KR102293271B1 - Method for Diagnosing Lymph Node Metastasis in Thyroid Carcinoma Using CYFRA 21-1 - Google Patents

Abstract

The present invention relates to a method for diagnosing thyroid cancer lymph node metastasis using lavage CYFRA 21-1. In the present invention, it was confirmed that the concentration of CYFRA 21-1 lavage solution was significantly higher in metastatic lymph nodes than in benign lymph nodes. Unlike lavage CYFRA 21-1, there was little overlap between benign and metastatic lymph nodes, and it was confirmed that the diagnostic cut-off value was hardly affected by surgery.
In addition, in the case of washing CYFRA 21-1 alone, it was confirmed that the sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy were superior to fine needle aspiration cytology and washing thyroglobulin. It was confirmed that the CYFRA 21-1 combination showed the highest sensitivity. Furthermore, since it was confirmed that the diagnosis accuracy was increased when washing CYFRA 21-1 measurement results were applied to the discrepancy results observed between fine needle aspiration cytology and washed thyroglobulin, it is usefully applied to information provision method for diagnosing thyroid cancer lymph node metastasis can do.

Description

Method for Diagnosing Lymph Node Metastasis in Thyroid Carcinoma Using CYFRA 21-1

The present invention relates to a method for diagnosing thyroid cancer lymph node metastasis using CYFRA 21-1, and more particularly, to thyroid cancer lymph node metastasis diagnosis, comprising determining whether thyroid cancer lymph node metastasis has occurred by measuring the CYFRA 21-1 concentration in thyroid cancer lymph node lavage fluid. It relates to a method of providing information for

The incidence of thyroid cancer has increased over the past several decades. Although thyroid cancer is known to have a good prognosis, it was confirmed that lymph node metastasis occurred in 20 to 31% of patients when thyroid cancer was diagnosed, and local recurrence was found in 5 to 20% of cancer patients after initial treatment (Siegel). RL et al. , CA Cancer J Clin. , 68:7-30, 2018; Sakorafas GH et al. , Surg Oncol ., 19:e57-70., 2010: Haugen BR et al. , Thyroid , 26:1- 133, 2015).

Fine needle aspiration cytology (FNAC) is useful for diagnosing cervical lymph node metastasis due to its high specificity, but the diagnosis is missed due to the small size of the lymph node, cystic changes, and technical problems. , a false-negative (if reported as a positive nodule on fine needle aspiration cytology despite an actual metastatic lymph node) is reported at a rate of 6 to 8% in general. Therefore, there is a need for a solution to overcome this problem.

Thyroglobulin (Tg) is a 660 kDa glycoprotein and is produced in thyroid follicle cells, so it is used as evidence of recurrence or metastasis when measured at high concentrations in lymph nodes after surgical treatment. It has been reported that irrigation thyroglobulin measurement in the fine needle aspiration lavage solution increases the sensitivity and can improve diagnostic accuracy and sensitivity when used concurrently with fine needle aspiration cytology (Cunha N et al. , Eur J Endocrinol ., 157:101-107). , 2007).

However, there are several problems related to the interpretation of thyroglobulin concentration values in fine needle aspiration lavage for thyroid cancer. First, thyroglobulin cutoff values have been established in a wide range using different measurement kits for different institutions (Kim MJ et al. , Clinical endocrinology , 70:145-151, 2009). Second, thyroglobulin can be secreted into lymph nodes because it is present in normal thyroid tissue before surgery. In this case, lavage thyroglobulin may be incidentally detected at a high concentration, which leads to false-positive results that make it difficult to diagnose thyroid cancer metastasis (when lavage thyroglobulin levels are high despite positive lymph nodes, not metastatic lymph nodes on thyroid fine needle aspiration cytology) will do Third, since thyroglobulin released from normal thyroid tissue can be mixed with lymph node fine-needle aspiration cell aspirate, patients with normal thyroid tissue or lobectomy rather than total thyroidectomy should be performed to normalize the condition. Residual thyroid tissue can lead to thyroglobulin false-positives. Due to the above-mentioned problems, the development of additional biomarkers for confirming lymph node metastasis of thyroid cancer is required.

