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  Table of Contents    
ORIGINAL ARTICLE  
Year : 2020  |  Volume : 63  |  Issue : 4  |  Page : 544-550
The clinical usefulness of chemokine C-X-C Motif Ligand 12 as a diagnostic marker for Papillary Thyroid Carcinoma


1 Department of Internal Medicine, Jeju National University Hospital, Jeju National University School of Medicine, Jeju City, Republic of Korea
2 Department of Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju City, Republic of Korea
3 Department of Anethesiology, Jeju National University Hospital, Jeju National University School of Medicine, Jeju City, Republic of Korea
4 Department of Thoracic and Cardiovascular Surgery, Jeju National University Hospital, Jeju National University School of Medicine, Jeju City, Republic of Korea
5 Department of Pathology Jeju National University Hospital, Jeju National University School of Medicine, Jeju City, Republic of Korea

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Date of Submission17-Sep-2019
Date of Decision19-Jan-2020
Date of Acceptance20-Jan-2020
Date of Web Publication28-Oct-2020
 

   Abstract 


Background: Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer worldwide. It is essential to develop methods for the accurate diagnosis of PTC to avoid unnecessary surgery. The chemokine C-X-C motif ligand 12 (CXCL12) is associated with various cancers. We aimed to investigate the efficacy of CXCL12 in the diagnosis of PTC in fine-needle aspiration (FNA) specimens. Methods: We prospectively collected samples from 58 patients who were scheduled for surgical treatment of PTC from 2013 to 2015. Tissue samples of 31 people with benign thyroid conditions were used as controls. Immunocytochemical and immunohistochemical staining for CXCL12 was performed on FNAs and corresponding tissue specimens. B-type Raf kinase (BRAF) V600E mutant protein expression and gene mutation were also analyzed to compare the clinical usefulness. Results: The mean age of the patients was 49.1 ± 1.4 years and 88.1% were women. Positive CXCL12 staining was observed in 6.5% of benign and in 98.3% of PTC samples; positive BRAF V600E mutant protein expression was found in 19.4% of benign and 93.1% of PTC samples. For the diagnosis of PTC for CXCL12 staining of FNA specimens, the calculated values were 93.1% sensitivity, 90.3% specificity, 94.7% positive predictive value, 87.5% negative predictive value, and 89.1% accuracy. CXCL12 had 100% sensitivity and specificity for the 12 cases of atypia of undetermined significance (AUS) diagnosed in FNA specimens. Conclusions: CXCL12 may be a useful diagnostic tool for PTC, especially when the FNA specimen is classified as AUS.

Keywords: AUS, CXCL12, PTC

How to cite this article:
Lee SA, Choi JH, Cho SJ, Chang JW, Maeng YH. The clinical usefulness of chemokine C-X-C Motif Ligand 12 as a diagnostic marker for Papillary Thyroid Carcinoma. Indian J Pathol Microbiol 2020;63:544-50

How to cite this URL:
Lee SA, Choi JH, Cho SJ, Chang JW, Maeng YH. The clinical usefulness of chemokine C-X-C Motif Ligand 12 as a diagnostic marker for Papillary Thyroid Carcinoma. Indian J Pathol Microbiol [serial online] 2020 [cited 2020 Dec 1];63:544-50. Available from: https://www.ijpmonline.org/text.asp?2020/63/4/544/299323





   Introduction Top


The incidence of thyroid cancer has increased worldwide, and the greatest growth has occurred in developed countries.[1] In Korea, thyroid cancer is ranked by the National Information Center as the leading type of cancer in women, with an incidence of 91.9 per 100,000 people. The incidence of this cancer has increased 25% annually over the past 10 decades.[2] It has been suggested that screening is the main factor driving this increase in the incidence of thyroid cancer. However, Cho et al. reported that the incidence of thyroid cancer has also increased in children, who do not undergo routine health examinations,[3] which suggests that the increasing incidence of thyroid cancer cannot be explained fully by the increased rate of screening alone.

