Fine needle aspiration cytology (FNAC) and measurement of thyroglobulin (Tg) in needle washout (FNA-Tg) are recommended for the diagnosis of metastatic or recurrent lymph nodes (LNs) in differentiated thyroid cancer (DTC). However, the effect of serum Tg antibody (TgAb) on FNA-Tg levels still remains unclear in the preoperative setting. We analyze the interference of serum TgAb on FNA-Tg levels as proof of concept in the diagnostic advantage of serum TgAb combined with FNA-Tg.
Subjects and methods
A total of 370 suspicious cervical LNs from 273 patients with DTC were included. The primary tumor was confirmed as DTC on preoperative pathology in all patients. We performed FNA-Tg measurement and FNAC on suspicious LNs and evaluated the diagnostic performance of FNAC and FNA-Tg according to TgAb status. Final diagnoses were confirmed by histological examination of excised specimens or by follow-up ultrasonography for at least 6 months.
Data from 273 subjects with suspicious 370 LNs were evaluated. Fifty-five LNs (14.9%) were from TgAb+ positive serum TgAb (TgAb+) patients. Serum Tg and FNA-Tg levels were significantly lower in patients with TgAb+ than in those with TgAb-negative (TgAb−). Final pathology confirmed 109 LNs (29.5%) asmalignant. Diagnostic performance of FNA-Tg at the same cutoff level was lower in the TgAb+ than TgAb− group. FNA-Tg cutoff levels determined by ROC curve were lower in the TgAb+ group.
The results suggested that the cutoff value of FNA-Tg should be lowered in suspicious LN before thyroidectomy in thyroid cancer patients with TgAb.
Thyroid cancer incidence has increased over the last decade worldwide. Although differentiated thyroid cancer (DTC) shows good prognosis, 5% to 20% of patients treated with total thyroidectomy developed cervical lymph node (LN) metastases at the time of diagnosis or during postoperative follow-up (1, 2).
Fine needle aspiration cytology (FNAC) is recommended for diagnosis of metastatic LNs in thyroid cancer (3, 4). When FNAC results are nondiagnostic or indeterminate, thyroglobulin (Tg) measurement in washout fluid of FNA (FNA-Tg) may improve the diagnostic performance of FNA. Many previous studies reported that FNA-Tg is more sensitive than FNAC, and a combination of FNAC and FNA-Tg can improve diagnostic accuracy for detecting metastasis (4, 5, 6, 7, 8, 9, 10, 11, 12, 13). Therefore, recent guidelines indicate FNAC with FNA-Tg for all suspicious LNs of thyroid cancer (14, 15, 16).
Positive serum Tg antibody (TgAb) is known to lower serum Tg (sTg) levels, and this may be even more important in DTC patients prior to thyroidectomy and/or radioactive iodine therapy in whom a higher rate of positive TgAb has been reported (17). Thus, the high rate of positive serum TgAb can lower sTg levels and influence FNA-Tg levels, which is possibly associated with altered diagnostic accuracy. Few prior studies indicate the potential interference of TgAb on FNA-Tg levels (5). However, the influence of TgAb on FNA-Tg remains unclear; furthermore, the status of the thyroid operation had not been considered in most of the earlier studies.
We aimed to determine the effects of serum TgAb on the cutoff value of FNA-Tg to detect metastatic lesions in suspicious LNs of preoperative DTC patients and to improve the diagnostic accuracy of FNA and FNA-Tg.
Subjects and methods
All three inclusion criteria should be satisfied before study enrollment: i) consecutive patients should have confirmed diagnosis of primary DTC, ii) ultrasound-guided FNAC were performed along with FNA-Tg measurement for suspicious LN, and iii) FNAC, FNA-Tg and TgAb measurement should be done before surgery.
