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ORIGINAL ARTICLE
Year : 2019  |  Volume : 16  |  Issue : 3  |  Page : 95-99

Assessment of serum midkine level in benign and malignant thyroid nodules. Can midkine be a marker of thyroid malignancy?


1 Department of Internal Medicine and Endocrinology, Faculty of Medicine, Ain Shams University, Cairo, Egypt
2 Department of Internal Medicine, National Institute of Diabetes and Endocrinology, Cairo, Egypt

Date of Submission10-Oct-2019
Date of Acceptance23-Oct-2019
Date of Web Publication18-Nov-2019

Correspondence Address:
Dr. Rana Hashem Ibrahim Elattary
New Cairo, 1st Setellment, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_38_19

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  Abstract 


Background: Thyroid nodules are a common clinical problem. The prevalence of malignancy in thyroid nodules is currently about 5%–15%. Fine-needle aspiration biopsy (FNAB) has improved the preoperative prediction of malignancy, but still has disadvantages including operator variability and nondiagnostic reports. Midkine (MK) is a novel heparin-binding growth factor; MK levels have been proposed as indicative of malignancy in numerous tumors. MK overexpression in thyroid cancer has been reported to be in correlation with clinicopathological features of the tumor, hypothesizing that MK might play a role as a biomarker for diagnosis and more aggressive behavior of thyroid cancer.
Aim: The aim of this study is to evaluate the value of serum MK (SMK) as a marker of malignancy in patients with nodular thyroid disease.
Patients and Methods: The current study included 75 individuals with age ranging from 25 to 80 years divided into 25 with malignant thyroid nodule (Group A), 25 with benign thyroid nodule (Group B), and 25 healthy individuals as a control group (Group C). Free triiodothyronine, free thyroxin, thyroid-stimulating hormone, and SMK levels were assessed. Individuals with thyroid nodules were submitted for neck ultrasonography and FNAB.
Results: On comparing the three studied groups, a high statistically significant difference in plasma MK levels was found (P < 0.001), being higher in Group A (malignant nodule) with a mean of 1.127 ± 0.527 than Group B (benign nodule) with a mean of 0.536 ± 0.301 with P < 0.001* and also higher in Group A (malignant nodule) with a mean of 1.127 ± 0.527 than Group C (control) with a mean of 0.366 ± 0.230 with P < 0.001*. There was significant difference regarding MK levels, with thyroid nodule contour being higher in thyroid nodule with irregular contour than thyroid nodule with regular contour (P < 0.001*) and calcification being higher in microcalcification than macrocalcification (P = 0.006*). There was high statistically significant difference regarding the level of MK between papillary carcinoma and follicular carcinoma (P < 0.001*).
Conclusions: SMK might be the indicator of malignant thyroid cytopathology, suggesting that MK might serve as a novel biomarker in the assessment of thyroid nodules. The present study explored the usefulness of MK as a biomarker in the differentiation between benign and malignant thyroid nodules in samples from serum.

Keywords: Benign/malignant thyroid nodules, free thyroxin, free triiodothyronine, serum midkine, thyroid malignancy, thyroid-stimulating hormone


How to cite this article:
Sheriba NA, Mahdy MM, Elattary RH, El-Nabarawy MM. Assessment of serum midkine level in benign and malignant thyroid nodules. Can midkine be a marker of thyroid malignancy?. Thyroid Res Pract 2019;16:95-9

How to cite this URL:
Sheriba NA, Mahdy MM, Elattary RH, El-Nabarawy MM. Assessment of serum midkine level in benign and malignant thyroid nodules. Can midkine be a marker of thyroid malignancy?. Thyroid Res Pract [serial online] 2019 [cited 2019 Dec 15];16:95-9. Available from: http://www.thetrp.net/text.asp?2019/16/3/95/271157




  Introduction Top


Thyroid nodule is typically asymptomatic, and 33%–68% of adults have thyroid nodules when evaluated by ultrasound. Most thyroid nodules are benign, but about 7%–15% of individuals with thyroid nodules harbor thyroid cancer. Thyroid nodules may also cause morbidity due to hyperthyroidism or local compression.[1]

