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Figure.
Kaplan-Meier estimates. A, Kaplan-Meier estimate for lateral neck disease-free interval, stratifying by sonographic status of the ipsilateral neck (P = .001). B, Kaplan-Meier estimate for disease-specific survival, stratifying by presence of sonographic abnormalities in the lateral neck compartments (P < .001). C, Kaplan-Meier estimate for recurrence-free survival (years to recurrence or death for any reason), stratifying by sonographic status of the lateral neck compartments (P < .001).

Kaplan-Meier estimates. A, Kaplan-Meier estimate for lateral neck disease-free interval, stratifying by sonographic status of the ipsilateral neck (P = .001). B, Kaplan-Meier estimate for disease-specific survival, stratifying by presence of sonographic abnormalities in the lateral neck compartments (P < .001). C, Kaplan-Meier estimate for recurrence-free survival (years to recurrence or death for any reason), stratifying by sonographic status of the lateral neck compartments (P < .001).

Table 1. 
Summary of Clinicopathological Characteristics
Summary of Clinicopathological Characteristics
Table 2. 
Univariate Cox Proportional Hazards Model for Lateral Compartment Recurrence-Free Interval Stratified by Clinical Variables
Univariate Cox Proportional Hazards Model for Lateral Compartment Recurrence-Free Interval Stratified by Clinical Variables
Table 3. 
Univariate Cox Proportional Hazards Model for Lateral Compartment Recurrence-Free Interval Stratified by Preoperative Sonographic Findings
Univariate Cox Proportional Hazards Model for Lateral Compartment Recurrence-Free Interval Stratified by Preoperative Sonographic Findings
Table 4. 
Cox Proportional Hazards Model for Lateral Neck Recurrence-Free Interval Stratified by Number of Abnormal Neck Compartments on Preoperative US
Cox Proportional Hazards Model for Lateral Neck Recurrence-Free Interval Stratified by Number of Abnormal Neck Compartments on Preoperative US
Table 5. 
Correlation Between Sonographic Abnormalities and Overall, Disease-Specific, and Recurrence-Free Survival Stratified by Age at Presentationa
Correlation Between Sonographic Abnormalities and Overall, Disease-Specific, and Recurrence-Free Survival Stratified by Age at Presentationa
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Original Article
February 21, 2011

Preoperative Lateral Neck Ultrasonography as a Long-term Outcome Predictor in Papillary Thyroid Cancer

Author Affiliations

Author Affiliations: Departments of Otolaryngology, Head and Neck Surgery (Dr Moreno) and Biostatistics (Mr Siegel), University of Arkansas for Medical Sciences, Little Rock; and Departments of Head and Neck Surgery (Drs Agarwal and Clayman and Mr de Luna), Endocrine Neoplasia (Dr Sherman), and Diagnostic Radiology (Dr Edeiken-Monroe), The University of Texas M. D. Anderson Cancer Center, Houston.

Arch Otolaryngol Head Neck Surg. 2011;137(2):157-162. doi:10.1001/archoto.2010.254
Abstract

Objective  To evaluate the long-term outcomes and prognostic value of our sonographically based surgical approach to the lateral neck for recurrences in papillary thyroid cancer (PTC).

Design  Retrospective medical chart review.

Setting  Tertiary cancer institution.

Patients  The study population comprised 331 consecutive patients primarily treated for papillary thyroid carcinoma (PTC) at a tertiary cancer institution between 1996 and 2003. The lateral neck compartments were surgically addressed only in the presence of abnormalities on ultrasonography (US).

Main Outcome Measures  Recurrence-free interval and overall, disease-specific, and recurrence-free survival.

Results  There were 112 male and 219 female patients, with a median age of 44.7 years (range, 11-87 years). The median follow-up time for the series was 77.9 months (range, 12.7-148.7 months). Preoperative US abnormalities were found in the right neck in 13.3%, in the left neck in 12.3%, and bilaterally in 11.2%; all of these patients underwent a lateral neck dissection at the time of the thyroidectomy. There were 11 recurrences in the series (0.3%), with a median time to presentation of 22.8 months (range, 6.0-55.3 months). Predictors of lateral neck disease-free interval were T stage and distant disease at presentation (P = .01 and P < .001, respectively) and the sonographic status of the ipsilateral and central neck (P = .001 and P  < .001). The number of abnormal neck compartments in US correlated with the risk of regional failure (P = .01). The presence of US abnormalities in the lateral neck decreased the 10-year disease-specific survival from 98.3% to 66.9% (P < .001).