Initially, 1050 LNs in 661 patients with suspicious LNs detected by neck ultrasound were targeted at a tertiary referral hospital between May 2011 and December 2013. Two hundred and seventy-three patients with 474 LNs who underwent lobectomy or total thyroidectomy before FNA were excluded. Additionally, 388 patients with 206 LNs were excluded due to no primary thyroid cancer (n=2), no follow-up or confirmation of LNs by pathology (n=155) and no data of preoperative sTg and TgAb (n=49) (Fig. 1). A total of 273 patients with 370 LNs were evaluated according to the presence or absence of TgAb. The institutional review board approved the study (KC14RISI0259).
Serum Tg, TgAb, FNAC and FNA-Tg measurement
Both serum and FNA washout Tg levels were measured using an immunoradiometric assay kit (CIS Bio International, Saclay, France), with a functional sensitivity of 0.7 ng/ml. Serum TgAb was measured by a competitive RIA kit (ZenTech, Angleur, Belgium). Positive TgAb was defined as serum TgAb of ≥70 IU/ml; negative TgAb as a serum TgAb of <70 IU/ml.
Ultrasound-guided FNAC was performed by one of several radiologists with the use of a 23-gauge needle. While a liquid-based cytology (LBC) was used in the diagnosis of primary thyroid tumor (18), FNAC for suspicious LN was evaluated by the conventional method: the aspirates were immediately smeared on slides, fixed in 95% ethanol and processed by both hematoxylin and eosin (H&E) and Papanicolaou stain. The same needle and syringe were rinsed with 2 ml of normal saline, and the washout fluid was submitted for FNA-Tg measurement.
FNAC and final pathology
Cytology findings of the LNs reviewed by experienced pathologists were categorized as non-diagnostic, benign and metastatic papillary thyroid carcinoma (PTC; suspicious malignancy, malignancy) (5, 10, 19, 20, 21).
Final outcome was confirmed by post-operative pathology in malignant LNs. When LNs were suspicious for malignancy in ultrasonography but cytology results revealed benign LNs, LN dissection and histopathologic confirmation were performed if there were malignant LNs in the same compartment (7, 13). Otherwise, decreased or same-size LNs in follow-up ultrasound after 6–12 months were defined as benign in the final outcome (21).
Data were expressed as mean±s.d. or median (minimum–maximum value). We performed receiver operating characteristic (ROC) curve analysis to confirm the cutoff level of FNA-Tg. Diagnostic performances of FNA and FNA-Tg were evaluated with respect to sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. The χ2 test or Fisher exact test was used to determine the differences between benign and metastatic LNs according to categorical variables. Statistical significance was determined when the P value was <0.05. All reported P values are two-sided. All analyses were conducted by SPSS Software (version 18.0).
Patient and LN characteristics
Finally, 273 patients with 370 LNs were included in this study. The median patient age at the time of FNA was 45 years (range 21–81) and 221 (81%) were female (Table 1). Of the 273 patients, 218 (79.9%) were in the TgAb negative (TgAb−) group and 55 (20.1%) in the TgAb positive (TgAb+) group. There was no significant difference in age but sex distribution between groups. However, FNA-Tg and preoperative serum Tg levels were significantly lower in the TgAb+ group vs TgAb− group (Table 1).
Patient characteristics according to TgAb.
|Number of patients (%)a||218 (79.9)||55 (20.1)|
|Male sex (%)||47 (21.6)||5 (9.1)||0.036|
|Preoperative serum Tg (ng/ml)||13.6 (0.2–557.6)||7.2 (0.0–71.2)||0.040|
|Preoperative TgAb (IU/ml)||12.6 (0.1–69.5)||209.2 (73.0–8560.0)||0.000|
|Number of lymph nodes (%)||289 (78.1)||81 (21.9)|
|FNA-Tg (ng/ml)||0.4 (0.0–1698.5)||0.9 (0.1–1121.2)||0.026|
Data are expressed as mean±s.d. or median (range).