Optimal prediction of malignancy in nodular thyroid disease is needed to achieve the best medical and surgical intervention. Fine-needle aspiration biopsy (FNAB) is widely used and has improved preoperative prediction of malignancy, but still has disadvantages including operator variability and nondiagnostic reports. Therefore, researchers have focused on identifying novel biologic markers that might be associated with malignancy in thyroid nodules.[2]

Midkine (MK) is a multifunctional cytokine predominantly expressed during embryogenesis, while in adult organisms, its expression is resumed during inflammation, tissue repair, and carcinogenesis. MK displays a number of activities that might be relevant for cancer development, for example, it has been demonstrated to act as a mitogen, an antiapoptotic, an angiogenic factor, a chemoattractant, a haptotactic factor, an immunomodulator, and an inductor of synthesis of several cytokines and growth factors, such as interleukin-8, transforming growth factor-beta, macrophage inflammatory protein-2, and monocyte chemotactic protein-1.[3]

In thyroid cancer, tissue MK overexpression has been reported to be in correlation with the clinicopathological features of the tumor, hypothesizing that MK might play a role as a biomarker for diagnosis and more aggressive behavior of thyroid cancer such as lymph node metastasis and extrathyroidal invasion. In addition, it has been found that benign adenomatoid nodules showed less MK overexpression than the malignant nodules.[4]

Aim of work

The aim of this study is to evaluate the value of serum MK (SMK) as a marker of malignancy in patients with nodular thyroid disease.


  Patients and Methods Top


This is a case–control study that included 75 individuals with age ranging from 25 to 80 years, enrolled from the Outpatient Clinic of Internal Medicine and Endocrinology of Ain shams University Hospital. Before inclusion, an oral consent was obtained from each patient after full explanation of the study protocol. The study participants were divided into three groups as follows: 25 individuals with malignant thyroid nodule proven by ultrasonography features and FNAB (Group A), 25 individuals with benign thyroid nodule proven by ultrasonography features and FNAB (Group B), and 25 normal individuals as control group (Group C). Exclusion criteria included patients with other malignancies, those with any inflammatory disease, or those with any tissue injuries.

Full medical history was taken from all participants, and thorough thyroid gland clinical examination was done.

Laboratory studies

Laboratory tests included thyroid profile (free triiodothyronine, free thyroxin, and thyroid-stimulating hormone which were measured using a double-antibody sandwich enzyme-linked immunosorbent assay [ELISA]) and SMK which was measured using a double-antibody sandwich ELISA.

The study participants with thyroid nodules (both benign and malignant) were submitted for neck ultrasonography, including sonographic features of thyroidal nodules and FNAB (by ultrasound guided).

Statistical analysis

Data analysis was performed using the SPSS program (version 17, 2012, IBM Corporation, USA). Quantitative data were expressed as mean ± standard deviation (SD), whereas numbers and percentages were used for qualitative data. Independent samples t-test was used when comparing two groups. One-way analysis of variance was used to compare between several groups. Post hoc test (Tukey's) was used to identify the least significant difference among the studied groups. Pearson's correlation coefficient (r) test was used for correlating data. Chi square test was used to compare nonparametric variables, in non- parametric data. Probability (P-value) less than 0.05 was considered significant and less than 0.01 was considered as highly significant.


  Results Top


This study was conducted on 75 individuals, with age ranging from 25 to 80 years. On comparing the three studied groups, there was a high statistically significant difference in plasma MK levels between them with P < 0.001, being higher in Group A (malignant nodule) with a mean of 1.127 ± 0.527 than Group B (benign nodule) with a mean of 0.536 ± 0.301 than Group C (control) with a mean of 0.366 ± 0.230 [Table 1].
Table 1: The comparison regarding thyroid profile done using kruskal-wallis test,(range,median) comparison regarding midkine level done using anova test( range, mean)

