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Diagnosis of Neck Recurrences in Patients with Differentiated Thyroid Carcinoma

Andrea Frasoldati, M.D., Ph.D1 Marialaura Pesenti, M.D.1 Marco Gallo, M.D.1 Angelo Caroggio, M.D.2 Diana Salvo, M.D.3 Roberto Valcavi, M.D.1
1

Unita Operativa di Endocrinologia, Arcispedale S. ` Maria Nuova, Reggio Emilia, Italy. Unita Operativa di Otorinolaringoiatria, Arcisped` ale S. Maria Nuova, Reggio Emilia, Italy. Unita Operativa di Medicina Nucleare, Arcisped` ale S. Maria Nuova, Reggio Emilia, Italy.

BACKGROUND. The follow-up of patients with differentiated thyroid carcinoma (DTC) is traditionally carried out with 131I whole body scan (131I WBS) and serum thyroglobulin (Tg) measurement. Neck ultrasonography (US) is also used. METHODS. We compared the roles of Tg measurement (IRMA assay) after l-thyroxine (T4) withdrawal, 131I WBS, and US in the diagnosis of DTC neck recurrences. Diagnosis of DTC neck recurrences was based on ne-needle aspiration biopsy (FNAB) or on histologic results. Four hundred ninety-four DTC patients (120 males, 374 females; mean age, 49.3 years), submitted to total thyroidectomy and subsequent radioablative 131I treatment, underwent serum Tg measurement off T4
therapy, 131I WBS, and neck US at our institution. Mean ( SD) follow-up time was 55.1 37.7 months. Neck DTC recurrences were detected in 51 (10.3%) patients (34 females, 17 males; mean age, 49.5 years). RESULTS. Neck recurrences occurred after 44.6 21.4 months from initial treatment. Serum Tg levels increased ( 2 ng/mL) off T4 therapy in 29 patients (sensitivity 56.8%), 131I WBS showed neck uptake in 23 patients (sensitivity 45.1%) and coexisting distant metastases were detected in 9 of 23 patients, and US identied neck recurrence in 48 patients (sensitivity 94.1%). Of these 48 neck recurrences, 19 were found in the laterocervical compartment and 29 in the central neck compartment. CONCLUSIONS. Traditional techniques for the surveillance of DTC patients are not as sensitive as US in the detection of neck recurrences. Neck US detects recurrences in patients with undetectable serum Tg levels and negative IWBS and should be performed as the rst-line test in the follow-up of all DTC patients. Cancer 2003;97:90 6. 2003 American Cancer Society. DOI 10.1002/cncr.11031

KEYWORDS: thyroid neoplasms, recurrence, ultrasonography, aspiration biopsy, follow-up studies.

Presented in part as an oral communication at the 83rd annual meeting of The Endocrine Society, Denver, Colorado, June 20 23, 2001. Address for reprints: Roberto Valcavi, M.D, Unita ` Operativa di Endocrinologia, Arcispedale S. Maria Nuova, Viale Umberto I, 50 42100 Reggio Emilia, Italy; Fax: 011-39-0522-296537; E-mail: valcavi. roberto@asmn.re.it Received May 3, 2002; revision received July 10, 2002; accepted August 5, 2002. 2003 American Cancer Society

p to 20% of patients with differentiated thyroid carcinoma (DTC) develop locoregional recurrences.1,2 Neck recurrences from DTC may include different clinical entities ranging from lymph node metastases to true tumor recurrences in the thyroidal bed that should be regarded as a serious, potentially lethal event. Eight percent of patients with local recurrences will eventually die of cancer.3 Periodic DTC patients follow-up is traditionally performed with 131 I whole body scan (131I WBS) and serum thyroglobulin (Tg) measurement off l-thyroxine (T4) therapy2,4 or, more recently, after recombinant human thyroid-stimulating hormone (rhTSH).2,5 However, at least one-fourth of recurrences and metastases from DTC do not concentrate iodine.6 Accordingly, negative radioiodine scans have been demonstrated in patients with metastases detected by other