Recently, a study has been reported to measure tumor markers in the washing fluid of fine needle aspiration cytology of lymph nodes in lung, breast, and ovarian cancer, where lymph node metastasis is common. Among them, cytokeratin fragment 21-1 (Cytokeratin fragment 21-1; CYFRA 21-1) is a soluble fragment of cytokeratin (CK) 19, which was expressed at high concentrations in cancer cells and was proposed as a tumor marker. In bodily fluids such as lung cancer malignant pleural effusions or breast cancer axillary lymph node specimens, the combination of CYFRA 21-1 was confirmed to have a superior diagnostic effect than fine needle aspiration cytology alone (Chen S et al. , Medical Science Monitor , 24:4254-4261, 2018; Han AL et al. , Translational oncology , 11:147-156, 2018)

In relation to thyroid cancer, it was confirmed that the cystic body fluid collected from thyroid cancer in the form of a cyst had a higher concentration of cytokeratin 19 (CK 19) than that of the benign thyroid tissue. However, there have been no studies to date on the usefulness of lymph node lavage CYFRA 21-1 as a complementary tool for diagnosing lymph node metastasis in thyroid cancer.

Accordingly, the present inventors made intensive efforts to select complementary biomarkers that improve the sensitivity and accuracy of methods such as conventional fine needle aspiration cytology and lavage thyroglobulin (Tg) for diagnosing lymph nodes of thyroid cancer. As a result, CYFRA in thyroid cancer lymph node lavage fluid It was confirmed that the sensitivity and accuracy of thyroid cancer lymph node metastasis diagnosis were improved by measuring the 21-1 concentration, and the present invention was completed.

It is an object of the present invention to provide an information providing method for diagnosing thyroid cancer lymph node metastasis using the fine needle aspiration lavage solution CYFRA 21-1.

In order to achieve the above object,

The present invention provides an information providing method for diagnosing thyroid cancer lymph node metastasis, which includes determining whether thyroid cancer lymph node metastasis has occurred by measuring the CYFRA 21-1 concentration in the lymph node fine needle aspiration lavage fluid of a patient suspected of thyroid cancer lymph node metastasis.

In a specific embodiment of the present invention, the cut-off value of CYFRA 21-1 in the fine needle aspiration washing solution may be 0.8 ng/ml to 1.5 ng/ml.

In another specific embodiment of the present invention, if the CYFRA 21-1 concentration in the lymph node fine needle aspiration lavage of a patient suspected of thyroid cancer lymph node metastasis is higher than the cut-off value of the CYFRA 21-1, it is information that the thyroid cancer has metastasized to the lymph nodes. can provide

In another specific embodiment of the present invention, the information providing method for diagnosing thyroid cancer lymph node metastasis may be performed simultaneously with measuring the concentration of thyroglobulin in the fine needle aspiration cytology) or the fine needle aspiration lavage solution.

In another specific embodiment of the present invention, the information providing method for diagnosing thyroid cancer lymph node metastasis is, when the results of lymph node metastasis through fine needle aspiration cytology and measurement of thyroglobulin concentration in the washing solution are inconsistent, CYFRA 21 in the washing solution -1 concentration measurements can be performed.

In the method for diagnosing thyroid cancer lymph node metastasis using CYFRA 21-1 of the present invention, it was confirmed that the concentration of CYFRA 21-1 wash solution was significantly higher in metastatic lymph nodes than in non-metastatic benign lymph nodes. In the lavage solution CYFRA 21-1, there was little overlap between benign and metastatic lymph nodes, and it was confirmed that the diagnostic cut-off value was hardly affected by surgery. In addition, in the case of washing CYFRA 21-1 alone, it was confirmed that the sensitivity, specificity, positive predictive value, negative predictive value, and diagnostic accuracy were superior to fine needle aspiration cytology and washing thyroglobulin. and washing CYFRA 21-1 combination showed the highest sensitivity (98.8%). Furthermore, when washing CYFRA 21-1 measurement results were applied to the discrepancy results observed between fine needle aspiration cytology and washed thyroglobulin, it was confirmed that 20 out of 22 lymph nodes were accurately diagnosed, providing information for diagnosing thyroid cancer lymph node metastasis method can be usefully applied.

