Utility of Thyroglobulin measurement in fine-needle aspiration biopsy specimens of lymph nodes in the diagnosis of recurrent thyroid carcinoma

Introduction

Papillary thyroid carcinoma (PTC) is the most common malignant tumor of thyroid. Though in majority of cases PTC behaves in an indolent fashion, it can spread through lymphatics within the thyroid gland (multi-focal disease) and metastasize to the cervical lymph nodes [13]. In patients with a previous diagnosis of PTC, the clinical or radiologic detection of enlarged cervical lymph nodes raises the suspicion of recurrent disease [34].

Fine needle aspiration biopsy (FNAB) can effectively diagnose PTC because its diagnosis is based upon the demonstration of classic nuclear features [56]. It has been shown that FNAB is effective alone or in conjunction with ultrasound guidance in the diagnosis of metastasis from PTC to the cervical lymph nodes [78]. However, in some instances the metastatic deposits of PTC in the lymph nodes may undergo degeneration and cystic change [911]. In such instances the FNAB of lymph nodes even with ultrasound guidance may only show colloid type material, cellular debris and macrophages without any identifiable tumor cells. These specimens are usually classified as “non-diagnostic or unsatisfactory for evaluation [91112].”

Measurement of thyroglobulin (TG) in the FNAB needle rinse from the cervical lymph nodes has been employed for detecting recurrent thyroid cancer in patients who have undergone total thyroidectomy and ¹³¹I therapy for differentiated thyroid cancer [11–19].

In this study we evaluated the role of FNAB-TG in detecting lymph node recurrence in patients with previous history of thyroid carcinoma at our institution.

Materials and Methods

FNAB

All lymph nodes were initially localized and measured (size range 0.7–3.7 cm) using a high-frequency linear 10–5 MHz transducer and an ATL 3000 ultrasound scanner (Advanced Technology Laboratories, Bothell, WA) (Fig 1). Ultrasound-guided FNAB was performed using a 25-gauge, 1.5 inch needle and an 8–5 MHz curvilinear transducer using real-time, free hand technique.

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Figure 1

Ultrasound image demonstrates a mixed cystic and solid appearing lateral cervical lymph node in a patient with previous thyroidectomy for papillary thyroid carcinoma.

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The first FNAB pass was evaluated on-site by the cytopathologist; it was divided between fresh smears and Normosol^® for Millipore-filter^® preparations. Half of the fresh smears were stained with Diff-Quik for immediate on-site evaluation and the others were placed in 95% alcohol for Papanicolaou staining. The second FNAB pass was washed in Normosol and the entire wash was submitted for TG assay.

Results

FNAB Findings

Metastatic PTC was diagnosed in 39 (34%) specimens (Fig 2). Fifteen aspirates (13%) were diagnosed as suspicious for PTC; these included 9 cases showing colloid and macrophages and no viable tumor cells present and 6 cases with atypical cell present suspicious for PTC. Thirty-five (30%) cases were diagnosed as reactive lymphoid tissue only no tumor seen, 23(20%) were classified as inadequate for evaluation due to lack of any lymphoid or epithelial cells, and in 3 (3%) cases the diagnosis included paraganglioma 1, PDCA 1 and carcinoma not further specified 1 case.

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Figure 2

Papanicolaou-stained fine-needle aspiration smear from a lymph node showing metastatic papillary thyroid carcinoma.

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Discussion

The well-differentiated thyroid carcinoma (WDTC) after surgical excision and radioiodine ablation is usually followed by basal and TSH stimulated serum TG measurement, ¹³¹I whole body scan and neck ultrasound [2021]. Since, well differentiated thyroid tumor cells retain their functionality, elevated serum TG levels are often indicative of residual tissue in thyroid bed or metastatic tumor [22–24]. Tumor recurrences in WDTC are often encountered in thyroid bed, lateral and central neck nodes [23–25]. The pathologic diagnosis of which is often required before submitting the patient to further surgical exploration because reactive/hyperplastic lymph nodes, reactive scar tissue and rarely post-surgical traumatic neuroma can mimic tumor recurrences on ultrasound examination [111416].