Neck Recurrences from Thyroid Carcinoma/Frasoldati et al. TABLE 1 TNM Classication of 494 DTC Patients in Follow-Up
T (%) T1 n T2 n T3 n T4 n 123 (24.8) 158 (32.1) 49 (9.9) 164 (33.2) N (%) N0 n N1 n 339 (68.7) 155 (31.3) M (%) M0 n M1 n 453 (91.7) 41 (8.3) TNM stage (%) Stage I n 241 (48.8) Stage II n 64 (12.9) Stage III n 155 (31.4) Stage IV n 34 (6.9)

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DTC: differentiated thyroid carcinoma.

methods.711 False-negative Tg levels in patients with persistent disease have also been reported, although less frequently.12,13 The role of neck ultrasonography (US) is still being debated. Neck US detects tumor recurrences,7,14,15 but is usually recommended only in selected cases and not in the routine follow-up of all DTC patients.1,2,13,16 Our study evaluates all cases of DTC neck recurrences at our institution in the last 12 years. We compared the diagnostic role of serum Tg levels measurement off T4 administration, 131I WBS, and neck US.

MATERIALS AND METHODS

Patients
We studied 494 DTC patients (120 males, 374 females; age range, 15 83 years; mean standard deviation [SD], 49.3 18.4) who underwent total thyroidectomy (Tx). Histologic specimens were classied using World Health Organization criteria.17 Four hundred twentythree (85.6%) patients had papillary (101 males, 322 females; age 15 80 years; mean SD, 49.2 14.4) and 71 (14.3%) had follicular carcinoma (21 males, 50 females; age 20 83 years; mean SD, 53.3 16.8). Tumor staging, based on the TNM system,18 is shown in Table 1. Prognostic risk was differentiated according to TNM staging. Stage III patients (n 305 [61.7%]) were classied as low risk and Stage IIIIV patients (n 189 [38.3%]) were classied as high risk.19 The initial surgical treatment included lymph node dissection in 243 (49.2%) patients (papillary [n 219], follicular [n 24]; Stage III [n 116], Stage IIIIV [n 127]). Surgical procedures were as follows: Tx and central compartment neck dissection (n 121); Tx and lateral modied neck dissection (n 39); and Tx and central and lateral modied neck dissection (n 83). Following surgery, radioiodine 50 100 mCi (1850 3700 MBq) was administered to all patients for thyroid remnant ablation regardless of risk class.2 Fiveseven days after 131I ablative administration, 131I WBS was carried out. Six-twelve months after the rst 131I dose, 53 patients with detectable serum Tg

levels off T4 therapy received a second radioiodine treatment (80 150 mCi). Following this second 131I administration, thyroid remnant ablation was obtained for all patients. Thyroid remnant ablation was conrmed by undetectable serum Tg levels and negative 131IWBS scan. Further radioiodine doses (100 200 mCi) were administered to 29 patients with evidence of distant metastases. All patients were treated with T4 suppressive therapy to obtain serum TSH levels below 0.05 U/mL. All patients without distant metastases had undetectable Tg levels at least once postoperatively. Patients with poorly differentiated tumors, patients who underwent partial surgery (lobectomy), patients with gross neck residual tumor, and patients with an anti-Tg antibody titer of 20 mU/mL or higher (normal value 20 mU/mL) were not included in this study.

Follow-Up
Mean SD follow-up time was 55.1 37.7 months. All DTC patients were monitored with serum Tg measurement, 131I WBS, and neck US.

