The differentiated thyroid cancers (DTCs) originating from the follicular cells are represented by the papillary-type cancers (PTCs), being the most common (70–80%) out of all thyroid malignancies, and the follicular-type cancers (FTCs) . These cancers have generally indolent behavior with low morbidity and mortality. The initial treatment for both PTC and FTC is made by (near) total thyroidectomy, with or without cervical lymph node (CLN) dissection, and 131I. The latter depends on the histological stratification [2,3]. After treatment, to replace the thyroid function and to suppress a further growth of any DTC cells, patients are placed on thyroid hormone therapy (i.e. levothyroxine, LT4) [2,3]. Despite the above-mentioned excellent prognosis, a minority of these patients shows recurrence (or multiple recurrence long-term). Thus, patients with DTC could benefit from regular follow-up throughout their life [2,3]. Even if PTC and FTC derive from the same progenitor (i.e. the thyroid follicular cell), they follow different ways of dissemination. In fact, PTC disseminates via the lymphatic apparatus with metastasis to the regional lymph nodes; FTC metastasizes through the hematogenic way to distant organs, such as lung or bone [4–7]. The involvement of central neck lymph nodes (VI level, see Fig. 1) is more common, and lateral compartments are involved frequently when VI level is affected by more nodal metastases.
During follow-up, serum markers (thyroglobulin) and imaging workup (neck ultrasonography; whole body scan, WBS) are used to identify persistence or recurrence of disease. The thyroglobulin measurement is nowadays the yard-stick for clinical management of patients with DTC, in the absence of antithyroglobulin antibodies (TgAb) . Cervical recurrences may be clinically detected, but now are most often discovered on neck ultrasonography ; WBS with radioactive iodine and/or 18F-fluorodeoxyglucose (18FDG) PET/computed tomography (CT) are performed when distant metastases are expected . In case of suspicious ultrasonography findings, fine-needle aspiration (FNA) is generally required to cytologically confirm or exclude recurrence . However, FNA sample may be inadequate or even false-negative, especially in lymph nodes with small metastases or partial involvement or cystic changes . To improve the diagnostic yield of FNA, several authors have proposed measurement of thyroglobulin in aspirates (FNA-Tg), particularly in the cases involving small, partially cystic, lymph nodes [13–21]. Unfortunately, differences in sample treatments, thyroglobulin assays and reference values make difficult the comparison between different series. As a consequence, guidelines for the method and codified reference values are claimed to routinely use this technique in clinical practice.
SERUM MARKERS AND IMAGING FEATURES FOR CERVICAL RECURRENCES OF THYROID CANCER
DTC recurrence within the neck is usually detected by serum thyroglobulin determination combined with physical examination and neck ultrasonography . Serum thyroglobulin is a pivotal tool to follow-up patients with DTC after surgical and radioiodine ablation of cancerous and all noncancerous thyroid cells.
Currently, serum thyroglobulin measurement during thyrotropin (TSH) stimulation is recommended to confirm complete thyroid ablation and monitor for the recurrence or persistence of DTC. Undetectable stimulated thyroglobulin values obtained at 6–12 months after treatment predicts complete remission of the disease and a very low risk of further recurrences (i.e. 0.5–1%) [2,3]. More recently, undetectable thyroglobulin during LT4 treatment was proved as a sufficient evidence to avoid TSH stimulation if highly sensitive assays are employed [22,23▪▪]. It has to be mentioned that several analytical (i.e. positive TgAb, heterophile antibodies, hook effect) or preanalytical (e.g. freezing or repeated freezing and thawing of sera, hemolysis or lipemia, preanalytical use of different serum separating tubes) conditions may affect the serum thyroglobulin determination.
