypes, OPN expression in classic variant was significantly higher than in microcarcinoma variant (p = 0.05). Otherwise, there was no statistically significant difference between other subtypes. There was no statistical significant difference between OPN cytoplasmic expression in follicular adenoma) and Hurthle cell adenoma (p = 0.08).
Figure 1: OPN immunoexpression in benign thyroid lesions. (A) OPN labelling in background normal thyroid tissue. OPN is expressed in the cytoplasm and nucleus of follicular cells [arrow]. Patchy strong staining is also observed within colloid (200×). (B) OPN labelling in background nodular goitre. Cytoplasmicand nuclear [arrow] labelling is shown in follicular cells (200×). (C) OPN labelling in background Hashimoto's thyroiditis. Cytoplasmic labelling is observedin follicular epithelium and in lymphocytes and macrophages. Nuclear labelling is seen also in follicular cells [arrow] (200×). (D) OPN labelling in follicularadenoma. Cytoplasmic staining is more prevalent and intense than previous sections. Nuclear labelling [arrows] is also seen (200×). Immunohistochemical labelling was done using anti-OPN antibody, diaminobenzidine as the chromogen, and haematoxylin as counterstain.

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Figure 2: OPN immunoexpression in malignant thyroid tumours. (A) OPN labelling in PTC. OPN is intensely and widely expressed in the cytoplasm and nucleus [arrow] of malignant follicular cells (200×). (B) OPN labelling in HCC. Cytoplasmic and nuclear [arrow] labelling is shown in malignant follicular cells (200×). (C) OPN labelling in FTC. Cytoplasmic labelling is observed in malignant follicular. Nuclear labelling is seen also in malignant follicular cells[arrow] (200×). (D) OPN labelling in ATC. Cytoplasmic and nuclear labelling [arrow] are seen in anaplastic cells (200×). Immunohistochemical labelling was done using anti-OPN antibody, diaminobenzidine as the chromogen, and haematoxylin as counterstain.

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Table 3: Distribution of scoring categories of OPN immunoexpression.

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Table 4: Differences in OPN immunoexpression in thyroid lesions examined.

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3.2. Relation of OPN immunoexpression in malignant cases to clinicopathological parameters

Details of the relation of OPN cytoplasmic expression with clinicopathological parameters are presented in [Table 5] and [Table 6]. OPN cytoplasmic expression was not associated with most of the clinicopathological parameters tests. However, statistically there was a narrow significant difference in some parameters; age, multifocality, lymphovascular invasion, and margin status. On the other hand, OPN cytoplasmic expression showed higher expression in patients who died than those alive (p = 0.012).
Table 5: Distribution of OPN cytoplasmic immunoexpression in relation to clinicopathological parameters of thyroid carcinoma (n = 117).

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Table 6: Regression analysis for OPN cytoplasmic immunoexpression.

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Binary logistic regression analysis showed that OPN cytoplasmic expression was an independent predictor of positivity of surgical resection margins and recurrence. However, OPN was not proven to be an independent predictor of nodal metastasis, distant metastasis, capsular invasion, or lymphovascular invasion. Kaplan–Meier survival analyses showed that OPN cytoplasmic immunoexpression in malignant cases had significant association with poor disease-free survival outcome (log rank = 11.975, p<0.001) [Figure 3].
Figure 3: Disease-free survival curve (Kaplan–Meier). (A) OPN cytoplasmic expression (log rank = 11.975, p < 0.001). (B) OPN nuclear expression (log rank = 0.011, p = 0.916).

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3.3. Osteopontin nuclear immunoexpression

Nuclear OPN expression was observed in all lesions examined. Representative sections are shown in [Figure 1] and [Figure 2]. Expression was lower than cytoplasmic expression. In addition, expression was higher in malignant cases than in benign, thyroiditis, goitre, and normal thyroid. However, there was no difference between other lesions [Table 4]. Binary logistic regression analysis showed that OPN nuclear expression was not proven to be an independent predictor of any of the parameters tested expect extrathyroid extension [p = 0.035] [Table 7]. There was no association between OPN nuclear expression and disease free survival [Figure 3] (log rank = 0.011, p = 0.916).
Table 7: Regression analysis for OPN nuclear immunoexpression.