Conclusions  Preoperative US is an excellent outcome predictor for lateral neck disease-free interval and for disease-specific survival in PTC. Sonographically based surgical approach provides excellent long-term regional control and validates current treatment guidelines.

The incidence of thyroid cancer in the United States has increased more rapidly than any other malignant disease over the past 20 years. This increase in incidence is likely influenced by improvements in diagnostic methods such as routine high-resolution ultrasonography (US) and fine-needle aspiration biopsy.1 In recent years, preoperative staging with high-resolution US has become a standard practice in most centers. This is reflected in the 2009 American Thyroid Association Guidelines Taskforce recommendation favoring routine preoperative imaging with US over other imaging modalities for patients with thyroid cancer.2

Although differentiated thyroid cancer can metastasize to the lymph nodes in up to 80% of the cases,3 the potential impact of nodal spread on oncologic outcomes has not been clearly defined and remains a concern, particularly in the older population. Initial studies suggested that the presence of nodal metastasis had no effect in overall or disease-free survival, but this notion has been refuted by recent series.4

The initial staging and elective surgical treatment of lateral neck compartment is still controversial. Wang et al5 have reported that in differentiated thyroid cancer neck recurrences are rare, concluding that efforts to diagnose and treat lateral neck disease are only justified in patients older than 45 years with tumors larger than 4 cm. Other authors have reported that routine sonographic evaluation of the lateral neck increased the sensitivity over physical examination by at least 20%, leading to a modification of the initial treatment plan in a significant proportion of patients.6

Although elective neck dissections of the lateral compartments have been advocated for patients who are at higher risk for failure by Japanese authors,79 a more conservative approach is widely accepted as the standard of care in the United States.2,10 This usually includes preoperative imaging followed by level 2 to 5 neck dissection only in the presence of documented disease in the jugular compartments by clinical examination and/or imaging. Despite this widespread practice, there is very limited evidence to support this approach, especially regarding the negative predictive value of US in long-term follow-up.11 Since US has been standard modality for initial staging in our institution since 1991, we sought to evaluate its long-term prognostic value and outcomes with our selective surgical approach to the lateral neck.

METHODS

The database of the University of Texas M. D. Anderson Cancer Center was queried to identify 505 patients who underwent definitive surgical treatment for thyroid cancer at our institution between January 1996 and December 2003. Of these patients, 331 met the inclusion criteria, which were defined as follows: (1) papillary thyroid carcinoma (PTC), all histological variants included, (2) preoperative US of the head and neck performed at our institution, (3) detailed description of US findings in the lateral neck compartments, (4) initial surgical treatment performed at M. D. Anderson Cancer Center, and (5) a minimum follow-up of 12 months.

Ultrasonography of the soft tissues of the neck was performed with a high-resolution scanner (Sequoia [Acuson, Mountain View, California]; Elegra [Siemens, Issaquah, Washington]; HDI 5000 [Phillips-ATL, Bothell, Washington]; and Powervision 7000 [Toshiba, Tokyo, Japan]) and a high-frequency linear-array transducer with frequencies from 7 MHz to 13 MHz. All head and neck scans were performed in the Radiology Department by radiologists specializing in cervical US. The preoperative status of the lateral neck compartments was determined based on the sonographic appearance of the lymph nodes. These were considered abnormal in the presence of enlarged size, cystic changes, rounded shape, eccentric cortical widening, decreased echogenicity, loss of fatty hilus, presence of calcifications, and increased intranodal vascularity.12

