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Units of Endocrinology (M.T., U.C., G.A., L.D., V.T.), Thoracic Surgery (N.B.), Nuclear Medicine (A.V., F.D., S.M., V.F.), and Clinical Chemistry (A.D.G.), Istituto di Ricovero e Cura a Carattere Scientifico Casa Sollievo della Sofferenza, 71013 S. Giovanni Rotondo, Italy; Unit of Endocrinology (R.B.), Tinchi-Pisticci Hospital, 75020 Matera, Italy; and Department of Clinical Sciences(S.F., V.T.), University "La Sapienza," 00161 Rome, Italy
Address all correspondence and requests for reprints to: Massimo Torlontano, M.D., via A. Massa 42, 71013 San Giovanni Rotondo (FG), Italy. E-mail: m.torlontano{at}tin.it.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of the study was to investigate the role of neck ultrasonography (US), whole-body scintigraphy (WBS), and serum thyroglobulin levels (Tg) after recombinant human (rh) TSH in the follow-up of very low-risk PTMC patients.
Design: The study was a 5-yr observational study based on a 6- to 12-month follow-up after near total thyroidectomy.
Setting: The study population consisted of ambulatory patients.
Patients: Eighty consecutive patients diagnosed with PTMC, who had not undergone postoperative radioiodine treatment because of unifocal tumor without lymph node metastases and who did not have anti-Tg antibodies, were included.
Main Outcome Measures: WBS and Tg after both rhTSH and neck US were measured.
Results: rhTSH-Tg was 1 ng/ml or less in 45 (Tg–) and more than 1 in 35 (Tg+) patients. WBS showed no pathological uptake in any patient. US identified node metastases in two Tg (+) and one Tg (–) patients. rhTSH-Tg levels positively correlated with thyroid bed iodine uptake (r = 0.40, P < 0.0001). To date (32 ± 13 months after surgery), all node-negative patients have undetectable Tg levels on LT4 treatment and negative US.
Conclusions: For the initial follow-up of PTMC patients without risk factors and anti-Tg antibodies and who did not undergo radioiodine treatment: 1) WBS is useless; 2) US is highly sensitive in detecting node metastases; and 3) detectable rhTSH-Tg levels mainly depend on small normal tissue remnants. In this subgroup of PTMC patients, neck US might be regarded as a primary tool for the initial follow-up.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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1 cm) (1), are being diagnosed with increasing frequency (2). The prognosis is excellent when the disease is intrathyroid, and such is frequently the case: locoregional recurrence is unusual and distant metastases are rare (3, 4, 5). Therefore, PTMC patients are treated with thyroidectomy alone, and postoperative radioiodine therapy is administered only in patients with specific risk factors for recurrent disease (3, 4, 5). When radioiodine ablation has not been performed, the protocol advocated in thyroid cancer patients who had been ablated may not apply, and the optimal follow-up strategy for these low-risk patients has yet to be defined. For low-risk patients with larger (i.e. > 1 cm), well-differentiated thyroid tumors, postoperative follow-up protocols are being revised (6, 7, 8, 9, 10). Diagnostic 131I whole-body scans (WBS) performed after thyroid hormone withdrawal or recombinant human (rh) TSH stimulation has displayed limited sensitivity for detecting recurrences. Measurement of rhTSH-stimulated thyroglobulin (Tg) levels has proved to be more sensitive for this purpose (7, 8, 9, 10), and neck ultrasound (US) has been advocated as the imaging modality of choice for the detection of local regional disease (10, 11, 12, 13, 14, 15, 16). There is no information in the literature on the use of this approach for PTMC patients who have not received postthyroidectomy radioiodine. The aim of our study was, therefore, to evaluate the respective role of WBS, serum Tg levels after rhTSH stimulation, and neck US for the detection of persistent/recurrent disease in the first follow-up examination of a consecutive series of PTMC patients who had not received radioiodine treatment after surgery.
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Patients and Methods |
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The study population was drawn from a series of 125 patients consecutively diagnosed with intrathyroidal PTMCs (T1) (17) during the period April 1999 to August 2004. Forty-five patients were excluded because they had undergone postoperative radioiodine ablation of residual thyroid tissue (n = 27, all with tumors that were multifocal, bilateral, and/or stage pN1) (17) or were positive for anti-Tg antibodies (n = 18). The remaining 80 patients (69 females, 11 males, aged 24–72, mean 49.4 ± 10.7 yr) were enrolled in the study and provided written informed consent to all study procedures. The study was approved by the local ethical committee.
