Persistent and recurrent disease in patients with papillary thyroid carcinoma with clinically apparent ( cN 1 ) , but not extensive , lymph node involvement and without other factors for poor prognosis

Objective: Lymph node metastases (LNM) are frequent in patients with papillary thyroid cancer (PTC). The risk of persistent disease (PD) and tumor recurrence (TR) is increased when factors for poor prognosis other than LNM exist, when LNM are numerous, large, detected by preoperative ultrasonography (US), or exhibit extranodal extension. This study evaluated the risk of PD and TR in patients with LNM not exhibiting these characteristics. Subjects and methods: Eighty-six patients with 5 or fewer LNM detected during intraoperative inspection, but not by preoperative US, who had no other factors for poor prognosis [tumors > 4 cm, extensive extrathyroid invasion, vascular invasion, aggressive histological subtype, distant metastases, incomplete tumor resection], were studied. All patients underwent total thyroidectomy followed by radioiodine ablation. PD was defined as metastases on initial post-therapy whole-body scans (RxWBS) or detected by imaging methods up to 12 months after ablation. TR was defined as structural disease diagnosed more than one year after ablation in patients without PD. Results: PD was diagnosed in 3/86 patients (3.5%). TR was observed in 2/83 patients (2.5%) after 62 months of follow-up. There was no case of death due to the disease. A correlation was observed between pre-ablation Tg and PD or TR [1/48 (2%) with Tg ≤ 2 ng/mL versus 2/22 (9%) with Tg > 2 ≤ 10 ng/mL versus 2/7 (28.5%) with Tg ≥ 10 ng/ml)]. It is noteworthy that 38 patients had up to 3 positive LN and pre-ablation Tg ≤ 2 ng/ml, and none of them had PD or TR. Conclusions: The frequency of PD and TR was low in patients with PTC with 5 or fewer LNM and without other factors for poor prognosis. Low postoperative stimulated Tg was predictive of the absence of PD and TR in these patients. Arch Endocrinol Metab. 2015;59(4):285-91


Lymph node involvement and prognosis
Arch Endocrinol Metab.2015;59/4 The most relevant discussion is to know the risk of persistent disease and tumor recurrence in the patients with LNM not exhibiting the characteristics described above (22) and in the absence of other factors for poor prognosis.The present study was conducted to answer this question.The criterion used for the definition of LN status (preoperative US and intraoperative inspection by the surgeon) agrees with current guidelines since there is no clear indication for elective LN dissection in patients with tumors ≤ 4 cm and without apparent extrathyroid invasion (1)(2)(3)(4)(5)(6)(7)23).

SUBJECTS AND METHODS
The data of patients with diagnosis of PTC treated at our institution from 2004 to 2012 were reviewed.The limit of 2012 was established to obtain a minimum follow-up of 24 months.The study was approved by the Research Ethics Committee of our Institution.

Patients
Patients with suspicious or diagnostic cytology of PTC were routinely submitted to neck US before surgery.For this study, only patients with negative preoperative US for LNM were selected.All patients underwent to-tal thyroidectomy.During intraoperative inspection by the surgeon, patients with a suspicion of LNM in the central neck compartment were submitted to bilateral dissection of this compartment combined with exploration of the lateral compartments.Elective LN dissection was not performed.Patients with tumors > 4 cm, extensive extrathyroid invasion (pT4), vascular invasion, aggressive histological subtype (tall-cell, columnar-cell, diffuse follicular variant), distant metastases (clinical examination or simple chest x-ray), or incomplete tumor resection were excluded.Additionally, patients with > 5 positive LN or LNM exhibiting macroscopic extranodal tumor invasion (16,19,21) also were excluded.Finally, patients with 5 or fewer positive LN detected during intraoperative inspection, but not by preoperative US, and in the absence of macroscopic extranodal extension; without other factors for poor prognosis were studied.About 3 months after surgery, before ablation, a new US scan was obtained to exclude patients with incomplete tumor resection (Figure 1).