In patients with abnormal sonographic findings in the lateral necks, a compartment-oriented lateral neck dissection encompassing levels IIa, III, IV, anterior level V, and ipsilateral level VI was performed at the time of the thyroidectomy. This surgical approach has become highly standardized in our institution, and we have previously reported limited morbidity with this technique.13 In the absence of sonographic abnormalities, the lateral neck was consistently spared at the time of surgery. This was done regardless of the T stage, histological variant or differentiation, patient's age, or other considerations reported in the literature.7,8

The pathology reports were reviewed, and all patients were staged according to the current American Joint Committee on Cancer staging system14 based on the documented histopathological findings. Adjuvant treatment with radioactive iodine was routinely given based on the postoperative whole-body scan uptake. For patients who underwent more ablation, the cumulative radioactive iodine dose used was considered. Basal and follow-up thyroglobulin levels as well as the presence of antithyroglobulin antibodies were documented. Adjuvant external beam radiation was used for patients with poorly differentiated cancer and/or extensive extrathyroidal spread, particularly when local recurrence would place the larynx, trachea, or esophagus at stake.

The clinical course was determined, and all patients who presented with recurrent disease were identified. Cervical recurrence was defined as metastatic involvement of any cervical lymph node developing 6 months or more after surgery. The timing and location of distant disease was documented when indicated; patients with persistently elevated serum triglyceride levels and negative imaging results 1 year after treatment were considered alive with disease for all statistical analyses.

This study was approved by the M. D. Anderson Cancer Center institutional review board. The data analysis was generated using version 8 of the SAS System (SAS Institute Inc, Cary, North Carolina). Categorical patient characteristics were summarized as proportions, while continuous characteristics were summarized as medians and quartiles. A recurrence event was defined as a recurrence on the left or right side of the neck. Years to recurrence was measured from the date of surgery to the recurrence date, with censoring at last follow-up if no recurrence event occurred by then. Years to recurrence was analyzed for association with other variables, initially by Kaplan-Meier plots with log-rank test and subsequently by Cox regression. Because only 11 recurrence events were observed among 331 patients, the Cox regressions were limited to univariate analysis to avoid overfitting and monotone likelihoods.15 Interaction on bivariate Cox regression was used to correlate age and sonographic findings and their impact on survival.

RESULTS

The clinicopathological characteristics the study group are summarized in Table 1. There were 112 male and 219 female patients, with a median age of 44.7 years (range, 11-87 years). TNM staging at presentation was as follows: 151 patients with a T1 tumor, 58 patients with a T2 tumor, 70 patients with a T3 tumor, and 52 patients with a T4 tumor. The tumor was located in the right thyroid lobe in 117 cases, left thyroid lobe in 73 cases, and thyroid isthmus in 8 cases and it was multicentric in 133 cases. A total thyroidectomy or completion thyroidectomy was performed in all the cases.

An ablative dose of radioactive iodine was initially used in 252 cases (76.1%) and was readministered, when indicated, based on clinical criteria. The total ablative dose used ranged from 28 to 455 mCi of iodine-131, with a mean of 115.7 mCi. External beam radiation therapy was used as part of the initial treatment scheme in 33 cases. The median follow-up time for the series was 77.9 months, with a range of 12.7 to 148.7 months.

Preoperative sonographic abnormalities were present in the right side of the neck in 44 patients (13.3%), left side of the neck in 41 patients (12.3%), and bilaterally in 37 patients (11.2%); all of these patients underwent a lateral neck dissection as part of their initial treatment. No lateral neck dissections were performed the group of patients with sonographically normal necks. Of the 331 patients, recurrence was seen in the lateral neck in 11 (3.3%) and was bilateral in 3 cases (0.9%). The median time for lateral neck recurrence was 22.8 months, with a range of 6 to 55.3 months.

The relationship between clinicopathological variables and lateral neck disease-free interval is demonstrated in Table 2. All lateral neck failures were observed in the group treated with adjuvant radioactive iodine (11 of 241 patients vs 0 of 79 patients; P = .06); the hazard ratio was not calculated for this variable. The association between preoperative sonographic findings and lateral neck failure is presented in Table 3. The sonographic status of the ipsilateral neck compartment was a predictor for recurrence-free interval (Figure, A), but the contralateral neck did not reach statistical significance. There was a correlation between the number of sonographically abnormal neck compartments and the relative risk of lateral neck failure, as given in Table 4.