Serum Tg measurement after T4 withdrawal (28 days)

Serum Tg levels of 2 ng/mL or higher were indicative of thyroid tissue persistence or thyroid tumor recurrence.5
131

I WBS

I WBS was performed 28 days after T4 withdrawal (mean standard error [SE] TSH levels: 63 12 mU/L). Scans were performed 48 and 72 hours after 131 I 5 mCi oral administration. 131I WBS was repeated annually until two consecutive 131I WBS negative imaging studies were obtained.13

131

Neck US examination
Neck US was performed alternatively at 6 12-month intervals by two operators (AF or RV). A 7.5-MHz sector transducer was used from 1989 to 1996. Subsequently a multifrequence 7.513-MHz linear probe

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was employed. The patient was examined in the supine position with hyperextended neck allowing the visualization of the central compartment. The following US features were suspicious for DTC neck recurrences: round oval shape (short to long axis ratio 0.7), hypoechoic, inhomogenous pattern, and/or intralesional punctate calcications, diffuse hypervascularity.7,20 22 The anatomic scheme level system adopted for the location of neck recurrences was described by Robbins et al.23 Level I corresponded to the submental and submandibular compartment; Levels IIV to the lateral (jugular chain and posterior triangle) compartment; and Levels VIVII to the central (para/ pretracheal and perithyroidal) compartment. Figure 1 shows typical US features of lateral and central compartment neck recurrences. Other imaging techniques (computed tomographic scan [CT], magnetic resonance imaging [MR], and positron emission tomography [PET]) were obtained in individual patients, in case of unclear and/or conicting results of the above mentioned follow-up techniques.

Diagnosis of DTC Neck Recurrence

Differentiated thyroid carcinoma neck recurrence is dened as a lesion occurring in a patient previously considered free of residual neck tumor after complete surgical removal and thyroid remnant ablation.24,25 In our series, diagnosis of DTC neck recurrence was based either on ne-needle aspiration biopsy (FNAB) or on histologic results. Written informed consent was obtained from all patients before FNAB. The FNAB was performed under US guidance, using a 7.513-mHz probe equipped with a needle pointing device.26 In brief, cytologic specimens were obtained with a 2225-gauge spinal needle connected to a 20-mL Cameco pistol-mounted syringe (Precision Dynamics, Burbank, CA). Biopsy samples were smeared for cytologic examination (FNAB-C). The needle was then washed out with 1 mL normal saline and the collected uid was sent to the laboratory for Tg measurement (FNAB-Tg). Substantially elevated FNAB-Tg levels are a reliable index for the diagnosis of neck DTC recurrence.26 28

FIGURE 1. Neck ultrasound transversal scans obtained for two thyroidectomized patients with differentiated thyroid carcinoma recurrences (arrows). (A) Central neck compartment: 6-mm round-shaped, hypoechoic inhomogenous mass stuck to the trachea. (B) Lateral neck compartment: 13-mm hypoechoic lesion with internal hyperechoic spots. CC: common carotid artery.
duplicate and a recovery test was performed on each sample. Anti-Tg antibody levels were measured by an immunoenzymatic assay (BioRad, Hercules, CA) with a 5.0-U/mL sensitivity and intraassay and interassay CVs of 10.0% and 15.0%, respectively, at a dose level of 275 U/mL. Titers less than 20 U/mL were negative. The frequency of neck DTC recurrences among different TNM-stage groups was compared using the chi-square test.

Laboratory Assays and Statistical Analysis

Both serum Tg and FNAB-Tg levels were measured by an immunoradiometric solid-phase assay (Sorin, Rome, Italy) with a sensitivity of 0.25 ng/mL. Intraassay coefcients of variation (CVs) were, respectively, 1.2% and 3.3% at 130 and 23-ng/mL dose levels. Interassay CVs were, respectively, 2.2% and 5.4% at 128 and 60-ng/mL dose levels. Samples were analyzed in

Neck Recurrences from Thyroid Carcinoma/Frasoldati et al. TABLE 2 TNM Classication of 51 Patients with DTC Neck Recurrence
T (%) T1 n T2 n T3 n T4 n 9 (17.7) 22 (43.1) 4 (7.8) 16 (31.4) N (%) N0 n N1 n 22 (43.1) 29 (56.9) M (%) M0 n M1 n 36 (70.6) 15 (29.4) TNM stage (%) Stage I n 17 (33.3) Stage II n 10 (19.6) Stage III n 14 (27.5) Stage IV n 10 (19.6)

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DTC: differentiated thyroid carcinoma.

