[Skip to Content]
[Skip to Content Landing]
Download PDF
A, Disease-free survival in patients with well-differentiated thyroid carcinoma by stage (P<.001, log-rank test). B, Disease-free survival by node location (P<.001, log-rank test). C, Overall survival by stage (P= .005, log-rank test).

A, Disease-free survival in patients with well-differentiated thyroid carcinoma by stage (P<.001, log-rank test). B, Disease-free survival by node location (P<.001, log-rank test). C, Overall survival by stage (P= .005, log-rank test).

Demographics, by Stage, of Patients With Well-Differentiated Thyroid Carcinoma
Demographics, by Stage, of Patients With Well-Differentiated Thyroid Carcinoma
1.
Akslen  LAMyking  AOSalvesen  HVarhaug  JE Prognostic importance of various clinicopathological features in papillary thyroid carcinoma. Eur J Cancer.1992;29A:44-51.
2.
Bacourt  FAsselain  BSavoie  JC  et al Multifactorial study of prognostic factors in differentiated thyroid carcinoma and a re-evaluation of the importance of age. Br J Surg.1986;73:274-277.
3.
Bellantone  RLombardi  CPBoscherini  M  et al Prognostic factors in differentiated thyroid carcinoma: a multivariate analysis of 234 consecutive patients. J Surg Oncol.1998;68:237-241.
4.
Cunningham  MPDuda  RBRecant  WChmiel  JSSylvester  JAFremgen  A Survival discriminants for differentiated thyroid cancer. Am J Surg.1990;160:344-347.
5.
Hannequin  PLiehn  JCDelisle  MJ Multifactorial analysis of survival in thyroid cancer: pitfalls of applying the results of published studies to another population. Cancer.1986;58:1749-1755.
6.
Hughes  CJShaha  ARShah  JPLoree  TR Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck.1996;18:127-132.
7.
Kerr  DJBurt  ADBoyle  PMacFarlane  GJStorer  AMBrewin  TB Prognostic factors in thyroid tumours. Br J Cancer.1986;54:475-482.
8.
Lerch  HSchober  OKuwert  TSaur  HB Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol.1997;15:2067-2075.
9.
Mazzaferri  ELJhiang  SM Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med.1994;97:418-428.
10.
McConahey  WMHay  IDWoolner  LBvan Heerden  JATaylor  WF Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc.1986;61:978-996.
11.
Shah  JPLoree  TRDharker  DStrong  EWBegg  CVlamis  V Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg.1992;164:658-661.
12.
Sellers  MBeenken  SBlankenship  A  et al Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg.1992;164:578-581.
13.
Steinmuller  TKlupp  JRayes  N  et al Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg.2000;166:29-33.
14.
Tennvall  JBiorklund  AMoller  TRanstam  JAkerman  M Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer.1986;57:1405-1414.
Original Article
July 2002

Impact of Nodal Metastases on Prognosis in Patients With Well-Differentiated Thyroid Cancer

Author Affiliations

From the Departments of Otolaryngology, (Drs Beasley, Eski, Witterick, and Freeman and Mr Lee) and Medicine (Dr Walfish), Mount Sinai Hospital, Toronto, Ontario.

Arch Otolaryngol Head Neck Surg. 2002;128(7):825-828. doi:10.1001/archotol.128.7.825
Abstract

Objectives  To study the clinical and pathological variables predicting lymph node metastases in patients with well-differentiated thyroid carcinoma and to examine the impact of these metastases on recurrence and survival.

Design  Cohort study. Median follow-up, 56 months.

Setting  Tertiary referral university teaching hospital.

Patients  The study included 522 consecutive patients with well-differentiated thyroid carcinoma treated between 1964 and 1999. Data were collected on age, sex, family history of thyroid disease, prior radiation exposure, stage of disease, pathological diagnosis, size of tumor, multifocality of disease, recurrence, and survival.

Intervention  Total thyroidectomy and postoperative iodine 131 ablation.

Main Outcome Measures  Disease-free and overall survival.