Two hundred and sixty-one (70.5%) of 370 LNs were benign (Table 2); 55 LNs were confirmed by surgery and subsequent postoperative pathology and 206 LNs by follow-up US. The other 109 LNs (29.5%) were confirmed as malignant on postoperative pathology (Table 2 and Fig. 2). According to the final outcome and TgAb status, we compared four LN groups (Table 2). In benign LNs, there were no significant differences in FNA-Tg and preoperative sTg between the TgAb+ and TgAb− groups; however, in malignant LNs, median sTg and FNA-Tg levels were significantly lower in patients with serum TgAb+ than in those with TgAb− (8.2 vs 29.7 ng/ml, P=0.000; 398.5 vs 881.3 ng/ml, P=0.012).
Lymph node characteristics according to final outcome and TgAb.
|Final outcome||Benign||Malignant||P value|
|TbAb−a||TbAb+b||TbAb−c||TbAb+d||a vs b||c vs d||a vs c||b vs d|
|Number of lymph nodes||200||61||89||20|
|FNA-Tg (ng/ml)||0.2 (0.0–1253.7)||0.3 (0.1–833.5)||881.3 (0.2–1698.5)||398.5 (0.3–1121.2)||0.930||0.012||0.000||0.000|
|Preoperative serum Tg (ng/ml)||11.5 (0.2–366.2)||6.8 (0.0–71.2)||29.7 (0.4–557.6)||8.2 (0.1–71.2)||0.127||0.000||0.004||0.767|
|Preoperative TgAb (IU/ml)||14.2 (0.1–66.9)||218.9 (75.9–8560.0)||12.5 (0.3–69.5)||515.8 (73–6483.1)||0.001||0.013||0.004||0.625|
Diagnostic performance of FNAC
Among 109 metastatic LNs, FNAC resulted in a correct diagnosis in 92 cases but faild to diagnose 17 cases with a resultant 84.4% sensitivity and 99.6% specificity. Among the 17 misdiagnosed metastatic LNs, 15 had been reported as benign, one unsatisfactory and one instance of macrophages on FNAC. Among 261 benign LNs, 259 LNs were correctly diagnosed as benign in FNAC but one LN showed malignancy and another LN as unsatisfactory.
FNA-Tg and final outcome
We compared sensitivity, specificity, PPV, NPV and diagnostic accuracy of FNA-Tg levels of LN according to the functional sensitivity of Tg (0.7 ng/ml) (3, 22) and the value determined by ROC curve (6.0 ng/ml), with those of FNAC (Table 4). In addition, FNA-Tg/sTg ratio was also used as a cut-off value to diminish the influence of sTg in preoperative patients (19, 23) (Table 4)
Comparison between diagnostic performances of FNAC, FNA-Tg and FNA-Tg/sTg ratio.
Functional sensitivity of thyroglobulin assay.
Cutoff value according to ROC.
FNAC alone showed the lowest sensitivity (88.4%) but the highest specificity (99.6%). With FNA-Tg 0.7 added to FNAC, sensitivity was the highest (99.1%) but PPV was the lowest (63.9%). The combination of FNA-Tg 6.0 and FNAC showed the best diagnostic accuracy, with 97.3% sensitivity, 94.6% specificity, 88.3% PPV, 98.8% NPV and 95.4% accuracy. The diagnostic value of FNA-Tg/sTg ratio was inferior to that of FNA-Tg alone.
All combinations of FNA-Tg and FNAC showed higher sensitivity and NPV than FNAC or FNA-Tg alone.