Ultrasound guided fine-needle aspiration biopsy (US-FNAB) can effectively diagnose tumor recurrences in > 90% of cases on the basis of morphology alone, however, false negative results can be seen in 6–8% of cases. This could be due to absence of tumor cells in the FNAB specimen, partial or focal involvement of the lymph node or extensive tumor cell degeneration in some cases of PTC [11–1926]. Measurements of TG in the rinse of the aspiration biopsy needle have been proposed for detection of neck lymph node metastasis from WDTC in patients after total thyroidectomy and radioiodine ablation [11–1926].

Pacini et al in 1992 first reported the use of TG measurements in FNAB specimens (FNAB-TG) of non-thyroidal neck masses in 35 patients. In this study FNAB-TG levels diagnosed metastatic thyroid cancer in 14 patients, which was confirmed by histopathologic follow-up. These authors concluded that FNAB-TG had better negative predictive value than cytology alone [11]. Cignarelli et al reported FNA-TG to be more sensitive than FNAB alone especially in cases where cystic degeneration of metastatic deposits in neck nodes may contain few degenerated or no tumor cells [15]. Similar results have been documented by various studies from other insititutions [12–1416–1926].

In the present study we analyze the usefulness of TG levels as an adjuvant to FNAB in the diagnosis of lymph nodes suspicious for recurrence of PTC under ultrasound in 115 cases in 89 patients with history of previous thyroid carcinoma. When analyzing our results some discrepancies between the cytological diagnosis and the expected TG level were noted. Of the eleven cases (11/39 28%) diagnosed as PTC and 4 cases (4/15 27%) diagnosed as atypical/suspicious for PTC on cytology with TG levels < 10 ng/ml, eight cases (8/15 53%) had a diagnosis of PTC-TCV on histologic follow-up. The PTC-TCV is an aggressive variant of PTC. Its pathologic diagnosis is dependent upon the characteristic morphology i.e. presence of elongated cells with height being three times the width, oncocytic cytoplasm and nuclear features of PTC. It has been shown that these tumors can be difficult to treat because of their loss of iodine-avidity and decreased or absence of thyroglobulin production; this is especially encountered in recurrent tumors [26].

The limitations of FNAB, particularly in the setting of cystic lymph nodes where sampling of diagnostic areas is potentially problematic, were highlighted by the correlation with TG levels. All of the 5 cases diagnosed as no tumor seen on cytology with TG levels ≥ 10 ng/ml resulted in PTC on surgical follow-up. Similarly, 3 cases considered non-diagnostic on cytology due to lack of any cells with increased TG levels resulted in PTC diagnoses on follow-up.

Particularly important are the results in the category of atypical/suspicious for PTC recurrence. The cases with TG levels ≥ 10 ng/ml resulted in the diagnoses of PTC on follow-up; however, all cases with TG levels within normal limits also resulted in diagnosis of malignancy. This led us to believe that the cytopathology findings should rule over TG levels especially in cases of atypical/suspicious cytologic results. TG levels will not aid in the distinction between benign and malignant if a cytological specimen is atypical enough to warrant this diagnosis.

The diagnostic value of FNAB and FNAB-TG could not be calculated in this study due to lack of histologic follow-up in majority of cases diagnosed as no tumor seen and non-diagnostic.

The presence of serum anti-TG antibodies (TG-Ab) which can occur in up to 25–30% of patients can seriously affect serum TG measurements leading to either false positive or false negative results [2728]. Therefore some authors have excluded patients with serum TG-Ab from their studies on the role of TG-FNAB in the diagnosis of recurrent WDTC [14]. Recently reports by Baskin et al and Boi et al have shown that TG-FNAB measurements are not affected significantly by the presence of TG-Ab in the FNAB specimen [1618]. In view of these studies we did not include the presence or absence of TG-Ab in this study.

In summary, we have demonstrated similar to other studies that TG can be effectively measured in FNAB specimens from lymph nodes. FNAB-TG measurement is a useful technique for the diagnosis of lymph node metastasis originating from well-differentiated thyroid carcinoma, particularly when confronted with abnormal-appearing lymph nodes of small size or that have undergone cystic change.