Ablation with 131 I
Approximately 4 months after thyroidectomy, all patients were submitted to ablation with 131 I [1.1-5.5 GBq (30-150 mCi)] after withdrawal of levothyroxine (L-T4) for Figure 1.Sequence of patient management and definitions used in this study.US: ultrasonography; RxWBS: post-therapy whole-body scanning.a These patients were excluded.b Imaging methods: US in all patients; chest and mediastinal CT if Tg > 1 ng/mL; MIBI scan and FDG-PET/CT if basal Tg > 1 ng/mL or Tg > 5 ng/mL after rhTSH or > 10 ng/mL after levothyroxine withdrawal, or Tg > 1 ng/mL in the presence of anti-Tg antibodies.was obtained for patients with Tg/T4 < 1 ng/ml and negative US. Patients with stimulated Tg > 1 ng/mL were submitted to chest CT (24).Additionally, 99m Tcsestamibi scans and FDG-PET/CT were performed on patients with Tg > 10 ng/mL after L-T4 withdrawal or > 5 ng/ml after rhTSH (24,25), or stimulated Tg > 1 ng/mL in the presence of TgAb (26).

Persistent disease
Persistent disease was defined as ectopic (metastatic) uptake on initial posttherapy whole body scanning (Rx-WBS) or metastases detected by the imaging methods 9-12 months after ablation (Figure 1).

Late follow-up
Patients without metastases detected on initial RxWBS or by the imaging methods 9-12 months after ablation were followed up by annual measurement of Tg/T4 and TgAb and neck US.Patients with initial Tg/T4 levels < 1 ng/ml, but with stimulated Tg > 1 ng/mL, were submitted to new Tg stimulation at an interval of 2 years (27).Imaging methods other than US (chest CT, 99m Tc-sestamibi scans, FDG-PET/CT and RxWBS after an empirical activity of 3.7 GBq 131 I) were performed when: (i) Tg/T4 < 1 ng/mL converted to levels > 1 ng/mL, (ii) there was an increase > 50% (25,27) in Tg (Tg/T4 or stimulated Tg) when Tg was already > 1 ng/mL, (iii) negative TgAb became positive, or (iv) there was an increase in already positive TgAb titers.The patients were maintained on a dose of L-T4 sufficient to obtain serum TSH ≤ 0.5 mIU/l.The time of follow-up ranged from 30 to 102 months (median 62 months).

Tumor recurrence
Tumor recurrence was defined as structural disease diagnosed more than one year after ablation in patients without persistent disease (Figure 1).
The diagnosis of tumor in lesions detected by the imaging methods was made by cytology or histology, and/or based on unequivocal ectopic uptake (excluding false-positive results) on RxWBS or FDG-PET/CT.US was performed with a linear multifrequency transducer for morphological analysis (B-mode) and for Doppler evaluation.US was performed by a radiologist with experience in thyroid and neck US.US was defined as negative when it did not detect suspicious lesions (28,29) or, in the presence of these lesions, when cytology and Tg measurement in the needle washout obtained by US-guided fine-needle aspiration were negative.Chest CT was performed by taking 5-mm sequential sections.99m Tc-sestamibi scans were performed under L-T4 therapy using a tracer dose of 720-925 MBq.FDG-PET/CT was carried out after stimulation with rhTSH.

Statistical analysis
The c 2 test was used to detect differences in the proportion of cases.Multivariate Cox regression models were used to assess the independent effect of different variables on the risk for persistent disease or tumor recurrence.A p value of less than 0.05 was considered to be significant.

Patients
The characteristics of the patients are shown in table 1.

Ablation with 131 I
The frequency of ectopic (metastatic) uptake on RxWBS is shown in table 2. Table 2 also shows the correlation between TgAb and Tg obtained immediately before ablation and the presence of metastases on RxWBS.In patients without TgAb, median Tg was 3.57 ng/dL.

Initial assessment after ablation
The results of assessment 9-12 months after ablation obtained for patients without metastases on initial RxWBS is shown in table 3.In this assessment, three patients had suspicious LN on US, but cytology was negative and Tg in the needle washout was < 1 ng/mL.

Late follow-up
Among patients without apparent disease until the first year after ablation, tumor recurrence was diagnosed in 2/83 (2.4%) patients (both with cervical metastases: one with positive cytology and the other with nondiagnostic cytology, but Tg in the needle washout > 400 ng/mL).Three patients exhibited suspicious LN on US during follow-up, but cytology was negative and Tg in the needle washout was < 1 ng/mL.

Evolution of patients with persistent disease or tumor recurrence
In the last assessment, after they had undergone new surgery (LN dissection) and/or had been treated with radioiodine and maintained under TSH suppression, three patients had achieved complete remission, structural disease persisted in one patient, and other patient had elevated Tg in the absence of apparent disease.There was no case of death due to the disease.

