Thyroid Cancer Patients With No Evidence of Disease: The Need for Repeat Neck Ultrasound

Abstract

Context

Ultrasonography (US) is considered the most sensitive tool for imaging persistent or recurrent papillary thyroid cancer (PTC) in the neck.

Objective

To clarify the usefulness of routine neck US in low- and intermediate-risk patients with PTC with no evidence of disease 1 year after thyroidectomy.

Design

Retrospective analysis of prospectively recorded data.

Setting

Academic center.

Patients

Two hundred twenty-six patients with PTC with sonographically normal neck lymph nodes and unstimulated serum thyroglobulin (Tg) levels that were either undetectable (<0.20 ng/mL) or low (0.21 to 0.99 ng/mL) at the 1-year evaluation.

Interventions

Yearly assessment: unstimulated serum Tg level, anti-Tg-antibody (TgAb) titer, TSH levels, and ultrasound examination of neck lymph nodes.

Main Outcome Measures

Rates of ultrasonographic lymph node abnormalities at the 3-year and last follow-up visits.

Results

In patients with an undetectable Tg level at the 1-year evaluation, sonographically suspicious neck lymph nodes were found in 1.2% of patients at 3 years and in 1.8% at the last visit [negative predictive values (NPVs) of 1-year Tg < 0.2 ng/mL: 98.8% (95% CI 95.8% to 99.9%) and 98.2% (95% to 99.6%), respectively]. Similar NPVs emerged for low detectable 1-year Tg levels [98.2% (90.3% to 99.9%) and 94.5% (84.9% to 98.9%) at the 3-year and last visits, respectively]. Seventy-five percent of the nodal lesions were likely false positive; none required treatment.

Conclusions

Low- and intermediate-risk patients with PTC with negative ultrasound findings and unstimulated Tg levels <1 ng/mL at the 1-year evaluation can be safely followed with clinical assessments and unstimulated serum Tg determinations. Neck US might be repeated if TgAb titers rise, or unstimulated Tg levels exceed 1 ng/mL.

The incidence of differentiated thyroid cancer (DTC) continues to rise worldwide, but the vast majority of these tumors are characterized by indolent courses (1) and very low mortality rates (2). The main challenge for clinicians is to avoid unnecessary diagnostic procedures and overtreatment in these low-risk patients, while continuing to identify those rare advanced cancers that might require more aggressive treatment and follow-up. The strategies recommended for managing DTCs are therefore becoming progressively more conservative in low-risk patients, with less radical surgery (3, 4), omission of radioiodine remnant ablation (RRA) (5), and more selective use of diagnostic procedures during follow-up (3).

Serum thyroglobulin (Tg) determinations and ultrasound studies of the neck remain the cornerstones of DTC follow-up protocols. The widespread use in the past of RRA was motivated in these low-risk patients, in large part, by the need to increase the specificity of the serum Tg determination as a marker of persistent/recurrent DTC by eradicating all possible non-neoplastic sources of Tg. For patients who have not undergone RRA, serum Tg is frequently undetectable (6), and when it is detectable, serial Tg assays are recommended on the assumption that stable or decreasing levels tend to exclude the presence of a growing volume of thyroid tissue (normal or neoplastic) (6).

Some investigators maintain, however, that a thorough ultrasound examination of the neck is the best way to detect persistent or recurrent DTC (7, 8). Papillary thyroid cancers (PTCs), which account for the vast majority of DTCs, almost invariably spread to cervical lymph nodes long before producing distant metastases. Ultrasonography (US) findings are unaffected by patients’ RRA status. Standardized criteria have now been defined for the sonographic classification of cervical lymph nodes as normal, indeterminate, or suspicious for malignancy (9). Neck US may identify small lymph node metastases before serum Tg levels become detectable (8), although there is no evidence that this early detection confers benefits in terms of patient outcomes (10). Furthermore, neck US is notoriously operator dependent, and false-positive rates as high as 67% have been reported (11–13). Indeed, abnormal findings are common during the follow-up of patients with PTC, and roughly two-thirds of neck lymph nodes classified as indeterminate disappear spontaneously with time (14).