The neck ultrasound examination is useful in both palpable and nonpalpable nodes. In 2003, Pacini et al. evaluated a series of 340 consecutive DTC patients and demonstrated for the first time that ultrasonography as a single test had higher accuracy than WBS in imaging locoregional recurrences. In particular, neck ultrasonography combined with serum (basal and/or stimulated) thyroglobulin identified patients requiring treatment with no necessity of WBS. This approach was confirmed in other studies [16,25] and is recommended by current guidelines [2,3]. Normally, a lymph node manifests at ultrasonography as solid hypoechoic, with oval-elongated shape, and well recognizable hilus (note: the size should be highly variable) (Fig. 2a). Conversely, loss of the hilar architecture, round shape, cystic change, hyperechoic punctuations (i.e. calcifications) and irregular-chaotic vascularization should be considered as suspicious for DTC metastasis (Fig. 2b–d). However, each of such suspicious characteristics reaches high sensitivity only when combined. Several articles evaluated ultrasonography parameters in detecting neck metastases from DTC and the hilus absence is reported as the highest sensitive one but with very low specificity [9,26,27]. Because of the lack of negative cases in these studies, ultrasonography specificity is not well set to date. In fact, a few prospective articles analyzed that this issue exists. In 2007, Leboulleux et al. prospectively evaluated diagnostic accuracy of ultrasonography parameters in a series of 28 benign and 28 malignant lymph nodes undergoing surgery. The most specific (100%) criteria were presence of cystic areas and hyperechoic punctuations. Of these, sensitivity was less than 60% and they are not reliable as a single criterion . Because of these significant limits of ultrasonography in detecting malignant lymph nodes, American Thyroid Association (ATA) guidelines recommend cautious observation and serial neck ultrasonography in those patients with small abnormal cervical lymph nodes . Small thyroid bed nodules are a commonly reported sonographic finding. Recently, Rondeau et al.[29▪▪] reported a retrospective study on 191 patients with at least one small (mean size 5 mm) thyroid bed lesion. Based on the data from this study and according to ATA guidelines , also these lesions should be followed-up by serial ultrasonography.
FINE-NEEDLE ASPIRATION CYTOLOGY
Enlarged cervical lymph nodes or nodules in the thyroid bed can be observed in inflammatory process or in case of metastatic disease. In the first situation, the FNA specimens contain lymphocytes with tingible bodies and macrophages (chronic inflammation) (Fig. 3), mixture of lymphocytes and granulocytes (acute inflammation), mixture of lymphocytes and multinucleated giant cells (granulomatous inflammation), or variable amount of necrosis (i.e. abscess and/or tubercolosis). In the second situation, epithelial cells with clear nuclei, nuclear pseudoinclusions and/or grooves, irregular nuclear membrane and arranged in papillary or follicular structures are seen interspersed with lymphoid cells (Fig. 4). Of note, it is common to get a large amount of densely packed lymphocytes when aspiring a lymph node. In such cases, it is difficult to see single metastatic cells and to recognize the typical nuclear features of PTC. Particularly tricking can be the presence of necrosis and/or necrotic debris suggesting a dedifferentiated and aggressive metastasis. Cytological outcome reports of lymph nodes specifically for the search of thyroid cancer metastases are detailed in Table 1. Generally, FNA achieves high sensitivity and specificity when combined with ultrasonography in detecting metastatic PTC. However, nondiagnostic specimens have been described in up to 10–20% of cases, mainly due to small size of the lesion or cystic changes [30,31]. In particular, the latter is not rarely reported, and the samples obtained from these lesions can lack epithelial cells, being recorded only fluid with scattered macrophages or hemosiderophages. Thus, malignant or benign diagnosis cannot be achieved, and nondiagnostic diagnosis should be preferred instead of negative report. Finally, in case of enlarged lymph node due to an extra thyroidal malignancy with suspicious ultrasonography features, the morphology alone sometimes is not discriminating between a thyroid and extra-thyroid process. In such cases of doubt concerning the origin of the neoplastic cells we perform thyroglobulin immunostaining or thyroid transcription factor (TTF)-1 immunostaining directly on the smears, on the liquid-based preparation or on the cell block (note: remember that TTF-1 is also expressed by lung adenocarcinomas, but in that case thyroglobulin immunostain is negative).