DISCUSSION
It does not seem adequate to classify all patients with LNM and without distant metastases (N1M0) into a single group (30) since their evolution is highly heterogenous.These patients (N1M0) have a poorer prognosis if the primary tumor measures more than 4 cm (11,15,19,31) or aggressive histological subtype (32), and if there is extensive extrathyroid invasion (pT4) (11,17,19,33) or vascular invasion (18,33).With respect to the characteristics of LN involvement, metastases detected by preoperative US (9)(10)(11)(12)(13)(14), the presence of more than 5 positive LN (11,(15)(16)(17)(18), metastases ≥ 3 cm (11,16,19), and extranodal extension (15,16,(18)(19)(20)(21) are also associated with a poor prognosis (4,5,7,22).In these cases, there is little controversy about the need for a more aggressive initial approach.Therefore, the present study was designed to define the rate of persistent disease and tumor recurrence in patients without other factors for poor prognosis, who presented nonextensive LN involvement (22).US is an accessible, noninvasive method consensually recommended before thyroidectomy.When preoperative US is negative, LNM, if present, are invariably < 3 cm and the vast majority is < 1-1.5 cm (11,(34)(35)(36)(37).For this reason, although the size of the LN and metastatic foci was not available for our patients, the fact that US was negative ensures the absence of LNM > 3 cm and makes LNM > 1.5 cm highly unlikely.Although defined as an exclusion criterion of the present study, macroscopic extranodal invasion is uncommon in the case of small LNM (16,20,38) and not present in large numbers (15,16,38).In fact, extranodal invasion was observed in only 7/466 patients with LNM < 3 cm and up to 5 positive LN in a previous series (16) and in only 1/87 patients with negative US and up to 5 positive LN in the present study (data not shown).A possible poor prognosis related to the location of LNM in the lateral compartments (N1b) also seems to be minimized when US is negative (9)(10)(11)(12).Finally, the efficacy of initial LN dissection, based on the persistence or not of LNM after surgery (39), is an important prognostic factor.In this respect, the fact that we included only patients with apparently complete tumor resection and postoperative US negative for LNM may have contributed to the result found.
Thus, persitent disease and tumor recurrence were found in only 3.5% and 2.5% (respectively) of patients without other factors for poor prognosis, with 5 or fewer positive LN detected during intraoperative inspection, but not by preoperative US, during a median follow-up of 5 years, a period during which 80% of recurrence are usually detected (40).Similar results have been reported by Ricarte-Filho and cols. in patients younger than 45 years (17) and by Leboulleux and cols.(15).It should also be noted that the patients had LNM that were detected during intraoperative inspection (cN1), and it could be possible that the rate of persistent disease and tumor recurrence are even lower among patients with LNM detected only during elective neck dissection (cN0pN1).
In low-risk patients without LNM (cN0), postoperative Tg < 1 ng/mL has shown an excellent negative predictive value (NPV) for PRD (41)(42)(43)(44)(45), even when they are not submitted to ablation with 131 I (41,44,45).In the present study, also in the subgroup of patients with LNM (cN1), postoperative stimulated Tg combined with neck US had an excellent NPV for persistent disease and tumor recurrence.Previous series involving a smaller number of patients with LNM also showed the absence of persistent disease on RxWBS in patients with low postoperative Tg (46)(47)(48)(49).However, there are studies reporting apparently different results.Nascimento and cols.evaluated 102 patients with stage T1-3N1 disease whose US showed no abnormalities and stimulated Tg was < 1 ng/ml after thyroidectomy (43).The authors showed unequivocal ectopic uptake on RxWBS in six patients and suspicious uptake in one but, different from our sample, five of these patients had more than 5 positive LN (43).Robenshtok and cols.studied 84 patients with stage T1-3N1 disease and postoperative Tg < 0.6 ng/mL and found ectopic uptake on RxWBS (SPECT/CT) in eight; however, in contrast to the cases studied here, seven of these patients had > 5 positive LN or LNM > 3 cm or vascular invasion or the aggressive histological subtype (50).Furthermore, in the latter study, Tg was not obtained under TSH stimulation and postoperative US was not performed (50).Finally, Lepoutre-Loussey and cols.found ectopic uptake on RxWBS in 28/171 patients with stage N1 disease, Tg-ablation < 1 ng/mL, and negative postoperative US (39).However, the authors did not report how many of these patients had tumors > 4 cm, aggressive histology, and extensive extrathyroid invasion, nor did they describe the characteristics of the LNM (size, number, extranodal extension).Furthermore, patients with TgAb were not excluded.Nevertheless, more studies are needed to determine the NPV of postoperative Tg in the absence of TgAb, especially under TSH stimulation and combined with US, in patients with LNM (N1) without other factors for poor prognosis and non-extensive LN involvement.This information is very important since the demonstration of an excellent NPV of low postoperative Tg would be an argument favoring the adoption of this criterion in order to also exempt patients with LNM and with the characteristics described above from ablation.
We conclude that persistent disease and tumor recurrence were low in patients with 5 Until 2006, Tg was measured with a radioimmunometric assay (ELSA-hTG; CIS Bio International, France) with a functional sensitivity of 1 ng/ml.After 2006, Tg was measured with a chemiluminescent assay (Access Thyroglobulin Assay, Beckman Coulter, Fullerton, CA) with a functional sensitivity of 0.1 ng/mL.TgAb were measured with a chemiluminescent assay [Immulite 2000, Diagnostic Products Corporation, Los Angeles, CA (reference value of up to 40 IU/ml) or AR-CHITET Anti-Tg, Abbott Laboratories, IL (reference value of up to 4.11 IU/mL)].