RESULTS
Differentiated thyroid carcinoma neck recurrences were detected in 51 of 494 (10.3%) patients (34 females, 17 males; age range, 17 83 years; mean SD, 49.5 17.85). Tumor neck recurrences occurred after (mean SD) 44.6 21.4 months from diagnosis. Of 51 patients, 23 (45.1%) had undergone Tx alone as initial surgical treatment, whereas 28 (54.9%) had undergone neck lymph node dissection (central compartment [n 9]; lateral modied [n 10], central and lateral modied [n 9]). The primary thyroid tumor was a papillary tumor in 42 patients (82.3%) and a follicular tumor in 9 patients (17.7%). The recurrence rate was comparable between the two histotypes (9.9% vs. 12.6%). The neck recurrence rate was higher in N1 versus N0 (18.7% vs. 6.5%, P 0.001) and in M1 versus M0 (36.6% vs. 7.9%, P 0.001) patients. TNM tumor staging in patients with DTC neck recurrences is shown in Table 2. Distant metastases were found by Tg and WBS in 29.4% of these patients. Neck recurrences were equally distributed among low-risk (Stages III) and high-risk (Stages IIIIV) patients (n 27 vs. 24, 52.9% vs. 47.1%, P NS). The rate of neck recurrence was comparable between patients submitted to Tx alone (9.1%) and patients submitted to Tx and lymph neck node dissection (11.5%). In the 51 patients with neck recurrences, serum Tg measurement, 131I WBS, and neck US gave the following results. 1) Serum Tg levels greater than or equal to 2 ng/mL off T4 therapy were detected in 29 (56.8%) patients. In another ve patients, serum Tg levels were detectable, although they were below 2 ng/mL. Therefore, any detectable Tg levels off T4 therapy were found in 34 patients (sensitivity 66.6%). Serum Tg levels were greater than or equal to 10 ng/mL in 23 patients and greater than or equal to 100 ng/mL in 14 patients. 2) 131I WBS showed neck 131I uptake in 23 (45.1%) patients. Nine patients also had evidence of at least one site of distant metastasis (lung [n 6], bone [n 3], brain [n 1], soft tissues [n 1]). 3) Ultrasound examination revealed neck recurrence in 48 (94.1%) patients. Nineteen (39.5%) patients presented

FIGURE 2. (A) Overall sensitivity of serum thyroglobulin (Tg; off T4 treatment), 131I whole body scan (131I WBS), and ultrasound (US) in the detection of differentiated thyroid carcinoma (DTC) neck recurrences. (B) Sensitivity of serum Tg (off T4 treatment), 131I WBS, and US in high and low-risk DTC patients with neck recurrences.

a lesion in the lateral and 29 (60.5%) in the central neck compartments. Mean ( SD) diameter of neck recurrences was 16.2 9.1 mm. Recurrences were palpable in only nine (17.6%) patients. Fourteen (29.2%) DTC neck recurrences were less than 1 cm in diameter. Three patients lacked US evidence of neck lesions, but 131I WBS, and serum Tg suggested the diagnosis of neck recurrence. This was conrmed by further imaging studies (CT [n 2], PET [n 1]) and histology. All CT/MR/PET Imaging scans were obtained in 22 patients with discordant neck US, serum Tg, and WBS studies. The sensitivity of serum Tg levels, 131I WBS, and US in the detection of DTC neck recurrences is shown in Figure 2. Ultrasound-guided FNAB (FNAB-C plus FNAB-Tg) was performed in 46 of 51 patients. FNAB was not performed in two patients because of lesion depth and/or contiguity to large vessels. Cytology alone was indicative of malignancy in 39 of 46 patients (84.8%), whereas cytology plus FNAB-Tg measurement was diagnostic in 44 of 46 (95.6%) patients. In the remaining