Optimal cutoff values of FNA-Tg in determining malignant LNs according to TgAb status
Diagnostic performance of FNAC, all FNA-Tg levels and their combinations were lower in the TgAb+ group than TgAb− group. When applying ROC curve cutoff of the entire group (6.0 ng/ml), sensitivity and PPV were reduced by >10% in the TgAb+ group, as compared to the TgAb− group (Table 5). Comparing FNA-Tg alone with FNAC combined with FNA-Tg at each cutoff value of FNA-Tg, there was no significant improvement in diagnostic performance found in the TgAb− group, but sensitivity was greatly improved (85–95%) in the TgAb+ group. Sensitivity and NPV improved when applying a lower cutoff value of FNA-Tg (6.0 ng/ml to 2.5 ng/ml) combined with FNAC in the TgAb+ group. On the contrary, TgAb− group showed better diagnostic performance when applying a higher cutoff of FNA-Tg (6.0 ng/ml to 8.5 ng/ml) (Table 5).
Comparison between diagnostic performances of FNA-Tg, FNA-Tg/sTg ratio according toTgAb status.
Functional sensitivity of thyroglobulin assay.
Cutoff value according to ROC regardless of TgAb status.
Cutoff value according to ROC in the absence of TgAb.
Cutoff value according to ROC in the presence of TgAb.
Presentation of LNs with discordant results
FNAC results and postoperative pathology were not in agreement in 19 LNs of the 19 patients: 15 LNs that were negative for malignancy in FNAC were malignant on postoperative pathology (Table 6). Four patients out of 19 discordant cases showed positive TgAb (21.1%). Among 15 malignant LNs, only three LNs showed FNA-Tg of <6 ng/ml (cases 1–3). Case 2 with positive TgAb (173.7 IU/ml) had 2.8 ng/ml of FNA-Tg, which could have been detected by the cutoff value (2.5 ng/ml) with ROC analysis in the TgAb+ group.
Another two non-diagnostic LNs were metastatic in the final report (cases 16 and 17) with FNA-Tg levels of >6 ng/ml, without TgAb. Case 18, initially misdiagnosed as papillary carcinoma by FNAC, was finally diagnose as parathyroid hyperplasia (Table 6).
Clinical characteristics of lymph nodes with discordant results between preoperative FNAC and postoperative pathology.
|LNs||Gender||Age||FNAC||Postoperative pathology||FNA-Tg||TgAb||Serum Tg||Cervical lymph node level|
|1||F||53||Negative for malignancy||Papillary carcinoma||0.2||1.1||14.4||L4|
|2||F||45||Negative for malignancy||Papillary carcinoma||2.8||173.7||23.4||R2|
|3||F||49||Negative for malignancy, many small and large polymorphic lymphoid cells||Papillary carcinoma||4.8||39.3||39.7||R4|
|4||F||35||Negative for malignancy||Papillary carcinoma||6.6||11.4||2.3||R4|
|5||F||60||Negative for malignancy||Papillary carcinoma||7.9||1552.2||9.1||R3|
|6||F||44||Negative for malignancy||Papillary carcinoma||9.3||24.4||11.8||L4|
|7||F||36||Negative for malignancy||Papillary carcinoma||26.0||8.6||514.4||L3|
|8||F||49||Negative for malignancy||Papillary carcinoma||27.1||191.1||36.9||R6|
|9||F||36||Negative for malignancy||Papillary carcinoma||29.4||664.2||71.2||R3|
|10||F||49||Negative for malignancy||Papillary carcinoma||36.2||13.0||28.9||L4|
|11||F||39||Negative for malignancy. Mainly blood and some inflammatory cells||Papillary carcinoma||890.8||22.0||15.2||R4|
|12||F||47||Negative for malignancy||Papillary carcinoma||1037.5||15.3||28.4||R2|
|13||M||63||Negative for malignancy||Papillary carcinoma||1195.5||13.0||5.7||R3|
|14||F||60||Negative for malignancy||Papillary carcinoma||1195.6||9.2||156.3||R4|
|15||M||43||Negative for malignancy||Papillary carcinoma||1295.7||6.8||49.6||L4|
|16||M||34||Non-diagnostic specimen; only fibrovascular and muscular tissue||Papillary carcinoma||413.8||12.1||25.4||L4|
|17||M||60||Other; many hemosiderin-laden macrophages||Papillary carcinoma||800.3||1.4||122.9||L4|
|18||F||40||Papillary carcinoma||Parathyroid hyperplasia||0.3||10.7||14.7||R6|
|19||F||38||Unsatisfactory; very low cellularity||Negative for malignancy||0.0||6.4||6.1||R4|
L, left; R, right; number, cervical lymph node area (2, 3, 4, 6).