1 is a schematic diagram showing the problems of the existing thyroid metastatic cancer diagnosis method and the high diagnostic efficiency of the washing solution CYFRA 21-1.
Figure 2 is data showing the distribution of lavage thyroglobulin and lavage CYFRA 21-1 values in benign and metastatic lymph nodes. The wash solution thyroglobulin values showed a significant overlap between benign and metastatic lymph nodes, whereas the wash solution CYFRA 21-1 values showed little overlap between benign and metastatic lymph nodes.
FIG. 3 is data showing the curves obtained for the cut-off values of thyroglobulin and CYFRA 21-1 of the most appropriate fine-needle aspiration lavage solution based on the sensitivity and specificity of diagnosis in the present invention.
4 is a schematic diagram showing the diagnostic performance of lavage CYFRA 21-1 in a case of diagnostic mismatch between cytosuction cytology and lavage thyroglobulin.

Hereinafter, the present invention will be described in detail.

The present invention relates to thyroid cancer, including the step of determining whether thyroid cancer has metastasized to a lymph node by measuring the concentration of cytokeratin fragment 21-1 (CYFRA 21-1) in the lymph node fine needle aspiration lavage of a patient suspected of having metastasized to the lymph node of thyroid cancer. It relates to a method of providing information for the diagnosis of lymph node metastasis.

In the present invention, the cut-off value of CYFRA 21-1 in the fine needle aspiration washing solution may be characterized in that it is 0.8 ng/ml to 1.5 ng/ml, and a fine needle to increase the accuracy of diagnosis The CYFRA 21-1 cut-off value in the aspiration wash is 1.1 ng/ml.

In the present invention, if the CYFRA 21-1 concentration in the lymph node fine needle aspiration lavage of a patient suspected of thyroid cancer lymph node metastasis is higher than the cut-off value of the CYFRA 21-1, information is provided indicating that the thyroid cancer has metastasized to the lymph node. do.

In the present invention, the information providing method for diagnosing thyroid cancer lymph node metastasis is characterized in that it is performed simultaneously with fine needle aspiration cytology or measurement of thyroglobulin concentration in fine needle aspiration lavage solution.

Specifically, the method of providing information for diagnosing thyroid cancer lymph node metastasis,

(a) performing fine needle aspiration of a patient suspected of thyroid cancer lymph node metastasis, then measuring the thyroglobulin concentration in the fine needle aspiration cytology or fine needle aspiration lavage solution and simultaneously measuring the CYFRA 21-1 concentration in the fine needle aspiration lavage fluid;

(b) determining whether or not lymph node metastasis is based on the results of the fine needle aspiration cytology and the concentration of thyroglobulin in the washing solution and CYFRA 21-1 in the washing solution;

It is characterized in that it is carried out in a method comprising a.

In the present invention, in step (a), fine needle aspiration cytology, measurement of thyroglobulin concentration in fine needle aspiration washing solution, and CYFRA 21-1 concentration measurement in fine needle aspiration washing solution can all be performed simultaneously.

In the present invention, the information providing method for diagnosing thyroid cancer lymph node metastasis includes measuring the concentration of CYFRA 21-1 in the wash solution when the results of lymph node metastasis through fine needle aspiration cytology and measurement of thyroglobulin concentration in the washing solution are inconsistent. characterized in that

Specifically, the method of providing information for diagnosing thyroid cancer lymph node metastasis,

(a) performing fine needle aspiration on a patient suspected of thyroid cancer lymph node metastasis, then measuring the thyroglobulin concentration in the fine needle aspiration cytology and washing solution;

(b) additionally measuring the concentration of CYFRA 21-1 in the washing solution when the results of the fine needle aspiration cytology and the measurement of the thyroglobulin concentration in the washing solution are inconsistent;

(c) determining whether lymph node metastasis is based on the CYFRA 21-1 concentration measurement result;

It is characterized in that it is carried out in a method comprising a.