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TABLE 3 Individual Data of Patients with DTC Neck Recurrences Exhibiting Negative (< 2 ng/mL) Serum Tg Levels off T4
Patient no. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 Gender F M F M F F F M F M F F F F F M F M F M F F Age (yrs) 23 74 69 28 79 74 72 61 67 76 52 74 53 63 35 49 17 49 35 50 41 48 Tumor histology Pap Pap Pap Pap Pap Pap Foll Pap Foll Pap Pap Pap Pap Pap Pap Pap Pap Pap Pap Pap Pap Pap TNM T1N1M0 T2N0M0 T2N1M0 T2N0M0 T2N0M0 T4N1M0 T2N1M0 T4N1M0 T4N1M1 T2N0M0 T4N1M0 T4N1M0 T1N1M0 T2N0M0 T2N1M0 T1N1M0 T2N1M0 T4N1M0 T1N0M0 T1N0M1 T4N1M0 T1N1M0 Stage I II III I II III III III IV II III III III II I III I III I IV I III Physical exam. Neg Neg Neg Neg Pos Pos Neg Pos Neg Neg Neg Neg Neg Neg Neg Neg Neg Pos Neg Neg Neg Neg Serum Tg (ng/mL) nd nd nd nd nd nd 1 nd nd nd 1.5 nd 1 nd nd nd nd 1 nd nd 1 nd US size (mm)a 7 11 5 8 50 34 23 18 25 25 13 29 8 33 14 9 12 20 15 nd 10 12
131

I WBS

Cytology Pos Pos Inad Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Pos Inad Pos Pos Inad Pos Pos

FNAB-Tg (ng/mL) 600 18 600 600 16 600 600 600 600 1 600 600 600 600 12 600 1 8 600

Recurrence histology Pos Pos Pos Pos Posb Posb Pos Pos Pos Pos Pos Pos Pos Posb

Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Neg Pos Pos Pos Pos Neg

DTC: differentiated thyroid carcinoma; Tg: thyroglobulin; US: ultrasonography; WBS: whole body scan; FNAB: ne-needle aspiration biopsy; Pap: papillary thyroid carcinoma; Foll: follicular thyroid carcinoma; Neg: negative; Pos: positive; nd: not detectable; Inad: inadequate. a Maximum diameter. b Poorly differentiated.

two patients, cytology and FNAB-Tg results were nondiagnostic. Ultrasound-guided FNAB was performed in another 45 patients with US ndings suspicious for a DTC neck recurrence. In all these cases, US-guided FNAB-C plus FNAB-Tg results were negative and no evidence of DTC recurrence was obtained by any other imaging technique. These patients had falsepositive results. This indicates a 0.10 false-positive rate and a 90.3% accuracy for neck US. Ultrasound falsepositive patients were followed up. So far, none of them have had neck recurrences. Serum Tg levels below 2 ng/mL off T4 treatment were observed in 22 (43.1%) patients with neck recurrences. Individual data are shown in Table 3. The majority (n 18 [81.9%]) of these patients also had a negative 131I WBS. Fine-needle aspiration biopsy-Tg was measured in 19 patients; intralesional Tg was detected in 17 (89.5%) patients. Thirty-eight patients underwent surgery. In all these patients, histologic evaluation demonstrated DTC neck recurrence (metastatic neck lymph nodes [n 30], tumor recurrence in the thyroidal bed [n 6], soft tissue metastasis [n 2]). Surgery was not performed on 13 patients due

to poor clinical conditions, patients refusal to undergo surgery, or unresectable disease. Serum Tg, WBS, and US sensitivities in the detection of the 38 cases of histologically demonstrated DTC neck recurrence were 55.2%, 44.7%, and 92.1%, respectively.