Table 1 .
Characteristics of the 86 patients studied

Table 2 .
Correlation between TgAb and Tg obtained immediately before ablation and the presence of ectopic (metastatic) uptake on RxWBS a Ectopic cervical uptake (lymph node metastases).bPulmonary uptake.

Table 3 .
Result of assessment 9-12 months after ablation obtained for patients without metastases on initial RxWBS a This patient had apparent disease on CT and FDG-PET/CT in lymph nodes.
or fewer positive LN detected during intraoperative inspection, but not by preoperative US; without other factors for poor prognosis [tumor ≤ 4 cm of non-aggressive histological subtype, without extensive extrathyroid invasion (pT4) or vascular invasion and known distant metastases (M1), and apparently complete tumor resection].Low postoperative stimulated Tg was predictive of the absence of persitent or recurrent tumor in these patients.significance of nodal metastases from papillary thyroid carcinoma can be stratified based on the size and number of metastatic lymph nodes, as well as the presence of extranodal extension.Thyroid.2012;22(11):1144-52. 23.UpToDate -Differentiated thyroid cancer: surgical treatment.Available from: <www.uptodate.com>.Accessed on: Set 23, 2013.24.Rosario PW, Furtado Mde S, Mineiro Filho AF, Lacerda RX, Calsolari MR.Value of diagnostic radioiodine whole-body scanning after initial therapy in patients with differentiated thyroid cancer at intermediate and high risk for recurrence.Thyroid.2012;22(11):1165-9.25.Rosario PW, Mourão GF, dos Santos JB, Calsolari MR.Is empirical radioactive iodine therapy still a valid approach to patients with thyroid cancer and elevated thyroglobulin?Thyroid.2014;24(3):533-6.26.Rosario PW, Mineiro Filho AF, Lacerda RX, dos Santos DA, Calsolari MR.The value of diagnostic whole-body scanning and serum thyroglobulin in the presence of elevated serum thyrotropin during follow-up of anti-thyroglobulin antibody-positive patients with differentiated thyroid carcinoma who appeared to be free of disease after total thyroidectomy and radioactive iodine ablation.Thyroid.2012;22(2):113-6.27.Valadão MM, Rosário PW, Borges MA, Costa GB, Rezende LL, Padrão EL, et al.Positive predictive value of detectable stimulated tg during the first year after therapy of thyroid cancer and the value of comparison with Tg-ablation and Tg measured after 24 months.Thyroid.2006;16(11):1145-9.28.Rosário PW, de Faria S, Bicalho L, Alves MF, Borges MA, Purisch S, et al.Ultrasonographic differentiation between metastatic and benign lymph nodes in patients with papillary thyroid carcinoma.J Ultrasound Med.2005;24(10):1385-9.29.Rosário PW, Tavares WC, Borges MA, Santos JB, Calsolari MR.Ultrasonographic differentiation of cervical lymph nodes in patients with papillary thyroid carcinoma after thyroidectomy and radioiodine ablation: a prospective study.Endocr Pract.2014;20(4):293-8.