"Fine needle aspiration" of the present invention is to sample tissue or cells using a thin hollow needle for tissue biopsy, and is a fine needle aspiration biopsy or fine needle aspiration cytology. Also called ;). The washing solution was obtained by washing a syringe with fine needle aspiration with saline, and thyroglobulin (hereinafter, hereinafter) and cytokeratin fragment 21-1 in the washing solution (Cytokeratin fragment 21-1; hereinafter, 'CYFRA 21-1') Concentration was measured.

In a specific embodiment of the present invention, the experiment was performed on 130 lymph nodes obtained from 103 patients. As a result of the final lymph node diagnosis, 88 lymph nodes (67.7%) were benign lymph nodes, and 42 lymph nodes (32.3%) were identified as metastatic lymph nodes. Among 88 benign lymph nodes, 37 lymph nodes (42.0%) at the time of initial diagnosis before surgery were subjected to cytology, and 51 lymph nodes (54.6%) during the follow-up period after total thyroidectomy or lobectomy. Cell aspiration cytology was performed. Among 42 metastatic lymph nodes, cytology was performed on 22 lymph nodes (52.3%) before surgery, and aspiration cytology was performed on 20 lymph nodes (47.6%) after total thyroidectomy or lobectomy. performed (Table 1).

In another specific embodiment of the present invention, as shown in FIG. 2 , as a result of measuring the concentrations of thyroglobulin and CYFRA 21-1 in the wash solution obtained from the F cell aspiration cytology, wash thyroglobulin and wash CYFRA 21-1 showed higher concentrations in metastatic lymph nodes than in benign lymph nodes. In addition, it was confirmed that lavage thyroglobulin values overlapped between benign and metastatic lymph nodes, whereas CYFRA 21-1 values showed little overlap between benign and metastatic lymph nodes ( FIG. 2 ).

As shown in FIG. 3 , as a result of analyzing the diagnostic performance of washed thyroglobulin and washed CYFRA 21-1, a cutoff value of 11.6 ng/ml (AUC 0.908, sensitivity 92.3%, and specificity 85.7%) was obtained for washed thyroglobulin. In the case of washing CYFRA 21-1, it was confirmed that a cutoff value of 1.1 ng/ml (AUC 0.929, sensitivity 92.3%, and specificity 91.2%) was shown.

In another specific embodiment of the present invention, as a result of confirming the individual diagnostic performance of fine needle aspiration cytology, lavage thyroglobulin and lavage CYFRA 21-1, as shown in Table 2, among the final results of 42 metastatic lymph nodes, cellular aspiration Cytological examination confirmed that 6 lymph nodes were misdiagnosed, and lavage thyroglobulin and lavage CYFRA 21-1 only misdiagnosed 3 lymph nodes. Of the 88 lymph nodes with positive final results, lavage thyroglobulin misdiagnosed 15 as metastatic lymph nodes, whereas cytoaspiration cytology and lavage CYFRA 21-1 incorrectly diagnosed 2 and 3 metastatic lymph nodes, respectively. did.

In addition, as a result of evaluating the diagnostic performance according to cytology cytology, washed thyroglobulin, washed CYFRA 21-1, and combinations thereof, as shown in Table 3, the aspiration cytology was performed with washed thyroglobulin and washed CYFRA 21-1. showed low sensitivity and high specificity compared to (A). Washed CYFRA 21-1 had superior specificity and negative predictive value compared to washed thyroglobulin D, E vs. B, C) were shown, and it was confirmed that the best diagnostic accuracy was shown. The combination of cytosolic cytology and washed thyroglobulin increased the sensitivity (88.1%) compared to cytotoxic cytology alone. was decreased, but showed the highest sensitivity and positive predictive value (PPV).