Rational planning of follow-up for DTC patients is now based largely on individual risk assessment. Initial factors considered include the tumor node metastasis (TNM) stage, which reflects the risk of disease-related mortality and the risk of recurrence [classified as low, intermediate, or high, according to criteria of the American Thyroid Association (ATA)]. This initial classification is reassessed based on the estimated response to therapy at the initial post-treatment assessment (∼6 to 12 months after surgery), depending on imaging findings and on serum Tg and Tg-antibody (TgAb) determinations (15). For low- and intermediate-risk patients with no structural or biochemical evidence of disease at 6 to 12 months after thyroidectomy, the use of further surveillance has not been established. In its 2015 Guidelines, the ATA states only that until more evidence is available, the interval between serum Tg measurements in these patients can probably be lengthened (up to 12 to 24 months). Guidance is even less straightforward on the use of neck US. It remains the mainstay of most DTC follow-up protocols, but optimal schedules have yet to be defined. The ATA suggests that routine use of neck US might be omitted for the low-risk subset of the remnant-ablated population with negative findings at the initial assessment, noting, however, that this recommendation (Number 65, D) is based on low-quality evidence and is therefore graded as “weak.” Recent prospective studies have shown that structural recurrence is extremely rare in these low/intermediate risk patients with an excellent response to initial treatment (16, 17).

To inform current debates on this issue, we conducted a retrospective analysis of observational data that had been prospectively collected in the database of a thyroid cancer follow-up center. Our aim was to clarify the usefulness of routine neck US surveillance in patients with low- and intermediate-risk PTC with negative US findings at the initial post-thyroidectomy assessment and unstimulated serum Tg levels <1 ng/mL—that is, below the threshold considered suspicious for persistent or recurrent malignancy.

Methods

The study protocol was approved by the Institutional Review Board, and written, informed consent was obtained from all patients whose data were analyzed. The database contains records on all patients being followed up in our center after thyroidectomy for DTC. The follow-up protocol provides for an initial assessment, 12 months after surgery, and reassessments at least once a year thereafter. Each assessment includes the following: (i) serum Tg determination (DYNO test Tg-plus, Brahms Diagnostics GmbH; functional sensitivity 0.2 ng/mL), performed while the patient is on levothyroxine (LT4); (ii) a radioimmunometric assay of circulating TgAb levels (Architect System Anti-Tg, Abbott Laboratories; functional sensitivity 0.31 IU/mL); and (iii) high-resolution gray-scale and color Doppler US studies of the thyroid bed and cervical lymph node compartments. Additional imaging procedures (18) and/or fine-needle aspiration biopsy for cytology [and/or other analyses (19, 20)] are ordered at the examiner’s discretion in accordance with evidence-based guidelines (21).

We retrospectively reviewed case records in the center’s database to identify patients diagnosed with DTC between 1 January 2007 and 31 December 2014. Those satisfying the following criteria were eligible for inclusion in the study cohort: (i) primary treatment consisting of total thyroidectomy (with or without central and/or lateral neck dissection and with or without RRA); (ii) histologically confirmed diagnosis of PTC; and (iii) complete follow-up data for the 1-year assessment and the 3-year follow-up visit (FUV-3). Exclusion criteria were the following: (i) histological diagnosis of follicular or Hürthle cell carcinoma (because of their peculiar clinical and biological features) (22), aggressive PTC variants (e.g., tall-cell, hobnail), or poorly differentiated carcinoma; (ii) TgAb positivity at the 1-year assessment; or (iii) a risk of recurrence, classified as high, according to the 2009 ATA Initial Risk Stratification System (21, 23).

Clinical findings, laboratory data (serum Tg, TgAb, and TSH levels), and neck ultrasound images and reports from the initial assessment (1 year) and each subsequent FUV were reviewed. Unstimulated serum Tg levels on LT4 were classified as follows: (i) negative (Tg-N; <0.2 ng/mL, i.e., undetectable, below our assay’s functional sensitivity threshold); (ii) indeterminate (Tg-I; detectable but <1 ng/mL); or (iii) suspicious (Tg-S; 1 ng/mL or higher). For the assessment of locoregional metastases, we evaluated the size, location, and features of each neck lymph node visualized during the ultrasound examinations. With the use of the scheme proposed in 2013 by the European Thyroid Association (9), we then classified each node as normal (preserved hilum, ovoid shape, normal size, absent or exclusively hilar vascularization, and none of the abnormal signs listed hereafter); indeterminate (nonvisualized hilum plus one or more of the following: round shape, increased short axis, or increased central vascularization); or suspicious (those with at least one of the following: microcalcifications, partially cystic appearance, peripheral vascularization, “thyroid-tissue like” appearance). At each time point, the patient’s US-defined neck lymph node status was classified as US-N if all visible nodes were considered normal; US-I if there were no suspicious nodes but at least one node classified as indeterminate; or US-S when at least one lymph node was classified as suspicious.