Results  A total of 347 patients with stage I disease and 118 with stage II disease were identified. The median age of patients with neck disease was 3 years younger than those without neck disease and most had papillary carcinoma. Patients with multifocal disease were more likely to have neck disease (P = .02). On univariate analysis, disease-free and overall survival rates were significantly lower in patients who presented with neck node metastases (P<.001 and P = .005); this difference in survival remained highly significant on multivariate analysis for disease-free survival (P = .001), with a relative hazard of 6.27.

Conclusions  When treated with total thyroidectomy and routine postoperative iodine 131 ablation, patients with well-differentiated thyroid carcinoma who present with neck node metastases outside the central compartment of the neck have an approximately 6-fold risk of developing recurrences, most of which occur in the neck.

THE IMPACT of neck node metastases on the prognosis of patients with well-differentiated thyroid carcinoma is uncertain.114 Many of the earlier studies mixed patients with thyroid carcinoma of different histological types and grades, making an interpretation of results difficult. Three major centers have published their results in the last 15 years, specifically looking at the impact of patient and tumor factors on recurrence and survival in well-differentiated thyroid carcinoma. Each has adopted a different approach to the management of this tumor.

In 1986, McConahey et al10 reported on a series of 859 patients with well-differentiated thyroid carcinoma who were treated with total thyroidectomy at the Mayo Clinic, Rochester, Minn. There was no significant difference in recurrence or survival in patients with or without neck node metastases. In 1992, Shah et al11 reported on a series of 931 patients who were treated in most cases with hemithyroidectomy at Memorial Sloane-Kettering Cancer Center, New York, NY. Again, the presence of neck node metastases had no impact on recurrence or survival. In neither series was the administration of postoperative iodine 131 ablation routine. A more detailed, matched-pair analysis of the series from the Memorial Sloane-Kettering Cancer Center published in 1996 confirmed that the presence of neck node metastases had no impact on recurrence or survival except in the older population.6 In 1994, Mazzaferri and Jhiang9 reported on a series of 1355 patients with well-differentiated thyroid carcinoma who were treated with total thyroidectomy and routine postoperative iodine 131 ablation at The Ohio State University, Columbus. The presence of neck node metastases was an independent predictor of recurrence and survival in this series.

Our goal was to study the clinical and pathological variables predicting lymph node metastases in patients with well-differentiated thyroid carcinoma and to examine the impact of these metastases on disease-free and overall survival in a series of patients who were treated in a consistent fashion by 3 surgeons and 1 endocrinologist at Mount Sinai Hospital in Toronto, Ontario.

PATIENTS AND METHODS

We reviewed the charts of 522 consecutive patients with well-differentiated thyroid carcinoma who were treated at Mount Sinai Hospital between 1964 and 1999. The patients were treated according to a standard protocol, with all patients undergoing total thyroidectomy unless their disease was unifocal and less than 1 cm in diameter and they had no history of radiation exposure. The patients with unifocal occult carcinoma underwent hemithyroidectomy and isthmusectomy alone and were included in the study as patients with stage I disease. The patients with neck node metastases that were preoperatively or intraoperatively palpable underwent regional neck dissection. All patients who underwent total thyroidectomy received an empirical dose of radioactive iodine ablation 6 weeks after surgery. The patients with extrathyroidal disease or extracapsular spread in metastatic neck nodes were considered for external beam radiation to the neck on an individual basis. The patients received sufficient doses of thyroxine to suppress thyrotropin levels and were followed up clinically and with yearly determinations of thyroglobulin levels to detect recurrence.

Data were collected on each patient's age, sex, family history of thyroid disease, prior radiation exposure, stage of disease (stage I, intrathyroidal disease; stage II, intrathyroidal disease with neck node metastases; stage III, extrathyroidal disease; and stage IV, presence of distant metastases), nodal disease location, pathological diagnosis, size of tumor, multifocality of disease, recurrence, location of recurrence, cause of death, and length of survival.