In another specific embodiment of the present invention, the diagnostic performance of lavage CYFRA 21-1 was evaluated in the case of diagnostic mismatch between cytoaspiration cytology and lavage thyroglobulin. Out of 130 lymph nodes, 108 (83.1%) had the same values as cytosuction cytology and washing thyroglobulin diagnosis (Fig. 4), and 22 out of 103 lymph nodes (8 metastatic lymph nodes and 14 benign lymph nodes) 6 out of 8 metastatic lymph nodes with a higher-than-standard washing thyroglobulin (cut-off value of 11.1 ng/mL) diagnostic result were confirmed as benign lymph nodes in the diagnosis of cytology and positive Of the 14 confirmed lymph nodes, lavage thyroglobulin diagnosed 13 lymph nodes as benign lymph nodes, and cell aspiration cytology diagnosed only one benign lymph node (Table 4 and Table 5). ).When washing CYFRA 21-1 was applied to the discrepancy sample, it was confirmed that 20 out of 22 lymph nodes (90.9%) were correctly diagnosed.

Thyroglobulin is produced in both thyroid cancer, benign tumors, and normal thyroid tissue. Therefore, when metastatic and normal tissue are present at the same time, it cannot be confirmed whether the increased thyroglobulin level is from metastasized or normal tissue (Indrasena BSH, World journal of biological chemistry , 8:81, 2017).

For patients with early diagnosis of thyroid cancer who have suspected lymph node metastasis before surgery, patients with residual lesions on the contralateral side after lobectomy, or candidates for evaluation of recurrent lymph nodes with residual tissue during cancer follow-up after initial treatment However, when the results of aspiration cytology are incomplete, the measurement of lavage thyroglobulin for the diagnosis of metastatic lymph nodes alone may omit several suspicious cases.

Therefore, measurement of lavage CYFRA 21-1 concentration can be used as a complementary biomarker to improve the accuracy of existing diagnostic methods such as fine needle aspiration cytology and lavage thyroglobulin.

Hereinafter, the present invention will be described in more detail through examples.

These examples are only for illustrating the present invention, and it will be apparent to those of ordinary skill in the art that the scope of the present invention is not to be construed as being limited by these examples.

Sample preparation and clinical characterization

Among 244 thyroid cancer patients from June 2016 to December 2017, among the lymph nodes of patients who had thyroid residual tissue removed by radioactive isotope treatment or did not receive radioisotope treatment at the time of initial diagnosis of thyroid cancer or during follow-up after surgery Fine needle aspiration cytology and lavage thyroglobulin were all measured in 388 lymph nodes suspected of metastasis. Among the above patients, 130 lymph nodes were collected from 103 patients, and fine needle aspiration cytology and washing thyroglobulin concentrations were measured. The above study was approved by the Catholic University of Korea, Catholic Medical Center, and Seoul St. Mary's Hospital Clinical Trial Committee (IRB approval No. KC17TESI0328).

Clinical features were observed for 130 lymph nodes obtained from 103 patients. At the time of fine needle aspiration cytology, the mean age of 103 patients was 47.0 years (16-38 years), and 66 patients (64.1%) were female. The clinical characteristics of benign and metastatic lymph nodes are shown in Table 1.

As a final lymph node diagnosis result, 88 (67.7%) lymph nodes were benign, and 42 (32.3%) lymph nodes were identified as metastatic lymph nodes.

Among 88 benign lymph nodes, fine needle aspiration cytology was performed on 37 lymph nodes (47.6%) at the initial diagnosis before surgery, and fine needles in 51 lymph nodes (54.6%) during the follow-up period after total thyroidectomy or lobectomy. Aspiration cytology was performed. Among 42 metastatic lymph nodes, fine needle aspiration cytology was performed on 22 lymph nodes (47.6%) before surgery, and fine needle aspiration cytology was performed on 20 lymph nodes (47.6%) after total thyroidectomy or lobectomy.