Analysis of data

We calculated the negative predictive value (NPV) of the 1-year Tg serum level on LT4. For these analyses, two definitions of test negativity were adopted: (i) an undetectable level (i.e., <0.2 ng/mL) and (ii) an indeterminate level (i.e., >0.2 ng/mL but <1 ng/mL). Each was evaluated for its ability to predict the absence of disease—defined as a neck lymph node status of US-N—at two separate time points: (i) the FUV-3 and (ii) at the final FUV documented in the database. Subsequently, a composite endpoint to define absence of disease was applied (both serum Tg < 1 ng/mL and US-N status). All NPVs were calculated with the 95% CI.

Results

Our database included 325 DTC patients treated with total thyroidectomy during the 8-year study period. After the exclusion of 15 patients diagnosed with follicular or Hürthle-cell thyroid cancer, of 12 with high-risk PTCs and 39 patients who were TgAb positive at 1 year, a total of 259 patients were stratified according to 1-year serum Tg levels and neck lymph node statuses (Table 1). For the purposes of the present analysis, we excluded the 14 (5.4%) patients whose neck lymph node status at 1 year was US-I or US-S, regardless of the serum Tg status. The remaining 245 (94.6%) patients therefore had no structural evidence of persistent/recurrent disease [i.e., all neck lymph nodes visualized on the initial US examination were normal (status: US-N; Table 1)]. We also excluded the 19 (7.8%) patients in this US-N subgroup whose 1-year serum Tg levels were classified as suspicious (Tg-S; >1 ng/mL), leaving a total of 226 cases—87.2% of the entire cohort—for analysis.

Table 1.

Unstimulated Serum Tg and Neck Lymph Node Statuses of the 259 Patients at the 1-Year Follow-Up

		Neck Lymph Node Status
		US-N (%)	US-I (%)	US-S (%)	Total
Serum Tg status	Tg-N, <0.2 ng/mL	171 (97.2)a	2 (1.1)	3 (1.7)	176
	Tg-I, 0.2–0.99 ng/mL	55 (88.7)b	4 (6.5)	3 (4.8)	62
	Tg-S, ≥1 ng/mL	19 (90.5)	1 (4.8)	1 (4.8)	21
Total		245 (94.6)	7 (2.7)	7 (2.7)	259

See Table 2 for further details.

^a

Cohort 1.

^b

Cohort 2.

As shown in Table 2, at initial assessment, all 226 patients were US-N and had serum Tg levels <0.2 ng/mL in 171 cases (Cohort 1) and between 0.2 and 0.99 ng/mL in the other 55 (Cohort 2). These two cohorts were analyzed separately to determine the NPV of their respective 1-year Tg status.

Table 2.

Baseline Characteristics^a of Cohorts 1 and 2

	Cohort 1 (n = 171)	Cohort 2 (n = 55)
Serum Tg and neck lymph node status	Tg-N + US-N	Tg-I + US-N
Age, y (median IQR)	46 (39–60)	47 (40–59)
Females	131 (76.6)	39 (70.9)
Neck dissection
Not done	119 (69.6)	42 (76.4)
Central compartment alone	45 (26.3)	9 (16.4)
Central and lateral compartments	6 (3.5)	4 (7.3)
Lateral compartment alone	1 (0.6)	0 (0)
Tumor size, mm (median IQR)	8 (5–12)	9 (4.75–15)
Tumor foci
Unifocal	126 (73.7)	45 (81.8)
Multifocal, unilateral	14 (8.2)	3 (5.5)
Multifocal, bilateral	31 (18.1)	7 (12.7)
Extrathyroidal extension
None	130 (76)	43 (78.2)
Microscopic	41 (24)	12 (21.8)
Lymph node status
Nx	86 (50.3)	32 (58.2)
N0	65 (38)	13 (23.6)
N1a	14 (8.2)	6 (10.9)
N1b	6 (3.5)	4 (7.3)
RRA
No	93 (54.4)	26 (47.3)
Yes	78 (45.6)	29 (52.7)
Estimated risk of recurrenceb
Low	113 (66.1)	39 (70.9)
Intermediate	58 (33.9)	16 (29.1)

Abbreviation: IQR, interquartile range.