Some investigators have become concerned about the rapidly increasing incidence and overdiagnosis of papillary thyroid carcinoma (PTC) in Korea.[2] It is simultaneously important to be able to avoid unnecessary surgery, undesirable consequences, and missing atypical cases with aggressive progression.[4] In the 1990s, when physicians did not assertively try to diagnose PTC, the EUROCARE working group reported that the 5-year survival rate for thyroid cancer was 71% for men, 79% for women, and 37%–42% in elderly patients.[5] In Korea, the 5-year survival rate for thyroid cancer has improved to nearly 100% because of efforts in the early detection and treatment using various methods.[6]

However, some concerns remain about the acute and chronic side effects of PTC treatment, including hoarseness, vocal cord paralysis, hypoparathyroidism, bleeding, and dry mouth. These side effects can be prevented by accurate diagnosis, appropriate selection of patients requiring surgery, and the development of markers that predict a poor prognosis. Therefore, it is necessary to develop methods for the accurate diagnosis of thyroid cancer, especially the most common pathological form, PTC, to avoid unnecessary surgery and to increase the chance of long-term survival.

Fine-needle aspiration (FNA) cytology is considered to be the best diagnostic test for confirming PTC in thyroid nodules. Although the cytology findings are usually straightforward, achieving an accurate diagnosis remains challenging for several reasons. First, a cytological aspirate specimen containing few cells with considerable nuclear atypia is often categorized as atypia of undetermined significance (AUS) by the Bethesda classification system.[6] AUS has a possibility of up to 15% of being thyroid cancer.[7] Repeated AUS identified in subsequent FNA specimens can lead to difficult decisions about whether to observe, undertake surgery, or use another diagnostic marker. Second, BRAF mutations are helpful for diagnosing PTC but have a low negative predictive value (NPV).[8] Third, other genetic mutations have been reported, but mutation studies are expensive and have some limitations when applying the results to clinical situations.[9],[10],[11] A more accurate diagnostic marker for PTC needs to be developed, especially for the cases of AUS, also called stromal cell-derived factor 1, is a member of the chemokine family that functions in conjunction with the G-protein-coupled receptor chemokine C-X-C motif receptor 4 (CXCR4).[12] The molecular mechanisms underlying the biological effects of CXCL12 are associated with the CXCR4-mediated activation of G-protein-coupled signaling molecules, including extracellular signal-regulated kinase 1/2, mitogen-activated protein kinase, c-Jun N-terminal kinase, and AKT.[13],[14] Although CXCL12 expression has been reported to have prognostic significance in some cancers,[15],[16] few studies have reported on the diagnostic role of CXCL12 expression in thyroid cancer.[17],[18] In this study, we evaluated the clinical usefulness of CXCL12 immunoreactivity in the diagnosis of PTC and compared its efficacy with that of BRAF V600E gene mutation analysis and detection of BRAF V600E mutant protein.


   Materials and Methods Top


Patients

Between 2013 and 2015, we collected samples from 59 patients who were scheduled for surgery because of thyroid nodules. The cytology diagnosis according to the Bethesda classification system included 1 benign, 12 AUS, 7 suspicious for malignancy, and 39 malignant specimens. Thirty tissue samples of benign thyroid conditions were obtained from the Korea Biobank (No. A-07) and used as controls. The study was conducted with the approval of the Institutional Review Board (IRB No. 2013-01-002). Written informed consent was obtained from all participants in this study. The biospecimens and data used for this study were provided by the Korea Biobank Network (No. A-07).

Protocol

The patients were diagnosed by FNA using a conventional smear technique in the usual clinical settings. We repeated the FNA for liquid-based cytology (LBC), in an operating room with the patient under anesthesia to avoid unnecessary pain. Routine Papanicolaou staining and immunocytochemical studies for CXCL12 and BRAF V600E mutant protein were performed on the LBC specimens. Surgically resected tissue specimens were also tested for routine diagnosis, immunohistochemical staining for CXCL12 and BRAF V600E mutant protein, and BRAF V600E gene mutation using a peptide nucleic acid (PNA) clamp methods.

Tissue microarray construction

Two tissue microarrays (TMAs) were constructed as described previously. In brief, hematoxylin and eosin (H&E)-stained slides were reviewed and the most representative tumor area was marked. The area was carefully marked on both H&E-stained slides and formalin-fixed, paraffin-embedded tissue blocks. A core (2 mm in diameter) of the representative area was obtained from each of fifty-nine cases of PTC and thirty cases of benign thyroid diseases, which included normal thyroid, nodular hyperplasia, follicular adenoma, and Hashimoto's thyroiditis. One section from each block was stained with H and E for tissue confirmation.