Although many clinical studies composed of total thyroidectomy patients evaluated optimal cutoff values of FNA-Tg levels in detecting metastatic LNs, there are no reliable studies on cutoff values of FNA-Tg levels in preoperative patients. Several studies were conducted on preoperative patients (7, 13, 23, 24, 25) but the small number of cases precluded any strong conclusion and the TgAb status was not considered. Prior studies also showed the effect of TgAb status on FNA-Tg levels but did not consider the operative status (5, 10, 26).
In this study, preoperative patients who were diagnosed with PTC and had LNs with metastatic feature in US underwent FNAC and Tg estimation in washout fluid of FNAC. Our study confirmed that positive serum TgAb lowered FNA-Tg levels and influenced the diagnostic accuracy of FNA-Tg in suspicious LNs of preoperative patients.
All preoperative patients had normal thyroid tissues, which indicated an increased proportion of TgAb-positive patients, as compared to thyroidectomy patients with or without radioiodine remnant ablation (27) As increased serum TgAb levels lower sTg levels (28), we hypothesized that increased serum TgAb levels in thyroid cancer patients have lower FNA-Tg levels and subsequently lower diagnostic accuracy of FNA-Tg in patients with suspicious LNs. Baskin et al. (26) first suggested that the measurement of FNA-Tg from LN was unlikely to be affected by the presence of TgAb in the peripheral blood, possibly because the intracellular Tg is not exposed to circulating TgAb, from the two patients who showed FNA-Tg levels of 24.9 and 67.5 ng/ml respectively but positive TgAb and undetectable sTg. Boi et al. (5) also concluded that the diagnostic performance of FNA-Tg seems to be not substantially affected by TgAb, although TgAb in FNA washout may lower FNA-Tg in a few selected cases. The rationale of no interference by TgAb is as follows: In metastatic LNs, FNA-Tg levels are much higher than TgAb levels that exist in the washout fluid. It can overcome interference by TgAb due to saturated TgAb-binding sites (5). Diluted TgAb in washout fluid (most likely being 1:50 or higher) (25) result in absence or scarcity of TgAb within the LNs.
However, one recent study by Jeon et al. (21) demonstrated that high serum TgAb levels could lower FNA-Tg levels, from 25 suspicious LNs in 14 patients who underwent total thyroidectomy and radioiodine remnant ablation. They showed a diagnosis based on FNA-Tg in metastatic LNs might have a lower sensitivity and NPV in the TgAb-positive patients (19, 26). Consistent with their results, our study also showed a lower diagnostic accuracy of FNA-Tg, whether combined with FNAC or not, in the TgAb-positive patients (Table 5). However, a high proportion of patients (55/273, 20.1%) with high TgAb levels existed in our preoperative LN case series, whereas only 15 patients out of 207 (7.2%), in Jeon et al. (21), showed high TgAb levels and were evaluated by FNA-Tg for suspicious LNs over follow-up after total thyroidectomy. These findings suggest that TgAb has greater effect on FNA-Tg level of preoperative patients and justify TgAb measurement when planning to perform FNA-Tg evaluation before surgery.
We measured FNA-Tg levels of 370 LNs from preoperative patients according to the presence of TgAb. As FNA-Tg levels per se are too low in uninvolved benign LNs, the effect of TgAb positivity on FNA-Tg levels was negligible. On the other hand, the FNA-Tg levels from malignant LNs were significantly high, indicating that serum TgAb positivity might affect FNA-Tg as well as sTg. Usually, women showed a higher rate of TgAb positivity than men. This could be explained by the higher prevalence of autoimmune thyroiditis in women than men (29).