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  4. Discussion Top

The histological distinction between some benign tumours and well-differentiated malignant thyroid neoplasms has many diagnostic difficulties. Moreover, a small group of patients with well-differentiated thyroid malignancies are subject to develop metastasis and subsequently a more aggressive management is required [23]. There is an advance in understanding the molecular events involved in thyroid cancer. However, the full understating of the molecular background of thyroid cancer needs to be unveiled for better diagnostic and therapeutic interventions. The efforts are being raised everywhere to discover more molecular markers of thyroid cancer for clinical application both diagnostic and prognostic.

OPN is a secreted protein and also is found intracellularly. OPN is involved in different pathophysiological situations. The intracellular OPN has cellular functions different from the secreted OPN as involvement in signal transduction pathways as well as cytoskeletal rearrangement and cell motility [28],[29],[30]. OPN had been shown to be overexpressed in several tumour types [15],[31] and OPN overexpression showed a strong correlation between levels of OPN protein and tumour progression in multiple tumour types from different anatomical sites and correlated with poor disease-free and overall patients survival [17],[32],[33].

The current study involved a group of thyroid tumours (benign and malignant) together with background thyroid tissues to characterise OPN immunoexpression. There was a dual subcellular OPN immunolocalisation; cytoplasmic and nuclear. This study showed for the first time the nuclear localisation of OPN in thyroid gland and its relation to patients’ outcome in malignant lesions. In our study, the cytoplasmic expression was dominant than nuclear expression in all tissues examined from normal to malignant tumours. Previously, OPN was shown to be perimembranous and cytoplasmic [34],[35],[36]. In thyroid cancers, only cytoplasmic localisation was reported and one study reported a cytoplasmic and membranous localisation [23]. In the current study, there was a strong immunostaining of OPN in colloid within normal thyroid follicles, goitre, and thyroiditis in addition to psammoma bodies. OPN immunoexpression was found also in macrophages in all lesions examined. These findings were reported as regarding psammoma bodies and macrophages in PTC [24]. The presence of OPN immunolocalisation in colloid and in psammoma bodies supports OPN role in thyroid physiological and pathological conditions. Our series of follicular adenoma and Hurthle cell adenoma is a large series reporting OPN expression than previous reports [3],[23]. OPN immunoexpression in adenoma was higher than in thyroiditis, goitre, and normal thyroid which is similar to reported previously [23]. In this study, OPN cytoplasmic immunoexpression was significantly higher in primary thyroid carcinoma than in other benign lesions and normal thyroid tissues. This stepwise increase from normal to thyroid carcinoma is consistent with previous reports [2],[3],[23],[26]. These findings raise the possibility that OPN may be used in differentiating benign thyroid lesions from malignant and supports than OPN overexpression is associated with tumorigenesis.

In our study, PTC constitutes the major bulk of malignant cases. In a recent study by Kang et al., OPN expression was lower in FV-PTC than other subtypes, and subsequently, they suggested that FV-PTC variant has better prognosis [3]. This notion was previously reported by Guarino and his colleagues [26]. In the current study, OPN cytoplasmic immunoexpression was higher in classic PTC than PTC microcarcinoma variant. PTC microcarcinoma is suggested to be an earlier stage in the papillary carcinogenesis [37]. This variant is considered as an indolent tumour with a relatively benign course because there is prevalence up to 35% in autopsy series and is also detected in up to 24% in total thyroidectomies for other benign condition [38],[39],[40]. This finding supports the relation of OPN upregulation with more aggressive variants in PTC.