DISCUSSION
In our series, neck recurrences occurred in about 10% of the patients followed-up for DTC, which agrees with previous data.1,2 We did not observe different recurrence rates between papillary and follicular histotypes. Age, tumor size, extrathyroidal invasiveness, and lymph node involvement are signicant independent prognostic factors for DTC recurrence.29 32 In our study, N1 and M1 patients were more likely to develop neck recurrences. However, about 50% of our patients with neck recurrences had been classied as low risk on the basis of the TNM staging system. These data strongly support the need for a careful surveillance of the neck region in patients with evidence of aggressive disease. They also indicate that neck monitoring should include low-risk patients. The sensitivity of traditional follow-up techniques, i.e., serum Tg and 131I WBS, in the detection of

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95

neck recurrences was unexpectedly low compared with US examination. Serum Tg levels off T4 treatment were below 2 ng/mL and 131I neck uptake was negative in about 43% and 55% of the patients with neck recurrences, respectively. Various factors may explain these ndings. First, the smallness of some tumor recurrences may minimize 131I uptake and Tg synthesis and release. Second, loss of tumor cell differentiation has been observed in patients with DTC local recurrences.33 Dedifferentiation may prevent neoplastic cells from taking up iodine, as suggested by reduced sodium iodide symporter (NIS) mRNA expression in metastatic thyroid carcinoma.34 Dedifferentiation may also explain the inability of neoplastic tissue to release Tg in sufcient amounts to be measured in the peripheral blood, even by sensitive assays. In a number of our patients, Tg was detected consistently in the needle wash-outs in spite of undetectable serum levels, extending previous observations.26,27 Third, although patients with positive anti-Tg antibodies were not included in our study, minor interference due to low levels of anti-Tg antibodies ( 20 U/mL) cannot be ruled out. Furthermore, Tg synthesis in tumor recurrence may be variable for other, unknown, reasons. This speculation is supported by the observation that intralesional Tg levels ranged from very low to exceedingly high values, independently from recurrence size or differentiation. This study shows that US is far more sensitive than serum Tg and 131I WBS in the detection of DTC neck recurrences and that US may discover neck recurrences in patients with an otherwise negative follow-up. Ultrasound-guided FNAB-Tg measurement in the needle wash-out provides an accurate diagnosis in most cases of neck recurrences. One-third of DTC recurrences in our study was less than 1 cm in diameter and about 60% were localized in the central neck compartment, i.e., in the upper mediastinum. Due to their small size and/or their deep location, a high percentage of neck recurrences were not suspected on clinical examination. An US examination may also permit a precise topographic localization of the lesions, increasing the chance for a curative surgery. However, this aspect was not addressed specically in our study. The limitation of US examination is that the accuracy of this technique is operator dependent.35 To our knowledge, there is no gold standard for neck DCT recurrence imaging. Some studies suggest that other techniques (CT, MR, and PET) may be useful.15 In our study, these techniques were adopted when neck US, serum Tg measurement, and 131I WBS were discordant. This approach allowed us to identify three cases of DTC neck recurrence. Systematic use of

CT/MR/PET may nd a few other neck recurrences. However, the high cost of these imaging techniques limits their routine use. DTC neck recurrences may vary according to location (central vs. lateral neck compartment), size (from millimeters to several centimeters), and histology (lymph node metastasis vs. tumor local recurrence or soft tissue metastasis). This heterogeneity includes a spectrum of clinical situations: at one end, small metastatic lymph nodes lacking any evidence of progressive disease; at the other, invasive bulks of tumor spreading to soft tissues and neurovascular structures. Further studies specically addressing the clinical value of different types of DTC neck recurrences are needed. In conclusion, neck US detects recurrences in patients with undetectable serum Tg levels and negative WBS. It should be performed as the rst-line test in the follow-up of all DTC patients.

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