Immunohistochemistry and immunocytochemistry

Immunohistochemical staining was performed on 4 μm-thick sections from TMA blocks. Tissues were stained with anti-CXCL12 antibody (R&D Systems, Minneapolis, MN, USA; 1:50 dilution) and anti-BRAF V600E monoclonal antibody (Spring Bioscience, Pleasanton, CA, USA; 1:50 dilution) using an automated immunostainer (Benchmark XT; Ventana Medical Systems Inc., Tucson, AZ, USA). For immunocytochemical staining of FNA samples, cells on LBC slides were fixed in 95% ethyl alcohol for 30 min and then processed as for immunohistochemistry.

The immunohistochemical and immunocytochemical staining results of TMA and FNA slides were examined independently. The extent of cytoplasmic staining was graded from 0 to 3+ as follows: 0, negative; 1+, focal weak staining; 2+, diffuse weak or focal strong staining; and 3+, diffuse strong staining. Scores of 1+, 2+, and 3+ were considered positive, and a score of 0 was considered negative. All specimens were scored twice by a pathologist (YHM) who was blinded to the mutation analysis results, and the evaluation was repeated by an independent observer. If discrepancies occurred, a consensus score was reached.

DNA extraction

A representative slide was selected from each tissue sample, and the most relevant area was marked for manual microdissection. Genomic DNA was extracted from 10-μm-thick sections of formalin-fixed paraffin-embedded tissue using a QIAamp DNA FFPE tissue kit (Qiagen, Valencia, CA, USA) according to the manufacturer's instructions.

Detection of the BRAF V600E mutation

The presence of the BRAF V600E mutation was tested using a PNA Clamp BRAF Mutation Detection kit (Panagene, Daejeon, Korea) according to the manufacturer's instructions. All reactions were performed in a total volume of 20 μL containing template DNA, the primer and PNA probe set, and real-time SYBR Green PCR Master Mix. All required reagents were included in the kit. The PCR cycling conditions were at 94°C for 5 min followed by 40 cycles of four steps at different temperature: 94°C for 30 s, 70°C for 20 s, 63°C for 30 s, and 72°C for 30 s.

The PNA probe, which is designed to hybridize completely to the wild-type BRAF allele, suppresses amplification of wild-type targets but allows amplification of the mutant allele. The threshold cycle (Ct) was automatically calculated from the PCR amplification plots where fluorescence was plotted against the number of cycles. The changes in Ct value (ΔCt) were calculated as the Ct value of the PCR of the samples minus the Ct value of the PCR of the PNA control. Higher ΔCt values indicate that the mutant was efficiently amplified. The cutoff value of 2.0 was used for identifying the presence of mutant DNA.

Statistical analysis

Statistical analysis was performed using PASW Statistics for Windows (version 18.0; SPSS Inc., Chicago, IL, USA). We calculated the sensitivity, specificity, positive predictive value (PPV) and NPV, and diagnostic accuracy. The χ2 test or Fisher's exact test was used to evaluate the significance of the correlation between the expression of CXCL12 and BRAF in the immunohistochemistry and immunocytochemistry analyses, and the BRAF mutation in TMA. We also used coefficient analysis to identify any correlation between CXCL12 or BRAF immunoreactivity and the T and N stage. P < 0.05 was considered to be statistically significant.


   Results Top


Baseline characteristics of patients

The mean age of the participants was 49.1 ± 1.4 years and 88.1% were women [Table 1]. The FNA results were AUS in 12 patients, suspicious for malignancy in 7, malignancy in 39, and benign in one. The final tissue diagnosis was PTC in fifty-eight patients and follicular adenoma in one patient. All PTC subtypes were conventional. The mean tumor size was 1.2 ± 0.1 cm (range 0.4-4.7 cm), 59% of participants had a single tumor and 51.7% had no lymph node metastasis. Thirty thyroid specimens from the Korea Biobank included 5 showing normal thyroid tissue, 5 nodular hyperplasia, 10 follicular adenoma, and 10 Hashimoto's thyroiditis.
Table 1: Baseline characteristics of the patients