The characteristics of the study population are summarized in Table 1
. All patients underwent near-total thyroidectomy. Central compartment lymph node dissection was also performed in 11 patients with preoperative cytological reports indicating papillary cancer. All these subjects exhibited a solitary nodule diameter of 1 cm or less with suspicious ultrasonographic features (hypoecogenicity plus irregular margins and/or microcalcifications and/or peripheral and central vascularization at color-Doppler: not incidental patients) (18). In the remaining 69 cases, PTMC had been diagnosed incidentally after surgery for multinodular goiter (incidental patients). No differences in age, gender, and diameter of tumor were found between incidental and not-incidental patients. In all cases, after the histological diagnosis of papillary microcarcinoma, fine sections were made to exclude adjunctive tumoral foci. After surgery, all patients received substitutive T4 therapy, aimed to obtain normal (and not suppressed) TSH levels. The initial follow-up examination took place 6–12 months after surgery and included clinical evaluation, neck US, and measurement of serum Tg and WBS after rhTSH stimulation (10). Patients were placed on a low-iodine diet and instructed to avoid iodine-containing foods for at least 20 d before the study. T4 therapy was maintained in all patients. On d 1, blood samples were drawn for determination of baseline serum TSH and Tg levels. Tg recovery and anti-Tg antibodies were evaluated in the same sample to validate the Tg assay results. Thereafter, each patient received an im injection of rhTSH (0.9 mg) (Thyrogen; Genzyme Transgenics Corp., Cambridge, MA). On d 2, a second injection of rhTSH (0.9 mg) was administered. On d 3, 185 MBq (5 mCi) 131I were given. On d 5, WBS and neck US were performed, and serum TSH and Tg levels were measured.
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Serum Tg was measured by an immunoradiometric assay (Byk-Sangtec, Dietzenbach, Germany) with a lowest detectable level of 0.1 ng/ml and clinical sensitivity of 1 ng/ml (6, 9, 10, 12, 14, 19). Tg recovery was evaluated in the same assay after the addition of 10 µl of a spiking solution containing 50 ng/ml (normal recovery values 70–130%). Serum TSH and anti-Tg antibody titers were measured with commercial kits.
WBS was performed with a double-
camera equipped with high-energy collimators and thick crystals (GCA 901; Toshiba, Tokyo, Japan). Scan speed was 5 cm/min, and a total of at least 140,000 cpm was recorded. Radioiodine uptake was calculated according to the Mayo Clinic method (20), and patients were than subdivided into two groups according to an uptake percentage more than or 0.5% or less (the latter corresponding to a not clinically significant residual tissue) (6, 9). Uptake confined to the thyroid bed was identified by means of anatomical landmarks and confirmed by the absence of abnormalities in lymph node regions on neck US. WBS scans were classified as positive only when uptake was noted outside the thyroid bed.
Both clinical evaluations, consisting essentially of neck palpation and neck US by a color Doppler scanner with multifrequency probes (7.5 to 12 MHz), were performed by the same two endocrinologists, both experienced in neck US examinations (M.T., U.C.). Lymph nodes were considered suspicious by one of the following US features: an arbitrarily chosen diameter 4 mm or more and rounded shape and/or presence of microcalcifications and/or cystic component. Adjunctive characteristics of suspected malignancy were absence of hyperechoic hilus and/or hypervascularization at color Doppler examination (11, 13, 14). All suspicious neck lymph nodes were subjected to fine-needle aspiration biopsy
Statistical analysis
Data are expressed as means ± SD. Comparisons between groups and differences between proportions were calculated using Student’s t test or Mann-Whitney U test and 
2 or Fisher’s exact test when appropriate, respectively. A parametric method was used to test correlation between serum Tg levels (after logarithmic transformation) and radioiodine uptake (Pearson).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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). Neck US, but not neck palpation, indicated small node metastases (all <1 cm in diameter and confirmed by histology) in three patients, including one who was Tg (–) (Table 2). On the contrary, WBS revealed uptake in the thyroid bed ranging from 0.1 to 10.2% (mean 3.1 ± 2.6%) but no pathological uptake in any of the 80 patients. After subdividing node-negative patients (n = 77) according to uptake percentage (i.e. or > 0.5%), all subjects with uptake 0.5% or less were Tg (–) (14 of 14 = 100%), whereas about half of those with higher uptake showed rhTSH-Tg levels greater than 1 ng/ml (33 of 63 = 52.4%, P = 0.003). Moreover, in the same 77 patients, there was a positive correlation between rhTSH-Tg levels and iodine uptake in the thyroid bed (n = 77, r = 0.40, P < 0.0001) (Fig. 2). Six patients [all Tg (–) at first follow-up] were lost to subsequent follow-ups. The remaining 74 patients had subsequent follow-ups at 12-month intervals, essentially consisting of biochemical and ultrasonographic controls under T4 substitutive therapy. To date (32 ± 13 months after primary treatment, range 10–72 months, and 23 ± 14 months after the first follow-up examination, range 4–60 months) all 32 patients who were node negative and Tg (+) during the initial follow-up currently do not exhibit any clinical and ultrasonographic sign of persistent or recurrent disease. Moreover, all four patients who displayed detectable serum Tg levels on T4 therapy at first examination have become subsequently Tg (–) on T4 therapy.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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We compared the diagnostic value of rhTSH-stimulated serum Tg levels, WBS, and neck US in the initial follow-up of 80 consecutively diagnosed PTMC patients without risk factors of persistent/recurrent disease and without detectable anti-Tg antibodies, who had undergone thyroidectomy without radioiodine ablation.