Histological diagnosis was performed on 80 out of 130 lymph nodes through surgery including lymphadenectomy, and the final results of the remaining 50 lymph nodes were diagnosed using follow-up image examination or repeated fine needle aspiration cytology. Among 42 metastatic lymph nodes, , it was confirmed that 40 cases were derived from follicular thyroid carcinoma and the remaining 2 cases were derived from anaplastic thyroid cancer.

Fine needle aspiration cytology test, measurement of lavage thyroglobulin and lavage CYFRA 21-1 concentration

2-1: Ultrasound and FNAC of suspected lymph nodes

Fine needle aspiration cytology of the suspected lymph node was performed by one of several radiologists specialized in the examination. Thyroid and cervical ultrasonography was performed on an HDI 3000 scanner (Advanced Technology Laboratories, Bothell, WA) and an HDI 5000 diagnostic ultrasound system (Philips Medical Systems, Bothell) with a CL10-5 MHz compact linear array transducer. , WA).

The criteria and description of FNAC in suspected lymph nodes are based on the consensus of the Korean Society of Thyroid Radiology (Shin JH et al. , Korean journal of radiology , 17:370-395, 2016); Suspicious lymph nodes were defined as lymph nodes with cystic changes, calcification, hyperechoicity, and abnormal vascular distribution in thyroid cancer.

After aspiration, the sample was immediately placed on a slide and fixed with 95% ethanol, and then hematoxylin and eosin and Papanicolaou stains were performed.

2-2: Measurement of serum thyroglobulin, serum thyroglobulin antibody (thyroglobulin antibody (Ab)) and washing thyroglobulin

Thyroglobulin was measured using a monoclonal antibody immunoradiometric assay (Cisbio Bioassays, Codolet, France). The assay sensitivity, representing the lowest concentration detected with a 95% probability, was 0.2 ng/mL. The functional sensitivity with a 20% change in efficiency was 0.7 ng/ml. Serum thyroglobulin Ab was measured using a competitive radioimmunoassay kit (ZenTech, Angleur, Belgium) and showed a functional sensitivity of less than 15 IU/ml.

Washing thyroglobulin concentration was determined according to a known method (Jo K et al. , Eur J Endocrinol ., 173:489-497, 2015), the same needle and syringe in which FNAC was performed was washed with 2 ml of physiological saline, and the washing solution The washing thyroglobulin concentration was measured in

2-3: Cleaning CYFRA 21-1 Measurement

The washed CYFRA 21-1 concentration was measured using an immunoradiometric assay kit (ELISA-CYFRA, Cisbio Bioassay, Codolet, France), and was measured using a sample remaining after washing thyroglobulin was measured according to the manual. Washed samples were centrifuged at 3200 rpm for 10 minutes. 100 μl of the centrifuged supernatant and 300 μl of I-125 anti-CYFRA 21-1 were added to an ELSA tube, and then gently mixed with a vortexer, followed by reaction at 2-8° C. for 20 hours. The tube contents were aspirated, 2 ml of washing solution was added, and the tube was emptied again, and the washing procedure was repeated 3 times. Finally, the remaining radioactivity was measured using ELISA coupled with a gamma counter (Packard II E5010 cobra Quantum Gamma Counter, Perkin-Elmer, Waltham, MA). The limit of detection with 95% probability is 0.05 ng/ml.

2-4: Fine needle aspiration cytology and analysis of final lymph node results

The results of fine needle aspiration cytology were judged by experienced pathologists specializing in thyroid cytology. The cytology results were divided into two groups, and metastatic lymph nodes were defined based on the presence of metastatic cells of thyroid cancer or the presence of suspicious atypical cells on cytology. A benign lymph node was defined as a case in which enlargement of the lymph node was confirmed due to an inflammatory reaction or only Kikuchi's diesase, cystic fluid, or blood was found.

Final lymph node results were analyzed based on postoperative pathological results or fine needle aspiration cytology results. According to a known method, lymph nodes were identified as metastatic lymph nodes when there was postoperative metastatic pathology in the same compartment in which fine needle aspiration cytology was performed (Sohn YM et al. , Yonsei medical journal , 53:126-131, 2012). If lymph node dissection was not performed, lymph nodes were identified as metastatic lymph nodes if they showed clear metastatic cell results with high lavage thyroglobulin concentrations or metastatic lesions on cervical computed tomography (CT) or magnetic resonance imaging (MRI).