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Immunoreactivity of CXCL12 in cytology and tissue specimens

In FNAs, 54 (93.1%) from patients with PTC showed positive immunoreactivity for CXCL12 [Table 2], which was graded as 1+ in 5 specimens, 2+ in 6 specimens, 3+ in 43 specimens. The cytoplasm of tumor cells was strongly positive for CXCL12 [Figure 1]e compared with benign controls [Figure 1]b.
Table 2: Distribution of CXCL12 immunoreactivity in cytology and tissue specimens

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Figure 1: Immunocytochemical findings in fine-needle aspiration cytology specimens. Benign thyroid disease showing (a) clusters of bland-looking follicular cells (Papanicolaou stain), (b) no CXCL12 expression, (c) no BRAF expression. Papillary thyroid carcinoma showing (d) atypical follicular cells with characteristic nuclear changes (Papanicolaou stain), (e) positive CXCL12, and (f) positive BRAF staining (original magnification, ×400)

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In the immunohistochemical analysis of TMAs, 57 PTCs (98.3%) showed diffuse cytoplasmic positivity for CXCL12 in the tumor cells [Figure 2]d, and they were scored as 1+ in 5 specimens, 2+ in 10 specimens, 3+ in 42 specimens. One PTC did not express CXCL12 in its tumor cells.
Figure 2: Immunohistochemical findings in tissue microarray specimens. Benign thyroid disease showing (a) follicles lined by benign follicular cells (H&E stain), (b) no CXCL12 expression, (c) no BRAF expression. Papillary thyroid carcinoma showing (d) papillary fronds lined by malignant cells (H&E stain), (e) positive CXCL12, and (f) positive BRAF staining (original magnification, ×200)

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Twenty-nine (93.5%) of the benign thyroid tissue samples were negative for CXCL12, and two samples (6.5%) showed weak immunoreactivity in a few cells (one specimen from follicular adenoma and one from Hashimoto's thyroiditis).

The results values were calculated for FNA and TMA specimens: sensitivity 93.1% and 98.3%, specificity 90.3% and 93.5%, PPV 94.7% and 96.6%, NPV 87.5% and 96.7%, and accuracy 89.1% and 96.6% for FNA and TMA specimens, respectively [Table 5].
Table 3: Distribution of BRAF V600E mutant protein immunoreactivity in cytology and tissue specimens

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Table 4: BRAF V600E mutation status

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Table 5: The sensitivity, specificity, PPV, NPV, and accuracy of CXCL12 and BRAF V600E mutant protein in FNA for diagnosis of PTC

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The expression of BRAF V600E mutant protein in cytology and tissue specimens

BRAF V600E mutant protein was expressed in 36 (62.1%) in FNA specimens from PTC patients [Table 3]. The protein was found in the cytoplasm of the tumor cells and was scored as 1+ in 8 specimens, 2+ in 12 specimens, 3+ in 16 specimens.

54 cases (93.1%) of the corresponding tissue specimens expressed the BRAFV600E mutant protein, whereas six specimens (19.4%) of the benign thyroid diseases showed focal cytoplasmic immunoreactivity.

BRAF V600E immunoreactivity had a sensitivity of 62.1% and 93.1%, specificity of 100% and 80.6%, PPV of 100% and 90.0%, NPV of 4.3% and 86.2%, and accuracy of 62.7% and 88.8% in FNA and TMA specimens, respectively [Table 5].

For FNA positive for both CXCL12 and BRAF, the respective sensitivity and specificity were 51.7% and 100%, the PPV and NPV were 100% and 3.4%, and the accuracy was 52.5% (data not shown). In TMA specimens positive for both CXCL12 and BRAF, the respective sensitivity and specificity were 91.4% and 100%, the PPV and NPV were 100% and 85.7%, and the accuracy was 94.3% (data not shown).

BRAF V600E mutation status

BRAF V600E mutation had a sensitivity of 58.6%, specificity of 100%, PPV of 100%, NPV of 4.0%, and accuracy of 59.3% in TMA specimens [Table 4]. Especially, specimen of follicular adenoma showed no BRAF V600E mutation.