Lymph node metastases were detected and removed in three cases: this low prevalence (3.8%), which is very similar to that reported in patients with unifocal tumors (5), is likely explained by the fact that patients with risk factors (multifocal and/or bilateral tumor and/or pN1 and then radioiodine ablated) were not included in the study. In fact, our selected population of very low-risk patients is not comparable with other series comprising the general population of individuals with PTMC, including both high- and low-risk patients.
Neck US proved to be highly sensitive for the detection of recurrent disease, identifying all three patients who had lymph node metastases. One of these was rhTSH-Tg (–), and the other two had detectable Tg levels (2.2 and 7.2 ng/ml, respectively). In contrast, WBS displayed a sensitivity of 0%, indicating that it is of little use in the follow-up of these patients. It only demonstrated, as expected, the persistence of normal thyroid tissue in the majority of these not radioiodine ablated patients (63 of 77 node-negative patients displayed a cervical uptake > 0.5%). Consequently, in our opinion the use of WBS in these patients should not be recommended. These findings, which are fully consistent with previous reports on larger tumors, confirm that in patients with low-risk papillary thyroid carcinoma, neck US is the imaging modality of choice for detection of local/regional metastases (10, 11, 12, 13, 14, 15, 16).
It is worth noting that, in the 77 node-negative patients, serum Tg levels after rhTSH stimulation were positively correlated with radioiodine uptake confined to the thyroid bed. Moreover, all patients with not clinically relevant amounts of residual thyroid tissue (i.e. with radioiodine uptake < 0.5%) showed undetectable rhTSH-Tg levels. It is thus reasonable to assume that, in the absence of demonstrable lymph-node metastases, the presence of Tg in the serum after rhTSH stimulation is usually related to small remnants of normal thyroid tissue rather than tumor persistence or recurrence. It is likely, therefore, that, in the 32 Tg (+) node-negative patients, serum rhTSH-Tg levels greater than 1 ng/ml were mainly related to the persistence of normal residual thyroid tissue, rather than tumor recurrence. This hypothesis is supported by our recent finding that most of the node-negative patients (about 70%) who were Tg (+) at first follow-up, radioiodine treated or not, became Tg (–) after T4 withdrawal within 2–3 yr, probably as a result of the progressive atrophy of these residual tissues; we cannot exclude that this progressive atrophy could, at least partially, depend of the long-term effects of the 185-MBq diagnostic radioiodine administration and/or the chronic TSH suppression due to T4 treatment (14). Taken together, these data suggest that, in a PTMC patient without risk factors (very low risk patient): 1) the optimal treatment may include surgery alone, whereas postsurgical radioiodine treatment should be discouraged; 2) at subsequent follow-up, diagnostic WBS should be avoided because it only confirms the persistence of normal residual tissue; and 3) the initial follow-up can be limited to neck US, possibly performed by an experienced clinician. Further specifically designed studies are needed to deeper investigate the usefulness of a serum Tg level determination after rhTSH stimulation, obtained 2 or 3 yr after thyroidectomy when the risk of false-positive results might be lower.
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Footnotes |
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Abbreviations: PTMC, Papillary thyroid microcarcinoma; rh, recombinant human; Tg, thyroglobulin; US, ultrasonography; WBS, whole-body scintigraphy.
Received May 26, 2005.
Accepted October 3, 2005.
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