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On comparing Group A (malignant nodule) and Group B (benign nodule) with regard to sonographic features of the nodules, there was high statistically significant difference regarding contour of the nodule with P = 0.001, in which 52% of Group A individuals (malignant nodule) had nodules with irregular contour, 48% had nodules with regular contour, whereas in Group B (benign nodule), only 8% had nodules with irregular contour and 92% had nodules with regular contour. Regarding calcifications with P = 0.002*, 36% of Group A individuals (malignant nodule) had nodules with no calcifications, 44% had nodules with microcalcifications, and 20% had nodules with macrocalcifications, whereas 84% of Group B (benign nodule) had nodules with no calcifications, 8% had nodules with microcalcifications, and 8% had nodules with macrocalcifications [Table 2].
Table 2: Comparison between Group A and Group B with regard to thyroid profile (thyroid-stimulating hormone, free triiodothyronine, and free thyroxin) and serum midkine level

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On comparing the different parameters of subcategories regarding the level of MK, we found that MK was statistically significantly higher in thyroid nodule with irregular contour than that with regular contour (P< 0.001*), with microcalcification than with macrocalcification (P = 0.006*), and it was statistically significantly higher in papillary carcinoma than follicular carcinoma and follicular adenoma after doing FNAB (P< 0.001*) [Table 3]; it has a significant positive correlation with the size of the nodule and age [Table 4].
Table 3: Comparing the different parameters of subcategories regarding the level of midkine

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Table 4: Correlation between midkine and all variables (age, thyroid-stimulating hormone, free triiodothyronine, free thyroxine, and size of nodules) in all patient groups

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  Discussion Top


The current study showed that SMK was statistically significantly higher in individuals with thyroid nodules and more in those with malignant nodules when compared to control group (P< 0.001). This agreed with the study of Ikematsu et al., 2000, who studied 135 normal and 150 cancer patients (including thyroid cancer) and found higher serum midkine (SMK) concentrations in various cancer types than normal persons and reported a reduction in SMK concentrations after surgery.[5]

On further evaluation of the patients with thyroid nodules, it was found that SMK was significantly higher in patients with malignant nodules than those with benign nodules (P< 0.001). Similarly, in a study by Jia et al., 2016, where TgAb-positive differentiated thyroid cancer (DTC) patients with and without metastases were tested for SMK level and assessed against benign thyroid nodules to assess whether MK could be a surrogate biomarker when Tg was not suitable to monitor the disease. They also found better diagnostic capability of MK to differentiate DTC from benign thyroid nodules and also displayed that MK was a good marker for predicting DTC metastases (P< 0.001).[6]

Furthermore, in a study by Zhang et al., 2014, 76 cases of papillary thyroid carcinoma (PTC) and 70 cases of multinodular goiter (MNG) were retrieved. The PTC group was further divided into subgroup 1 (16 cases with synchronous metastases) and subgroup 2 (60 cases without metastases). MK level was significantly higher in the PTC group than in the MNG group with good differential diagnostic capabilities.[7]

This was disagreed with the study done by Kuzu et al., 2016, on 105 patients between the ages of 26 and 82 years with nodular goiter, and the levels of SMK and nodular midkine were measured. The levels of SMK were higher in patients with malignant nodules than in the patients with benign nodules, but the difference was statistically insignificant (P = 0.066) (P > 0.05). This difference could be attributed to lack of data on alteration of MK levels or the low number of malignant cases in both studies.[2]

On comparing Group A (malignant nodules group) with Group B (benign nodules group), there was a significant difference between both groups in contour of nodules (P< 0.001), where malignant group had more nodules with irregular border than the benign group, and further statistical analysis showed higher MK level in nodules with irregular border (1.1 ± 0.5) than in those with regular border (0.7 ± 0.4) (P = 0.013).

In agreement to our study, Kuzu et al., 2016, stated that MK levels were detected as being statistically significantly higher in nodules with irregular border than those with regular borders (P = 0.001).[2]

On comparing Group A (malignant nodules group) with Group B (benign nodules group), there was a statistically significant difference between both groups in calcification of nodules (P = 0.002), where malignant group showed more nodules with microcalcifications than those with macrocalcifications or no calcifications, and further analysis showed a higher level of MK in nodules with microcalcifications than that with macrocalcifications (P = 0.006).