^a

Unless otherwise specified, results are reported as number (%) of patients.

^b

As defined by the 2009 ATA Guidelines (21, 23). For patients diagnosed before publication of the 2009 ATA Guidelines, risk levels were retrospectively recalculated based on risk factors prospectively recorded in the database at the initial post-treatment assessment.

Cohort 1

As shown in Table 3, at the FUV-3, the neck lymph node statuses of 169 of the 171 patients were still US-N (NPV of a Tg-N + US-N status at 1-year evaluation: 98.8%; 95% CI 95.8% to 99.9%). The other two patients had indeterminate lymph node abnormalities on the FUV-3 ultrasound examination. Both patients were persistently Tg-N, and the US-I nodes could no longer be visualized at the final FUV, strongly suggesting that the FUV-3 imaging findings were false positives. A 1-year Tg-N + US-N status was also strongly predictive of the absence of lymph node disease at the last FUV [NPV 98.2% (95% CI 95% to 99.6%)]. At this point, two other Cohort 1 patients were US-I, and a third was US-S. In the latter case, the sonographic finding of a suspicious lymph node was reflected by the simultaneous appearance of TgAb positivity. The two patients who were US-I at the last FUV would have been missed if assessment had been based on serum Tg and serum TgAb assays alone. However, neither of these cases required any intervention: for this reason, cytology and fine-needle aspiration-washout Tg determination were not performed to confirm the diagnosis. In five cases, Tg levels rose above 1 ng/mL during follow-up (one case at FUV-3; four cases at last FUV). Details on these cases are provided in Table 4 (Cohort 1). The emergence of suspicious Tg levels in patients who were persistently US-N probably reflects the presence of residual non-neoplastic thyroid tissue or a transient increase in Tg production caused by endogenous TSH stimulation (or potential measurement errors) (24) (Table 4, Cohort 1). As suspicious Tg levels at the end of follow-up may also indicate occult persistent disease, we also applied a composite endpoint (either serum Tg ≥ 1 ng/mL or abnormal lymph nodes at neck US); the resulting NPV was 95.9% (95% CI 91.7% to 98.3%).

Table 3.

Cohort 1 Patients: Unstimulated Serum Tg and Neck Lymph Node Statuses at FUV-3 and at Last FUV^a

		Neck Lymph Node Status at FUV-3			Total (%)
		US-N (%)	US-I (%)	US-S (%)
Serum Tg status at FUV-3	Tg-N, <0.2 ng/mL	138 (80.7)	2b (1.2)	0 (0)	140 (81.9)
	Tg-I, 0.2–0.99 ng/mL	30 (17.5)	0 (0)	0 (0)	30 (17.5)
	Tg-S, ≥1 ng/mL	1c (0.6)	0 (0)	0 (0)	1 (0.6)
Total		169 (98.8)	2 (1.2)	0 (0)	171 (100)
		Cervical Lymph Node Status at Last FUV
Serum Tg status at last FUV	Tg-N, <0.2 ng/mL	143 (83.6)	2d (1.2)	1e (0.6)	146 (85.4)
	Tg-I, 0.2–0.99 ng/mL	21 (12.3)	0 (0)	0 (0)	21 (12.3)
	Tg-S,≥1 ng/mL	4c (2.3)	0 (0)	0 (0)	4 (2.3)
Total		168 (98.2)	2 (1.2)	1 (0.6)	171 (100)

^a

Median (interquartile range): 72 (59 to 94) months after surgery.

^b

Details on these patients are reported in Table 4.

^c

Both patients’ indeterminate lymph nodes had disappeared by the last FUV.

^d

These two patients are not the same with indeterminate lymph nodes at FUV-3.

^e

In this case, detection of the suspicious, nonthreatening lymph node (7.6 × 8 mm; with hyperechoic foci and no visible hilum) was accompanied by the development of TgAb positivity. The node posed no threat to surrounding structures, and the risk of recurrence was classified as low, according to the 2009 ATA Guidelines (21, 23).

Table 4.