Otherwise, the reproducibility of the fine needle aspiration cytology results was confirmed. Lymph nodes are classified as benign, not metastatic, if the final postoperative biopsy of the suspected lymph node is benign, or if subsequent imaging tests, including thyroid ultrasonography, do not increase the size of the lymph node in unoperated patients. was considered.

2-5 : Statistical analysis

All statistical analyzes were performed using SPSS software version 14 (SPSS software, version 14; Chicago, IL, USA). Continuous variables are expressed as mean and standard deviation values when the distribution is normal, and median values when the variable is non-normal distribution. Comparisons of basic clinical features between benign and metastatic lymph nodes were performed by independent t-tests for continuous variables.

Receiver Operating Characteristic (ROC) curve analysis was used to determine the cut-off levels of lavage thyroglobulin and lavage CYFRA 21-1 in the data of the present invention. Evaluating the diagnostic performance of fine needle aspiration cytology, lavage thyroglobulin and lavage CYFRA 21-1 for sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and diagnostic accuracy did.

McNamara's test was used to statistically compare the sensitivity and specificity between diagnostic tools. All p-values <0.05 were considered significant and two-sided testing was used.

Determination of cut-off values of wash thyroglobulin and wash CYFRA 21-1

In the analysis of diagnostic performance of lavage thyroglobulin and lavage CYFRA 21-1, the diagnosis of metastatic lymph nodes was determined using a cut-off value of 11.6 ng/ml for lavage thyroglobulin (AUC 0.908, sensitivity 92.3% and specificity 85.7%). , was determined using a cut-off value of 1.1 ng/ml (AUC 0.929, sensitivity 92.3% and specificity 91.2%) for wash CYFRA 21-1 ( FIG. 3 ).

Preoperative cut-off values were 10.0 ng/ml (AUC 0.919, sensitivity 90.9%, specificity 87.5%, 95% CI 0.84-0.994) for lavage thyroglobulin and 114.4 ng/ml (AUC) for lavage thyroglobulin after surgery. 0.924, sensitivity 80%, specificity 84.3%, 95% CI 0.865 ~ 0.982) showed a difference.

However, the preoperative CYFRA 21-1 cut-off value was 0.85 ng/ml (AUC 0.965, sensitivity 90.9%, specificity 99.5%, 95% CI 0.904 to 0.990), and the postoperative CYFRA 21-1 cut-off value was 0.98 ng/ml (AUC 0.967, sensitivity 95%, specificity 98%, 95% CI 0.918 to 0.999), there was no significant difference in lavage CYFRA 21-1 cutoff values between preoperative and postoperative lymph nodes.

Confirmation of diagnostic performance of fine needle aspiration cytology, lavage thyroglobulin and lavage CYFRA 21-1

4-1: Fine-needle aspiration cytology Confirmation of individual diagnostic performance of lavage thyroglobulin and lavage CYFRA 21-1

Table 2 shows the correlation between the final results and fine needle aspiration cytology, lavage thyroglobulin and lavage CYFRA 21-1. Of the final results of 42 metastatic lymph nodes, fine needle aspiration cytology misdiagnosed 6 cases, whereas lavage thyroglobulin and lavage CYFRA 21-1 misdiagnosed only 3 each. Of the 88 lymph nodes whose final result was confirmed as benign lymph nodes, lavage thyroglobulin misdiagnosed 15 as metastatic lymph nodes, whereas fine needle aspiration cytology and lavage CYFRA 21-1 made 2 and 3 metastatic, respectively. The lymph node was misdiagnosed.

4-2: Comparison of diagnostic performance according to fine needle aspiration cytology, lavage thyroglobulin, lavage CYFRA 21-1 and combinations thereof

In the present invention, the diagnostic performance according to fine needle aspiration cytology, lavage thyroglobulin, lavage CYFRA 21-1 and combinations thereof was evaluated to predict metastatic lymph nodes (Table 3).