The 5- and 10-year overall survival for the series were 97.6% and 82.5%, respectively, with a 5- and 10-year disease-specific survival (DSS) of 99.0% and 89.1%, respectively.

The sonographic status of the lateral neck compartments at presentation was a significant outcome predictor for both overall survival and DSS. The presence of sonographic abnormalities was associated with a decrease in 5- and 10-year overall survival from 98.3% to 96.5% and from 95.4% to 52.8%, respectively (P < .001). Sonographic abnormalities were also associated with a reduction in 5- and 10-year DSS from 100% to 97.3% and from 98.3% to 66.9%, respectively (P < .001), as shown in the Figure, B. Indeed, of the 18 patients who died of the disease, 15 (83.3%) had involvement of the lateral compartment and 6 (33.3%) had metastatic disease at the time of the initial diagnosis.

The sonographic status of the lateral neck compartments was also a predictor for recurrence-free survival (RFS), defined as survival time to recurrence or death for any reason. The 5- and 10-year RFS were 96.6% and 95.3%, respectively, for the sonographically normal group, vs 87.8% and 69.6% for the sonographically abnormal group (P < .001). The Kaplan-Meier estimate for RFS is shown in the Figure, C.

The predictive value of baseline US for overall survival, DSS, and RFS was statistically significant for patients regardless of age at presentation; interaction analysis between US and age on bivariate Cox regression was nonsignificant for survival outcomes (Table 5).

COMMENT

Papillary thyroid carcinoma is an endocrine neoplasia with an increasing incidence and a high tendency to spread to regional lymph nodes. In case series considering subclinical disease, regional spread has been reported to be as high as 80%.16 The ideal surgical approach to the central and lateral neck compartments in patients with a clinically negative neck is still a matter of debate. A prophylactic dissection is more widely accepted for the central compartment, where it has shown that it may improve DSS,217 not without increasing the risk of permanent hypocalcemia and recurrent laryngeal nerve injury.4 On the contrary, the management of the lateral neck compartments is usually more conservative, and surgical treatment is reserved for patients with clinical or radiological evidence of disease. Since the reported rate of recurrence in the lateral neck is in the 5% to 15% range, it is usually believed that treating the neck when metastasis becomes apparent does not affect overall outcome.18

A more aggressive approach to the negative neck has been proposed by Japanese authors, in part because of their limited access to radioactive iodine.9 Noguchi et al7,8 has demonstrated that a modified lateral neck dissection may improve DSS in patients older than 60 years or in the presence of extracapsular extension or a large (>25 mm) primary tumor.

The surgical management of clinically positive disease in the lateral necks is less controversial, and the current American Thyroid Association guidelines recommend a level 2 to 5 ipsilateral neck dissection.2 It has been proposed that a compartment-oriented procedure, such as level 2 to 5 neck dissection, decreases the risk of recurrence compared with more conservative approaches such as enucleation (“berry picking”) or limited neck dissections.19,20

In our institution, for almost 2 decades, we have relied on a baseline US assessment of the lateral neck compartments to determine which patients should undergo surgical treatment of the neck. In these patients, a standardized compartment-oriented procedure is performed involving the resection of levels II to IV and anterior level V. In the absence of sonographic abnormalities, the lateral neck compartments are not surgically addressed regardless of the tumor size, histological variant, patient age, or status of the central neck. We sought to evaluate the long-term effectiveness of this approach, particularly with respect to oncologic outcomes and risk stratification.

We found involvement of the lateral neck compartments in almost 25% of the patients, with roughly half of them harboring bilateral neck disease. This rate of involvement of lateral neck compartments falls within the 20% to 30% range reported in the literature.21 In terms of lateral neck failure, we found that this approach yielded excellent results, with only 11 patients (0.3%) having recurrence in the lateral compartment during the surveillance period. This compares favorably with the 2% to 20% range reported in the literature11,2224 and is below the 1.7% regional recurrence rate reported for papillary microcarcinomas.9 We believe that this favorable outcome is a product of the early sonographic detection of neck disease and a systematic surgical and interdisciplinary approach to cases when indicated.