THYROGLOBULIN MEASUREMENT IN NEEDLE WASHOUT
To improve the diagnostic yield of FNA several authors have proposed measurement of thyroglobulin in aspirates (FNA-Tg). The measurement of thyroglobulin in the needle washout after aspiration was first proposed in 1992 by Pacini et al.. There, sensitivity was reported 100% for FNA-Tg and 85% for cytology and no FNA-Tg false-positive results were observed in postoperative patients. After, Frasoldati et al. analyzed 69 lymph nodes recording 84% sensitivity and 95% specificity for FNA-Tg, and in a following article by the same authors on 51 patients the combination of FNA-cytology and FNA-Tg approached to 95% sensitivity . Cunha and co-workers  evaluated 83 enlarged cervical lymph nodes from 67 patients affected by DTC: the FNA-Tg had a sensitivity of 100% while cytology alone missed nine of 20 metastases. Subsequently, many studies reported an increased sensitivity of FNA-Tg, especially to the diagnosis of poor cellular material obtained from cystic or small lymph nodes. A total of 256 samples from 145 patients were evaluated for FNA-Tg and compared with corresponding cytological smear and histology of 46 surgical specimens by Sigstad et al.. The FNA-Tg reached 100% sensitivity and performed better than cytology in cystic or very small lesions. Although the above articles investigated the cutoff limit for FNA-Tg in detecting metastasis, a higher serum/FNA-Tg ratio was proposed by Uruno et al.. One hundred twenty-nine lymph nodes were evaluated and similar sensitivity between FNA-Tg (81.4%) and cytology (78%) was found . Altogether, 36.4% of cases judged benign and 37.5% of cases judged inadequate by cytology were positive by FNA-Tg measurement and metastases were confirmed histologically.
Circulating serum antithyroglobulin antibodies interference
Whether circulating TgAb should affect the FNA-Tg is still a matter to debate. An article by Boi et al. analyzed the issue reporting that FNA-Tg measurement was proved to be unaffected by positive serum TgAb. More precisely, lower FNA-Tg concentrations were found in FNA washout fluids containing TgAb than those TgAb free. The presence of TgAb in washout fluids could be due to blood contamination or even to active intra-nodal TgAb synthesis . The interference of such TgAb on FNA-Tg measurement, however, does not affect the clinical performance of the test (i.e. the FNA-Tg levels were in any case well detectable) . The most probable explanation is that the exceedingly elevated thyroglobulin concentration in positive FNA-Tg is able to saturate TgAb binding sites. More recently, Cappelli et al.[34▪] challenged this assumption by reporting on two patients with lymph node metastases from PTC and detectable serum TgAb. Lymph nodes FNA was performed both before and after recombinant human thyrotropin (rhTSH) stimulation and detectable FNA-Tg levels were found only after rhTSH stimulation in both patients. The authors proposed that high TgAb concentrations in metastatic lymph nodes may prevent the detection of thyroglobulin in FNA washout fluids. They also suggest that the thyroglobulin excess induced by rhTSH stimulation may ‘saturate’ all TgAb binding sites explaining why thyroglobulin was only detectable after rhTSH stimulation in their patients. However, the accuracy of lymph nodes sampling was not definitely confirmed, FNA samples were not examined by a cytopathologist and a first generation thyroglobulin assay was used by these authors. As a consequence their anecdotal conclusions cannot support the ‘rhTSH-stimulated FNA-Tg measurement’ in daily clinical practice .
PREPARING THE SAMPLE AND ASSESSING CUTOFF VALUES
All in all, it is well demonstrated that the presence of thyroglobulin in the needle washouts is even more sensitive than cytology in diagnosing DTC relapse in lymph nodes and neck masses [15–21,31,32]. However, when looking at different studies two main methodological problems are obvious.
Firstly, different FNA procedures and sample preparation protocols were applied by different clinicians. Apart from differences in FNA techniques (i.e. aspiration versus capillarity), different dilution volumes and washing solutions were used; however, few data exist on the preanalytical phase of FNA-Tg measurement. At Oncology Institute of Bellinzona, we evaluated 156 lesions from 108 patients with suspicion of DTC recurrence at neck ultrasonography examination. Following collection of cytology samples the needles were washed by 1 ml of normal saline. Washes aliquots were randomly collected into three different tubes (i.e. plain serum tube, serum separator tube and lithium-heparin tube). A strong relationship was found between FNA-Tg values measured on different tubes. However, the FNA-Tg was significantly higher in plain tubes as compared to serum separator or lithium–heparin ones, respectively (P < 0.001). Of more importance, the FNA-Tg measurement in plain serum tubes and serum separator tubes was positive in all patients with proved DTC recurrences (sensitivity 100%) whereas false-negative results occurred in two patients by lithium–heparin tubes (sensitivity 98%). As a consequence, we proved that the preanalytical phase may introduce significant variability in FNA-Tg measurement and negatively impact its diagnostic accuracy. Practically, FNA-Tg bias should be reduced by using a fixed dilution fluids volume and plain tubes . Also, different technical problems should be considered when thyroglobulin is measured in biological fluids. Intermethod variability requires to perform thyroglobulin measurements with the same method and, optimally, in the same laboratory . The hook effect appears to result when a massive excess of antigen exhaust the binding capacity of the thyroglobulin capture antibody on the solid-phase support. This leads to reporting of inappropriately normal or low serum thyroglobulin values in samples with very high thyroglobulin concentrations, that frequently occurs in FNA washout fluids . Samples dilution or batching must be used to detect hook effect before reporting the thyroglobulin concentration, especially if low or undetectable FNA-Tg values are found in the original sample.