In our study, the cytoplasmic expression of OPN in malignant lesions showed no association with gender, extrathyroid extension, capsular invasion, tumour size, stage, nodal metastasis, distant metastasis, margin status, or recurrence which was similar to that reported by Briese et al. [23]. OPN overexpression was associated with stage, grade and progression, and poor prognosis in many cancers [32]. Other few studies on thyroid malignancy showed different findings from ours. Sun et al., found that OPN is overexpressed in primary tumours with nodal metastasis than those without nodal metastasis [2],[3]. Guarino et al. reported the same in addition to OPN correlation with larger tumour size [26]. Also OPN overexpression was reported to be prominent at the invasive front of tumour as well as necrotic areas [25]. The conflicting results may be related using OPN expression on mRNA level, using OPN immunostaining intensity only and in part due to too small sample size.

The mechanistic link between OPN and tumour growth and metastasis has been suggested and studied in different tumours with few on PTC. OPN overexpression in tumour metastasis is associated with more malignant phenotype [41],[42]. OPN exerts its tumorigenic effects through CD44 variants and/or binding to αvβ integrins and promotes signalling pathways involved in tumour cell adhesion, migration, and lymph node metastasis [2],[43]. In PTC cell lines and tissues, OPN upregulation is characterised by the presence of RET-RAS-MAPK rearrangements [3],[26],[44],[45]. In breast cancer, STAT3 is suggested to play an essential role in mediating OPN-related tumorigenesis [46]. Antiapoptotic effect of OPN may be implicated in facilitating tumour growth [47]. There may be a link between OPN overexpression and induction of growth factors as the hepatocyte growth factor [48],[49] and angiogenesis [50]. OPN-related enhancement of tumour growth may involve matrix-degrading enzymes [51], which was supported in prostate cancer with positive correlation between matrix metalloproteinase-9 expression and OPN [45].

Although there was no association of OPN cytoplasmic immunoexpression and most clinicopathological features, interestingly in this study, the patients died earlier showed higher cytoplasmic OPN immunostaining. In addition, OPN cytoplasmic overexpression is associated with poor survival outcome. This finding is novel for our study and has not been reported before. In our study, nuclear OPN expression was significantly higher in thyroid cancer than other lesion. This means that nuclear localisation in malignancy is associated with tumorigenicity. Nuclear OPN is suggested to play a role in mitosis and correlated with chromatin condensation during cell division [34]. This is the first published work regarding the relation between OPN nuclear immunolocalisation and clinicopathological features in thyroid cancer. However, there was no association of nuclear OPN expression with any of these features apart from extrathyroid extension.

In our perspective, the limitations of the current study were short survival times in recently diagnosed patients. In addition, samples from nodal metastasis are better to be compared with primary tumours.

  5. Conclusion Top

In this subset of thyroid lesions cytoplasmic OPN immunoexpression showed a stepwise upregulation from normal thyroid up to malignant lesions. OPN cytoplasmic expression was not associated with most clinicopathological features; however OPN overexpression is associated with poor survival outcome. Nuclear OPN expression was less than cytoplasmic and is associated with extrathyroid extension of thyroid cancer. The current results showed that there may be an association between OPN overexpression and thyroid carcinogenesis. Whether OPN plays a role or not is yet to be determined by focusing on its mechanistic association with invasion and metastasis.

Conflict of interest

The authors confirm that no part of this work has been submitted or published elsewhere and that there are no conflicts of interest.

Authors’ contributions

WG made substantial contributions to the design of the study, scored osteopontin immunostaining, interpreted data, performed statistical analysis, and drafted the manuscript. MA reviewed the clinical data and contributed to the design of the study and revised the manuscript. OH reviewed the clinical data and contributed to the design of the study and revised the manuscript. JM performed histological examination and selection of paraffin blocks included in study, contributed to the design of the study and revised the manuscript. The manuscript has been read and approved by all of the authors, the requirements for authorship have been met, and each author believes that the manuscript represents honest work.

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  [Figure 1], [Figure 2], [Figure 3]

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]

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