In agreement to our study, Kuzu et al., 2016, stated that MK levels were detected as being statistically significantly higher in nodules containing microcalcification than those with macrocalcification or without calcification (P = 0.001). There was no significant difference between the levels of MK for patients with nodules containing macrocalcification and no calcification.[2]

A retrospective case–control study was done by Smith-Bindman et al., 2014, on 8806 patients who underwent 11,618 thyroid ultrasound examinations during the study period including 105 patients subsequently diagnosed with thyroid cancer. The ultrasound nodule characteristics such as microcalcifications, size >2 cm, and an entirely solid composition were the only findings associated with the risk of thyroid cancer.[8]

Regarding MK and FNA results of Group A (malignant nodules group), there was highly statistically significant difference between papillary and follicular carcinomas (P< 0.001), where MK level was significantly increased in papillary cancer nodules with a level of 1.2 ± 0.5 in comparison of a level of 0.8 ± 0.4 in follicular carcinoma nodules.

Similarly, in the study by Jee et al., 2015, which found that there is higher MK/TG ratio in FNAB materials were obtained from PTC than follicular carcinoma, and higher MK concentrations in FNAB materials were obtained from PTC than the MK concentrations found in patients with benign thyroid disease but the difference was statistically insignificant. The discrepancy in findings might be due to the use of different assays, which might, for example, detect different variants of MDK. The study also reported that metastatic PTC had more MK concentrations than those without metastasis and argued that MK may be beneficial both in the diagnosis and in the prognosis of malignant thyroid disease.[9]

On correlating different parameters with each other in all the three groups, we found that there was a statistically significant positive correlation between MK and age (r = 0.317) and size of nodules (r = 0.306) (P< 0.05).


  Conclusions Top


It can be concluded that SMK was significantly higher in patients with thyroid nodules compared to control group and significantly higher in those with malignant than with benign nodules. which might be the indicator of malignent thyroid cytopathy, suggesting that MK might serve as a novel biomarker in the assessment of thyroid nodules? The present study explored the usefulness of MK as a biomarker in the differentiation between benign and malignant thyroid nodules in samples from serum.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Dionigi G. Surgery for benign thyroid disease in 2018. Gland Surg 2018;7:239-41.  Back to cited text no. 1
    
2.
Kuzu F, Arpaci D, Unal M, Altas A, Haytaoglu G, Can M, et al. Midkine: A Novel biomarker to predict malignancy in patients with nodular thyroid disease. Int J Endocrinol 2016;2016:6035024.  Back to cited text no. 2
    
3.
Krzystek-Korpacka M, Diakowska D, Grabowski K, Gamian A. Tumor location determines midkine level and its association with the disease progression in colorectal cancer patients: A pilot study. Int J Colorectal Dis 2012;27:1319-24.  Back to cited text no. 3
    
4.
Kato M, Shinozawa T, Kato S, Awaya A, Terada T. Increased midkine expression in hepatocellular carcinoma. Arch Pathol Lab Med 2000;124:848-52.  Back to cited text no. 4
    
5.
Ikematsu S, Yano A, Aridome K, Kikuchi M, Kumai H, Nagano H, et al. Serum midkine levels are increased in patients with various types of carcinomas. Br J Cancer 2000;83:701-6.  Back to cited text no. 5
    
6.
Jia Q, Meng Z, Xu K, He X, Tan J, Zhang G, et al. Serum midkine as a surrogate biomarker for metastatic prediction in differentiated thyroid cancer patients with positive thyroglobulin antibody. Sci Rep 2017;7:43516.  Back to cited text no. 6
    
7.
Zhang Y, Meng Z, Zhang M, Tan J, Tian W, He X, et al. Immunohistochemical evaluation of midkine and nuclear factor-kappa B as diagnostic biomarkers for papillary thyroid cancer and synchronous metastasis. Life Sci 2014;118:39-45.  Back to cited text no. 7
    
8.
Smith-Bindman R, Lebda P, Feldstein VA, Sellami D, Goldstein RB, Brasic N, et al. Risk of thyroid cancer based on thyroid ultrasound imaging characteristics: Results of a population-based study. JAMA Intern Med 2013;173:1788-96.  Back to cited text no. 8
    
9.
Jee YH, Celi FS, Sampson M, Sacks DB, Remaley AT, Kebebew E, et al. Midkine concentrations in fine-needle aspiration of benign and malignant thyroid nodules. Clin Endocrinol (Oxf) 2015;83:977-84.  Back to cited text no. 9
    



 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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