Fine needle aspiration cytology showed lower sensitivity and higher specificity than lavage thyroglobulin and lavage CYFRA 21-1 (A). Washed CYFRA 21-1 showed superior specificity and negative predictive value (D, E vs. B, C) compared to washed thyroglobulin, and it was confirmed that it showed the best diagnostic accuracy.

The combination of fine needle aspiration cytology and washing thyroglobulin increased the sensitivity (88.1%) compared to fine needle aspiration cytology alone. CYFRA 21-1 alone showed higher sensitivity, specificity, positive predictive value, negative predictive value and diagnostic accuracy than fine needle aspiration cytology or washer thyroglobulin alone.

When the results of washing CYFRA 21-1 were added to the results of fine needle aspiration cytology and washing thyroglobulin, it was confirmed that the overall diagnostic accuracy decreased, but showed the highest sensitivity and positive predictive value.

4-3: Confirmation of lavage CYFRA 21-1 diagnostic performance in diagnostic discrepancy between fine needle aspiration cytology and lavage thyroglobulin

In the present invention, the diagnostic performance of lavage CYFRA 21-1 was evaluated in the case of diagnostic mismatch between fine needle aspiration cytology and lavage thyroglobulin.

Of the total 130 lymph nodes, 108 (83.1%) had the same values as the fine needle aspiration cytology and wash thyroglobulin diagnosis (Fig. 4), and 22 of 103 lymph nodes (8 metastatic lymph nodes and 14 benign lymph nodes) ), the diagnostic values were inconsistent.

Six of the eight metastatic lymph nodes (7 papillary thyroid cancer metastasis and 1 anaplastic metastasis) with a washout thyroglobulin (cut-off value of 11.1 ng/mL) were confirmed as benign lymph nodes in the diagnosis of fine needle aspiration cytology. (Table 4 and Table 5). Of the 14 confirmed benign lymph nodes, lavage thyroglobulin diagnosed 13 lymph nodes as metastatic lymph nodes, and fine needle aspiration cytology diagnosed only one metastatic lymph node.

When washing CYFRA 21-1 was applied to the discrepancy sample, 20 out of 22 lymph nodes (90.9%) were correctly diagnosed. That is, 8 metastatic lymph nodes with values above the wash CYFRA 21-1 cut-off value (1.1 ng/mL) were classified as metastatic lymph nodes, and 12 benign lymph nodes with values below the cut-off value were converted to benign lymph nodes. was determined as

Claims (5)

Comprising the step of determining whether thyroid cancer has metastasized to lymph nodes by measuring the concentration of CYFRA 21-1 in the lavage fluid of a fine needle aspiration of a patient suspected of having metastasis to the thyroid cancer lymph node,
Thyroid cancer lymph node metastasis, which provides information that the thyroid cancer has metastasized to the lymph nodes if the concentration of CYFRA 21-1 in the lymph node fine needle aspiration lavage of the patient suspected of thyroid cancer lymph node metastasis is higher than the cut-off value of CYFRA 21-1 How to provide information for diagnosis.
According to claim 1, wherein the cut-off value of CYFRA 21-1 in the fine needle aspiration washing solution is 0.8 ng/ml to 1.5 ng/ml, providing information for diagnosing thyroid cancer lymph node metastasis Way.
delete The method of claim 1, wherein the information providing method for diagnosing thyroid cancer lymph node metastasis is performed simultaneously with fine needle aspiration cytology or measurement of thyroglobulin concentration in fine needle aspiration lavage solution, thyroid cancer lymph node metastasis diagnosis How to provide information for
According to claim 1, wherein the information providing method for diagnosing thyroid cancer lymph node metastasis, when the results of lymph node metastasis through fine needle aspiration cytology and washing thyroglobulin concentration measurement are inconsistent, measuring the CYFRA 21-1 concentration of the washing solution An information providing method for diagnosing thyroid cancer lymph node metastasis, characterized in that.

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