Clinical efficacy of CXCL12 and BRAF immunoreactivity in specimens classified as AUS

The FNA cytology results were classified as AUS in 12 patients; the final diagnosis was follicular adenoma in one patient and PTC in 11 patients. To identify the clinical usefulness of CXCL12 and BRAF V600E immunoreactivity in identifying AUS, we analyzed the sensitivity, specificity, PPV, NPV, and accuracy of CXCL12 and BRAF V600E immunoreactivity in these cases [Table 5]. CXCL12 was positive in 11 and negative in one. All of the positive patients were diagnosed with PTC in the surgical specimens, and the negative patient was diagnosed with follicular adenoma. The sensitivity, specificity, PPV, and NPV were all 100% in the FNA specimens of AUS. A BRAF V600E gene mutation was detected in only four of the 11 PTC patients with AUS cytology, and the sensitivity was 36.3% and specificity was 100% (data not shown).

Correlation between CXCL12 and BRAF expression and tumor stage

We analyzed the correlations of CXCL12 and BRAF expression with tumor stage [Table 6]. CXCL12 positivity greater than 1 + in FNA specimens did not correlate significantly with the N stage (P = 0.323) or T stage (P = 0.565). However, a 3 + score for CXCL12 immunoreactivity correlated with the N stage (P = 0.031) but not the T stage (P = 0.952). Therefore, strong positive staining for CXCL12 was clinically associated with lymph node metastasis. A BRAF positivity over 1 + was correlated with the N stage (P = 0.028) and T stage (P = 0.037) in TMA specimens, but not correlated in FNA specimens (data not shown, N stage P = 0.145, T stage P = 0.557).
Table 6: Correlation of tumor stage with CXCL12 immunoreactivity in FNA

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   Discussion Top


Our results suggest that CXCL12 immunoreactivity may be a useful marker for the diagnosis of PTC in thyroid nodules. CXCL12 is a better marker than BRAF V600E protein expression or BRAF V600E mutation, even in nodules classified as AUS. In addition, strong CXCL12 reactivity correlated with a higher N stage.

Jung et al. suggested that CXCL12 may be an effective supplementary diagnostic marker for PTC in preoperative FNA cytology using the cell block method.[17] They reported 93.6% sensitivity, 88.6% specificity, 91.7% PPV, 91.2% NPV, and 91.5% accuracy for CXCL12 staining of PTC. In another study, CXCL12 had 90.8% sensitivity, 96.8% specificity, 98.9% PPV, 76.9% NPV, and 92.2% accuracy in tissue specimens of PTC.[16] Our results showed that CXCL12 immunoreactivity had 93.1% sensitivity, 90.3% specificity, 94.7% PPV, 87.5% NPV, and 89.1% accuracy in FNA specimens and 98.3% sensitivity, 93.5% specificity, 96.6% PPV, 96.7% NPV, and 96.6% accuracy in TMA specimens, these values are similar to those of the previous reports.[16],[17],[18],[19] The important difference between the previous reports and this study is that our study was performed prospectively to reduce the possibility of selective bias. We included patients who were scheduled for surgical treatment of malignant or suspicious malignant thyroid nodule in FNA cytology. The cytology and tissue specimens were obtained in an actual clinical environment. We believe that the results of our study may be more relevant than those of retrospective studies.

Previous studies have reported that cytokeratin 19 (CK19), Hector Battifora mesothelial epitope-1 (HBME-1), and galectin-3 (GAL-3) are good markers for PTC.[20] However, the diagnostic values for discriminating malignant from benign thyroid lesions were 71-88% sensitivity and 65%–85% specificity.[21] Combining these markers produced values of only 62.1% sensitivity and 97.6% specificity for diagnosing PTC. These findings suggest that, alone or in combination, these markers had limited value for the diagnosis of PTC. CXCL12 alone had >90% sensitivity and specificity in our study, which suggests that CXCL12 may provide a more accurate diagnosis when used with other markers to diagnose PTC.