We found that the preoperative sonographic status of the lateral neck compartment was a strong predictor of lateral neck disease-free interval. Despite the fact that US has a positive predictive value of 98% for detection of extension into the lateral neck,11 recent evidence suggest that it may have a limited sensitivity when microscopic nodal involvement is taken into consideration. In a large series of patients treated for papillary microcarcinoma, Ito et al24 found that preoperative US detected only 39% of the pathologically confirmed lateral lymph node metastasis and estimated that microscopic disease may be present in more than 30% of the sonographically negative lateral neck compartments. Interestingly, the evidence suggests that the clinical course of patients with sonographically positive neck disease differs from those with microscopic nodal involvement, despite their reported high frequency. This was addressed by Wada et al9 in a series of 590 patients treated for papillary microcarcinoma, where the rate of lateral neck recurrence was significantly higher in the group treated for sonographically positive disease, while there was no difference between those who had a prophylactic neck dissection and those observed in the group with a negative preoperative US finding. The authors concluded that there is no indication for elective surgical treatment of the lateral neck in patients with papillary microcarcinoma.

Ultrasonography allows to differentiate patients with macroscopic and microscopic disease, and this difference may prove critical in terms of the necessity of surgical treatment, sensitivity to adjuvant therapy, and ultimately for clinical outcome. Our current findings underscore the role of US as a selection tool to identify patients at higher risk of regional failure, who will require surgical treatment of the neck.

The quality of the high-resolution US may be affected by multiple variables. Ultimately, the quality is determined by the US machine, probe, technologist, interpretation of the radiologist, quality of needle aspirate, and cytologist interpretation. Any one of these components may drastically affect the utility of this approach to preoperative evaluation of patients with thyroid malignant disease.

In this series, the sonographic status of the ipsilateral and central compartments was a strong outcome predictor for recurrence-free interval in the lateral neck. A plausible explanation for this finding is related to its ability of US to detect minimal nodal changes and effectively act as a surrogate for disease burden in the neck. This hypothesis is further supported by the correlation between the number of sonographically abnormal compartments and the risk of long-term regional failure (Table 4). It is well known that the lateral neck is the second echelon for lymphatic spread in PTC and that the presence of positive lymph nodes in the central neck increases the risk of lateral neck disease.25 Even more, recent evidence correlates with the number of positive lymph nodes found in the central and contralateral compartment—a direct measure of disease burden—with the risk of involvement of the lateral neck.26

We found that T stage and distant metastasis at presentation were also associated with a higher rate of lateral neck recurrence. The association between primary tumor size and lateral neck failure has been previously described in multiple series.7,27 One of the accepted hypothesis for this association has been proposed by Noguchi et al,8 who stated that that the increase in neck recurrence could be secondary to the increased risk in extracapsular spread observed in larger tumors. Interestingly, both primary tumor size and the presence of extracapsular extension were found to be independent risk factors for lateral neck failure in a recent series.27 These findings suggest that other factors may be playing a role and further studies are needed to reach significant conclusions.

The impact of lymph node involvement in the risk of regional recurrence has been documented in multiple series, including the present.9,11 However, the impact of nodal extension on overall and DSS is not as clear and is still a matter of debate. Historically, it was thought that positive lymph nodes increased local recurrence but no survival which led to a conservative approach to lymphatic disease in PTC.28 This concept has been questioned in light of new evidence such as a large case-control study of 595 patients who died of differentiated thyroid cancer reported by Lundgren et al.29 In that study, the presence of lymph node disease at presentation was one of the few outcome predictors for DSS in multivariate analysis (odds ratio = 1.9). Our current findings further support the association between nodal disease at presentation and overall and DSS, regardless of the patient age at the time of diagnosis (Table 5).

Local or regional disease is rarely the cause of death in these patients; most of them will succumb to uncontrolled distant disease, which may be present at the time of the diagnosis in up to one-third of patients. Regional lymphatic metastases into the lateral neck compartments appear to be an indicator for the biological behavior and the distant metastatic potential of the disease. We found that the systematic use of appropriate surgical and adjuvant treatment in these patients rendered excellent results in terms of regional control. Survival appeared to be determined by the development and course of systemic disease and was not correlated with the locoregional disease status. We believe that preoperative neck US may have a role as an overall outcome predictor and could be used to identify patients who may benefit from more aggressive systemic treatment modalities or even novel therapeutic approaches.