Second, significant differences in serum thyroglobulin measurement are obtained in different thyroglobulin assays. The international collaborative studies showed that serum thyroglobulin values vary as much as 40–60% between methods. The introduction and use of international reference standard (CRM 457) significantly reduces (to about 30%) but does not eliminate intermethod variability . The current between-method biases could still produce a magnitude in thyroglobulin changes exceeding the within-person variability of serum thyroglobulin concentrations (10–15%). The large variability between different thyroglobulin assays is one of the causes of the wide variety of FNA-Tg cutoff values proposed by different authors. In prior studies, the mean thyroglobulin and 1 or 2 SDs, FNA-Tg more than serum thyroglobulin or different fixed thyroglobulin values have been reported as threshold values that differentiate nonmetastatic from metastatic lymph nodes in a wide range from 0.9 to 50 ng/ml [13–21,29▪▪]. In addition, thyroglobulin also can be detected in FNA washout fluid from even nonmetastatic lymph nodes in the presence of a thyroid gland. However, only few articles addressed differences between athyrotic patients and those DTC patients awaiting thyroid surgery. A substantial overlap of FNA-Tg results was proved in the latter group and thyroglobulin levels as high as 88.8 ng/ml were reported in benign lymph nodes from DTC patients awaiting surgery [18,21]. Accordingly, Boi et al. adopted a different FNA-Tg cutoff depending on the presence (i.e. cutoff 36 ng/ml) or the absence (i.e. cutoff 1.7 ng/ml) of the thyroid gland . In apparent contrast, Bournaud et al. and Salmashoglu et al. found a unique threshold of 0.93 ng/punction (ng/p) and 28.5 ng/ml, respectively, give high sensitivity and specificity, even in nonthyroidectomized patients. However, among 114 and 225 consecutive patients with thyroid cancer they evaluated 13 (11%) and 80 (35%) patients prior to thyroidectomy, respectively. Even if we cannot directly compare such studies, due to differences in thyroglobulin assays and samples treatment, a significant increase in FNA-Tg cutoff values was observed when more nonthyroidectomized patients were enrolled. All in all, the accuracy of the FNA-Tg measurement seems to be superior in patients previously treated by total thyroidectomy compared with those awaiting thyroid surgery [40,41] and, consequently, we suggest to combine cytology and thyroglobulin measurement when lymph node FNA is performed before thyroidectomy. Interestingly, recent studies showed that a cutoff level of 1 ng/ml, as obtained by sensitive thyroglobulin assays, provides high sensitivity in DTC patients previously treated by thyroidectomy. Snozek and colleagues [42▪▪] measured thyroglobulin in 122 FNA samples from 88 athyrotic DTC patients, by employing a high-sensitive immunochemiluminometric assay (functional sensitivity 0.1 ng/ml). Fifty of 52 nonmalignant samples (96.2%) had thyroglobulin 1 ng/ml or less, whereas all 70 malignant FNA had thyroglobulin greater than 1 ng/ml. By using a different high sensitive immunoradiometric thyroglobulin assay (functional sensitivity 0.2 ng/ml) and adopting the receiver operating characteristic curve-derived cutoff of 1.1 ng/ml, we obtained 100% sensitivity, specificity, and accuracy .
FNA-Tg measurement is the more accurate tool to detect neck recurrences and cervical metastases from DTC. Providing strict standardization of preanalytical and analytical phase (Table 2) FNA-Tg may suffice to confirm or exclude neck DTC recurrence in patients with concurrent well differentiated PTC, suspicious neck ultrasound findings and increased serum thyroglobulin after thyroidectomy. Using a sensitive thyroglobulin assay, a cutoff level of 1 ng/ml provides high sensitivity in patients previously treated by thyroidectomy. However, FNA-Tg accuracy increases by adding cytological exam when FNA is performed before thyroidectomy, in patients with more aggressive histological types, and if low serum thyroglobulin and/or positive serum TgAb occur.
Conflicts of interest
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.
Financial disclosures: none.
Funding resources: none.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 99–100).
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