Characteristics of Patients Classified as Tg-S + US-N at FUV-3, Last FUV, or Both

Cohort/Patient No.	TNM Stagea	Estimated Risk of Recurrenceb	RRA	WBS	FUV-3		Last FUV
					TSH, mIU/L	Tg, ng/mL	TSH, mIU/L	Tg, ng/mL
1/1	pT3m, N1b	Intermediate	Y	Thyroid bed uptake	21.4	1	96	0.1
1/2	pT1a	Intermediate	N	ND	0.35	0.13	4.38	1.4
1/3	pT2	Low	N	ND	1.02	0.71	2.86	1.2
1/4	pT1a	Low	N	ND	0.04	0.1	5.4	1.1
1/5	pT1a	Low	N	ND	0.36	0.08	7.7	3.1
2/1	pT1am	Low	N	ND	0.3	1.1	1.4	0.14
2/2	pT1am	Low	N	ND	3.1	2.1	1.32	0.81
2/3	pT2m	Low	N	ND	0.48	1	2.17	0.23
2/4	pT1a	Low	N	ND	4.58	2.5	2.63	1
2/5	pT1a	Low	N	ND	2.55	1.20	2.30	1.7
2/6	pT1a	Low	N	ND	3.19	0.76	6.1	1

Abbreviations: N, no; ND, RRA and WBS not done; WBS, post-therapy whole-body I¹³¹ scintigraphy; Y, yes.

^a

American Joint Committee on Cancer TNM, seventh edition.

^b

According to the ATA Guidelines (21, 23).

Cohort 2

Analysis of FUV-3 data for Cohort 2 (Table 5) showed that the NPV of a US-N + Tg-I status at 1 year was essentially the same as that associated with a 1-year US-N + Tg-N status (98.2%; 95% CI 90.3% to 99.9%). All but one of the 55 patients in this cohort were still US-N at FUV-3. In the remaining patient, the ultrasound examination revealed a single abnormal lymph node that was classified as indeterminate. It retained its indeterminate features on subsequent ultrasound examinations, suggesting that it might well have reflected true loco-regional recurrence. Again, however, the node was quite small, and it posed no threat to surrounding structures. Intervention was thus deferred. Even without the routine yearly ultrasound examinations, this case would have been flagged for attention by the serum Tg level, which had increased to >1 ng/mL by FUV-3 (Table 5). At the last FUV, two other patients had developed lymph node anomalies, in both cases classified as indeterminate. Neither required intervention. Both lesions would have been missed (at 1-year evaluation and at the final FUV) if follow-up had been based on Tg and TgAb assays alone. However, a 1-year Tg-I–US-N status was still a strong predictor of the absence of structural lymph node disease at the last follow-up [NPV 94.5% (95% CI 84.9% to 98.9%)]. As in Cohort 1, several Cohort 2 patients developed suspicious serum Tg levels during follow-up in the absence of sonographic evidence of lymph node disease (US-N + Tg-S). Details on these six cases are provided in Table 4 (Cohort 2). Furthermore, in this cohort, with the application of a composite endpoint (either Tg-S or abnormal lymph nodes), the resulting NPV was 89.1% (95% CI 77.7% to 95.9%).

Table 5.

Cohort 2 Patients: Unstimulated Serum Tg and Neck Lymph Node Statuses at FUV-3 and Last FUV^a

		Neck Lymph Node Status at FUV-3			Total (%)
		US-N (%)	US-I (%)	US-S (%)
Serum Tg status at FUV-3	Tg-N, <0.2 ng/mL	37 (67.3)	0 (0)	0 (0)	37 (67.3)
	Tg-I, 0.2–0.99 ng/mL	12 (21.8)	0 (0)	0 (0)	12 (21.8)
	Tg-S, ≥1 ng/mL	5b (9.1)	1c (1.8)	0 (0)	6 (10.9)
Total		54 (98.2)	1 (1.8)	0 (0)	55 (100)
		Neck Lymph Node Status at Last FUV
Serum Tg status at last FUV	Tg-N, <0.2 ng/mL	35 (63.6)	2 (3.6)	0 (0)	37 (67.2)
	Tg-I, 0.2–0.99 ng/mL	14 (25.5)	0 (0)	0 (0)	14 (25.5)
	Tg-S, ≥1 ng/mL	3b (5.5)	1c (1.8)	0 (0)	4 (7.3)
Total		52 (94.5)	3 (5.5)	0 (0)	55 (100)

^a

Median (interquartile range): 86 (59–99) mo after surgery.