The AUS category of the Bethesda classification system is a major concern for clinicians making decisions about surgical treatment. The guidelines state that when the result of the first FNA is AUS, the FNA must be repeated to be able to allow the use of molecular markers such as BRAF mutation for obtaining accurate results.[22] However, BRAF mutation studies have some limitations for the diagnosis of PTC because of their low NPV. According to a systematic review and meta-analysis, despite a high specificity, BRAF V600E mutation showed low sensitivity as a diagnostic marker in indeterminate nodules.[23] In this study, the prevalence of BRAF V600E mutation was 58.9%, which is lower than the ~70% prevalence reported in a previous study in Korean subjects.[24],[25] In AUS cytology specimens, especially, positivity of BRAF V600E mutation decreased to 36.4%. This suggests that BRAF V600E mutation has limitation for diagnose of PTC in AUS patients. By contrast, CXCL12 showed 100% sensitivity, specificity, PPV, NPV, and accuracy in FNAs categorized as AUS in this study. Although the number of cases was small, these findings suggest that CXCL12 may be a good option for assessing thyroid nodules with AUS results in FNA cytology.

The BRAF V600E mutation has been suggested as a supplementary molecular marker for the diagnosis of PTC in clinical guidelines.[22] Recently, BRAF V600E immunohistochemical staining using a specific antibody was reported to have a strong correlation with PTC and to be inexpensive, uncomplicated, and more sensitive than BRAF V600E mutation analysis.[26],[27],[28] We performed BRAF V600E immunohistochemical staining on both cytology and tissue samples from the same patients. The results were 62.1% and 93.1% sensitivity, 100% and 80.6% specificity, 100% and 90.0% PPV, 4.3% and 89.7% NPV, and 62.7% and 88.8% accuracy in FNA and TMA specimens, respectively. These results are consistent with those of previous studies.[26],[27],[28] The sensitivity of BRAF V600E immunoreactivity was similar to the 20%–60% sensitivity of the BRAF V600E mutation.[29] Our result showed that BRAF V600E immunohistochemistry was not superior to CXCL12 in this study.

The BRAF V600E mutation is a well-known prognostic marker.[30],[31],[32] It was previously reported to be a poor prognostic marker for the persistence of PTC, independent of other clinicopathological features including multifocality, aggressive variants, absence of infiltration of the tumor capsule, tumor size, and lymph node metastasis. We found that strong expression (3+) of CXCL12 correlated with lymph node metastasis but not with multifocality, infiltration of the tumor capsule, or tumor size. We suggest that CXCL12 immunoreactivity may be an alternative to BRAF V600E mutation analysis in the diagnosis of PTC because immunohistochemistry or immunocytochemistry is a much simpler, more stable, and less expensive method than gene mutation detection tests.

This study has some limitations. First, the specimen number is too small. However, we performed this study prospectively to make the circumstances more equivalent to the actual clinical setting and to exclude possible selection bias. Despite the small number of samples, we included various specimens diagnosed as AUS, suspicious malignant, and malignant by FNA, and we found that CXCL12 was an effective diagnostic marker of PTC in FNA cytology. Second, all of the PTC specimens in this study were conventional PTCs. Unfortunately, we could not select patients because of prospective study. And thyroid cancer of Korean showed different distribution compared to Western. The prevalence of PTC (>95%) is higher and that of other variant type of PTC (<3% of PTCs), follicular thyroid cancer (<4%), medullary thyroid cancer (<1%), and anaplastic thyroid cancer (<1%) was lower than Western.[33] Therefore, we could not confirm the diagnostic significance of CXCL12 in other thyroid cancers, such as follicular variant PTC, follicular thyroid cancers, Hurthle's cell cancers, and other type thyroid cancer.

In conclusion, CXCL12 immunoreactivity may be a useful diagnostic tool for diagnosing thyroid nodules. The use of this test may facilitate more accurate diagnosis of PTC, especially in cases categorized as AUS from FNA cytology. We also found that strong reactivity for CXCL12 was related to lymph node metastasis. Further prospective studies with a larger number of samples are needed to confirm the efficacy of CXCL12 in diagnosing PTC.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

This work was supported by a research grant from the Jeju National University Hospital research fund of Jeju National University in 2017.



Conflicts of interest

There are no conflicts of interest.



 
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Correspondence Address:
Young Hee Maeng
Aran 13 gil, Jeju.si, Jeju Special Self.Governing Province - 63241
Republic of Korea
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/IJPM.IJPM_722_19

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