Our results indicated that FNA-Tg had a high NPV, a characteristic of a good diagnostic tool. Diagnostic performance of the combination of FNAC and FNA-Tg levels was better than the single use of FNAC or FNA-Tg (Table 4). When we used an FNA-Tg cutoff value of 6.0 ng/ml for preoperative patients, the TgAb− group showed the best diagnostic performance, but lower sensitivity and NPV were shown in the TgAb+ group. In comparison, lowering the FNA-Tg cutoff value led to increased sensitivity and NPV in the TgAb+ group (Table 5). This finding supported the hypothesis that the cutoff level of FNA-Tg in TgAb+ group should be lower than in the TgAb− group. Interestingly, combining FNAC with FNA-Tg showed the same sensitivity but lower specificity in the TgAb− group, because of one false-positive FNAC result.
It has been suggested that sTg level should be considered with FNA-Tg by sTg to FNA-Tg ratio (23, 30, 31). This approach could potentially overcome interference by sTg with FNA-Tg, especially in preoperative patients, and therefore needs validation. In our study, a serum-to-FNA-Tg ratio of 1.0 had an 88.1% sensitivity and 93.9% specificity, which showed inferiority to FNA-Tg alone or FNA-Tg combined with FNAC (Table 4).
Generally, FNAC, FNA-Tg levels and their combination had lower diagnostic performance in TgAb+ group compared to the TgAb− group. These results indicated that a positive TgAb status has a low diagnostic rate at any cutoff level (Table 5). According to the current guidelines, there is no recommendation to measure serum TgAb levels preoperatively (16). However, TgAb should be measured in preoperative thyroid cancer patients with planned FNAC or FNA-Tg assays for suspicious LNs. Our results suggested a lowering of cutoff value of FNA-Tg levels when TgAb is present in patient serum.
For evaluation of FNAC on LN, we used the conventional smear (CS) method rather than LBC. There were several studies that showed better diagnostic performance in LBC than in CS in evaluating thyroid nodule (18, 32). However, there were rarely studies showing the usefulness of LBC in FNAC of the LN. One study showed that the diagnostic efficacy of FNAC of the LN is identical between the CS and LBC (33). In another study by Tripathy et al. (34) that evaluated 40 LNs (20 reactive hyperplasia, 12 granulomatous lymphadenitis, three lymphoma and five metastatic carcinoma), Reed–Sternberg cells were more easily diagnosed on LBC smears due to mono-layering. From a few prior studies, we could see the potential of LBC in FNA-Tg diagnosis. In the near future, comparative study should be included between LBC and the CS method for the improvement of diagnostic efficacy in LN FNAC.
The strength of this study was that all 370 LNs in 273 patients were preoperative cases that had never been assessed in detail up to that point. However, we did not measure the levels of TgAb in the FNA washout fluid (FNA-TgAb). This makes it impossible to know the exact impact of FNA-TgAb on FNA-Tg levels, even though FNA-TgAb is unlikely to have an influence on FNA-Tg levels, according to several reports (35, 36): first, the high Tg levels in metastatic LN (FNA-Tg) overcomes the blocking capacity of FNA-TgAb. Secondly, the FNA-TgAb is too low to interfere. Another limitation was that all suspicious LNs evaluated by FNAC and FNA-Tg were not pathologically confirmed. The LNs considered to be benign by FNAC were not the target of surgery, hence their final outcomes were dependent on follow-up US in 6–12 months.
Our data indicated that serum TgAb should be measured along with FNAC and FNA-Tg on suspicious LNs in preoperative patients, due to the different cutoff values of FNA-Tg based on serum TgAb status. We propose that the cutoff value of FNA-Tg should be lowered before thyroidectomy in thyroid cancer patients with positive serum TgAb.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported.
This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.
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