^b

Details on these patients are reported in Table 4.

^c

This patient had a single node classified as indeterminate, which was detected at FUV-3 and confirmed in the subsequent visits, but it was small and posed no threat to surrounding structures and therefore, required no intervention. (At FUV-3 and last FUV, Tg levels were 1.8 and 3.5 ng/mL, respectively, and TSH levels were 3.8 and 0.68 mU/L.) At last FUV, no metastases had been found outside the neck.

RRA

Among the 226 patients who were US-N and had serum Tg levels <1 ng/mL at the 1-year evaluation, 107 (47.3%) underwent radioiodine ablation. In these patients, at the end of follow-up, five abnormal lymph nodes were found (four indeterminate and one suspicious): NPV 95.3% (95% CI 89.4% to 98.5%). Only one case had the serum Tg levels increasing above 1 ng/mL at the time of the last visit, being part of the subgroup of patients with indeterminate nodal lesions.

In the remaining 119 patients not undergoing radioactive iodine treatment, only one indeterminate lymph node was detected [NPV 99.2% (95% CI 95.4% to 100%)]. Seven other patients had serum Tg levels ≥1 ng/mL; if these cases were all considered suspicious for recurrence, then the NPV would decrease to 93.3% (95% CI 87.2% to 97.0%).

Discussion

The aim of the follow-up protocol of DTC patients is to detect abnormalities that might require further treatment. Serum Tg assays performed without interrupting LT4 therapy have displayed high sensitivity and specificity in the detection of persistent/recurrent DTC (25–27), even if their pitfalls prompted research of other biomarkers (28, 29). Neck US is a more expensive and time-consuming approach, but several studies (7, 8) have shown that in a substantial proportion of patients, it is even more sensitive than serum Tg for identification of locoregional lymph node disease, identifying some lesions before the biochemical markers become positive. In the cohort described by Torlontano et al. (8), 23/38 (60.5%) cytologically proven lymph node metastases were first visualized at neck US, and the non-stimulated serum Tg was still negative (<1 ng/mL) at that time. Matrone et al. (7) reported that basal ultrasensitive Tg levels, evaluated soon after total thyroidectomy, were <1 ng/mL in 9 of 20 (45%) patients with detectable nodal metastases at neck US. However, as noted above, the impact on survival of this earlier detection has yet to be demonstrated (10), and not all detectable findings require further diagnostic evaluations or immediate intervention (30). In the presence of any structurally identifiable neck disease, volume, rate of growth, proximity to vital structures, symptoms, and patient preference should drive decision-making and determine whether a lesion represents an “actionable” finding. Furthermore, the high frequency of false-positive US findings can needlessly increase patient anxiety, as well as the cost of follow-up (by prompting additional testing). We speculated that routine use of neck ultrasound might safely be omitted in the follow-up of patients with PTC whose initial post-thyroidectomy scan showed no evidence of disease. To test this hypothesis, we retrospectively analyzed yearly serum Tg and US findings prospectively collected in a well-characterized cohort of low- and intermediate-risk patients with PTC who were US-N and Tg-N or Tg-I at the initial post-treatment assessment (6 to 12 months after thyroidectomy, with or without RRA).

Our findings suggest that subsequent surveillance of these patients, which represented over two-thirds of those being followed in our center after thyroidectomy for DTC, can safely be based on periodic serum Tg assays without routine use of neck US. In patients who were US-N at the 1-year evaluation, the concomitant finding of serum Tg levels that were undetectable (<0.2 ng/mL) strongly predicted the absence of sonographic evidence of cervical lymph node disease at FUV-3 and also at the final follow-up (median 72 months; NPVs: 98.8% and 98.2%, respectively). Importantly, similar findings emerged for US-N patients with detectable low Tg levels at the first-year FUV that did not exceed 1 ng/mL Tg (Cohort 2: NPVs at FUV-3 and last FUV: 98.7% and 94.5%, respectively).