Appropriate staging and surgical planning are essential in seeking successful outcomes in thyroid cancer. The long-term results presented in this series justify our conservative approach to the lateral neck compartment in PTC and validate current treatment recommendations of multidisciplinary guidelines.2,10

In conclusion, we found that preoperative US of the lateral neck is an excellent outcome predictor for lateral neck disease-free interval and for DSS in PTC. Tumor T stage, distant metastasis at presentation, and the number of abnormal neck compartments on US were associated with a higher rate of lateral neck failure. Overall, the sonographically based surgical approach to the lateral neck resulted in excellent results in terms of regional control, with an exceedingly low recurrence rate of 0.3%. These results validate current guidelines recommendations for initial sonographic survey of the lateral neck in PTC and the use of this information for the surgical management of these patients.

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Article Information

Correspondence: Gary L. Clayman, DMD, MD, Department of Head and Neck Surgery, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 1445, Houston, TX 77030 (gclayman@mdanderson.org).

Submitted for Publication: June 14, 2010; final revision received September 8, 2010; accepted October 19, 2010.

Author Contributions: Mr Siegel had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Moreno and Clayman. Acquisition of data: Moreno, Agarwal, de Luna, and Edeiken-Monroe. Analysis and interpretation of data: Moreno, Siegel, Sherman, Edeiken-Monroe, and Clayman. Drafting of the manuscript: Moreno, Agarwal, de Luna, and Clayman. Critical revision of the manuscript for important intellectual content: Siegel, Sherman, Edeiken-Monroe, and Clayman. Statistical analysis: Siegel. Administrative, technical, and material support: Moreno, Agarwal, and Edeiken-Monroe. Study supervision: Moreno and Clayman.

Financial Disclosure: None reported.

Funding/Support: This study received intradepartmental funding from The University of Texas M. D. Anderson Cancer Center.

Previous Presentation: This study was presented at the American Head and Neck Society 2009 Annual Meeting; May 30, 2009; Phoenix, Arizona.

References
1.
Heller  KS Do all cancers need to be treated? the role of thyroglobulin in the management of thyroid cancer: the 2006 Hayes Martin Lecture. Arch Otolaryngol Head Neck Surg 2007;133 (7) 639- 643
PubMedArticle
2.
Cooper  DSDoherty  GMHaugen  BR  et al. American Thyroid Association (ATA) Guidelines Taskforce on Thyroid Nodules and Differentiated Thyroid Cancer, Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid 2009;19 (11) 1167- 1214
PubMedArticle
3.
Mazzaferri  EL Management of a solitary thyroid nodule. N Engl J Med 1993;328 (8) 553- 559
PubMedArticle
4.
Dionigi  GDionigi  RBartalena  LBoni  LRovera  FVilla  F Surgery of lymph nodes in papillary thyroid cancer. Expert Rev Anticancer Ther 2006;6 (9) 1217- 1229
PubMedArticle
5.
Wang  TSDubner  SSznyter  LAHeller  KS Incidence of metastatic well-differentiated thyroid cancer in cervical lymph nodes. Arch Otolaryngol Head Neck Surg 2004;130 (1) 110- 113
PubMedArticle
6.
Kouvaraki  MAShapiro  SEFornage  BD  et al.  Role of preoperative ultrasonography in the surgical management of patients with thyroid cancer. Surgery 2003;134 (6) 946- 954, discussion 954-955
PubMedArticle
7.
Noguchi  SMurakami  NYamashita  HToda  MKawamoto  H Papillary thyroid carcinoma: modified radical neck dissection improves prognosis. Arch Surg 1998;133 (3) 276- 280
PubMedArticle
8.
Noguchi  SYamashita  HUchino  S Modified radical neck dissection is better than partial dissection of lymph nodes. World J Surg 2009;33 (3) 394- 396
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