Yearly US examinations in the 226 patients considered in this study revealed only one lymph node that was classifiable as suspicious, but its presence was simultaneously highlighted by the development of TgAb positivity. A second abnormal node with persistently indeterminate features was accompanied by rising values of Tg. Four other abnormal nodes were observed that were not accompanied by increased Tg or TgAb levels. None met current ATA Guideline requirements for intervention: suspicious, nonthreatening lymph nodes whose smallest diameters are <8 to 10 mm can, in fact, be managed with active surveillance, with biopsy being reserved for lesions that are larger and/or growing and only when positive findings are likely to modify management (21).

These findings are consistent with those of previous studies (11–13, 16, 17), which showed that the routine use of US in patients with undetectable serum Tg level rarely reveals cases of recurrence, but it does increase the frequency of false-positive abnormalities (11–13). This was confirmed in our cohort, where some indeterminate lymph nodes subsequently disappeared without intervention. Routine use of neck US in this setting is therefore increasingly difficult to justify, and yet, in a tertiary referral center in the United States, the annual rate of neck sonographies performed in patients with low-risk PTC increased by 5.3-fold between 2003 and 2012 (31). Given the growing incidence of low-risk PTC throughout the world, regular US surveillance of these patients on a routine basis is likely to become less and less cost effective (32). Intense follow-up protocols may allow earlier detection and treatment of asymptomatic recurrences, but there is no proof that such gains have any positive impact of such on survival and quality of life (10), and they may lead to unnecessary surgery with potentially serious side effects (33).

It is worth recalling that our findings cannot be extrapolated to patients with follicular thyroid cancers or aggressive PTC variants (and certainly not to poorly differentiated TCs). However, as noted above, patients with classic PTCs account for the vast majority of those diagnosed with thyroid carcinoma (1, 22). Other limitations of our study were its single-center scope and the relatively small size of the study cohort, which (among other things) precluded reliable exploration of potential prognostic factors and features associated with neck recurrences. The total duration of follow-up might also appear to be relatively short (median: 6 to 7 years), but it more than covers the period during which over 85% of all DTC recurrences are reportedly found (i.e., the first 3 years after the initial treatment) (8). The strengths of our study, on the other hand, include the facts that the data we retrospectively analyzed had been prospectively collected in a well-characterized cohort, the US examinations were performed by a single team of physicians with extensive training and experience in thyroid sonography (34), and (above all) the biochemical assessments were carried out in the same laboratory with the same assays over the entire study period.

In conclusion, our findings indicate that patients with low- and intermediate-risk PTC whose initial post-thyroidectomy assessment reveals no US evidence of cervical lymph node disease, no evidence of TgAb, and serum Tg levels on LT4 therapy that are below 1 ng/mL can be safely followed with regular clinical assessments and unstimulated serum Tg assays, even if they have not undergone RRA. Repeat cervical US should be reserved for those patients with rising TgAb titers or increasing serum Tg levels that exceed 1 ng/mL. The relevance of these findings for the cost of DTC follow-up and the quality of life of the patients are by no means negligible, as the patients affected represent a substantial fraction of all DTC patients treated with thyroidectomy.

Acknowledgments

Financial Support: M.S. contributed to this paper as the recipient of the “Visiting Professor for Research Activities 2016” Grant at University of Rome, Sapienza (ID Number: C26V16RBXB).

Author Contributions: G.G., V.R., R.F., and L.L. contributed to this paper as part of their PhD studies in Biotechnologies and Clinical Medicine at the University of Rome, Sapienza.

Additional Information:

Disclosure Summary: The authors have nothing to disclose.

Data Availability: The datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

Abbreviations:

Abbreviations:
 
• ATA

  American Thyroid Association

 
• DTC

  differentiated thyroid cancer

 
• FUV-3

  3-year follow-up visit

 
• LT4

  levothyroxine

 
• NPV

  negative predictive value

 
• PTC

  papillary thyroid cancer

 
• RRA

  radioiodine remnant ablation

 
• Tg

  thyroglobulin

 
• TgAb

  thyroglobulin antibody

 
• Tg-I

  thyroglobulin levels-indeterminate

 
• Tg-N

  thyroglobulin levels-negative

 
• Tg-S

  thyroglobulin levels-suspicious

 
• TNM

  tumor node metastasis

 
• US

  ultrasonography

 
• US-I

  ultrasonography neck lymph node status with no suspicious nodes but at least one node classified as indeterminate

 
• US-N

  ultrasonography neck lymph node status normal

 
• US-S

  ultrasonography neck lymph node status with at least one lymph node classified as suspicious