Patients with extrathyroidal extension or distant metastases were excluded from the statistical analysis so that the variables predicting neck nodes disease and the effect of this on recurrence and survival could be determined independently of these poor prognostic factors. For patients with stage I and stage II disease, the difference in age and tumor size was compared using the Mann-Whitney U test. A Pearson χ2 test was used to look for an association between the presence of nodal metastases and patients' sex, family history of thyroid disease, prior radiation exposure, pathological diagnosis, and the presence of multifocal disease. Multivariate analysis was carried out using multiple logistic regression. Comparison between the disease-free and overall survival rates in patients with stage I and II disease were calculated using the Kaplan-Meier method and a log-rank test for univariate analysis and the Cox proportional hazards model for multivariate analysis. The Kaplan-Meier method and the log-rank test were used to carry out a separate analysis comparing disease-free survival in patients who presented with stage I disease; stage II disease limited to the central compartment of the neck, ie, paratracheal or anterior laryngeal nodes; or stage II disease in the superior mediastinum, lateral aspect of the neck, or multiple sites.

RESULTS

A total of 347 patients presented with stage I disease (intrathyroidal disease) and 118 with stage II disease (intrathyroidal disease with neck nodes metastases). The nodal metastases were located in the central compartment of the neck (paratracheal or anterior laryngeal) in 44 cases, superior mediastinum in 7 cases, and lateral aspect of the neck (levels 2, 3, 4, and 5) in 28 cases; multiple sites were involved in 23 cases. In 16 cases, the location of the nodes could not be determined from the chart.

The median age of patients with neck disease was 3 years younger than those without (Table 1). Although the difference is small, it is significant (n = 465, P = .007, Mann-Whitney test) because of the large number of patients in the series. There was no significant difference in the sex of the patients, their family history of thyroid disease, or their history of radiation exposure (Table 1). As expected, most patients with neck node metastases had papillary carcinoma, and the difference was highly significant (n = 447; P = .001, Pearson χ2) (Table 1). The tumor size did not significantly predict the presence of neck node metastases, but patients with multifocal disease were more likely to have neck disease (n = 431; P = .02, Pearson χ2) (Table 1). Multivariate analysis confirmed the strong relationship between neck node disease and papillary carcinoma (P = .001, multiple logistic regression). The relationship between age and neck node status was no longer significant (P = .36, multiple logistic regression). Almost all cases of multifocal pathology had papillary carcinoma (data not shown), so the multivariable analysis to assess the strength of this variable in predicting neck node disease was carried out only in patients with papillary carcinoma. The presence of multifocal disease remained a significant predictor of neck node disease in these patients (P = .02, multiple logistic regression).

Recurrence data were available on 269 patients with stage I disease and on 109 patients with stage II disease. Disease-free survival rates were lower in patients with well-differentiated thyroid carcinoma who presented with neck node metastases (P<.001, log-rank test) (Figure 1, A). The relationship remained highly significant on multivariate analysis (P = .001, Cox regression; relative hazard, 6.27; 95% confidence interval, 3.33-11.81), including stage of disease, age of patient, size of nodule, tumor pathology, and multifocality in the analysis. The median follow-up for patients without recurrence was 56 months (range, 3-387 months), and the median time to recurrence was 13.5 months (range, 1-354 months).

When the effect of neck node disease was broken down to examine the location of the nodes that are significantly predictive of recurrence, it became evident that patients with nodes in the superior mediastinum and lateral neck area and those with multiple nodal site involvement have significantly worse disease-free survival rates than patients with only central compartment nodes (P = .003, log-rank test) and those with no nodal disease (P<.001, log-rank test) (Figure 1, B). This difference in disease-free survival between patients with central compartment and other neck node disease remained significant on multivariate analysis (P = .02, Cox regression), with the same variables included as those mentioned above. There was no significant difference in disease-free survival between patients with central compartment nodes and those without neck nodes at presentation (P = .15, log-rank test).

Of the 37 patients with stage I disease, 8 had a local recurrence, 15 had a recurrence in the neck, and 1 had a recurrence at a distant site; the location was unknown in 13 patients. Of the 45 patients with stage II disease, 2 had a local recurrence, 30 had a recurrence in the neck, and 2 had a recurrence at a distant site; the location was unknown in 11 patients. There was a significant association between neck disease at presentation and recurrence in the neck (P = .02, Pearson χ2). Subclinical recurrence was treated with iodine 131 ablation and close monitoring of the patient for evidence of gross disease. Palpable recurrence or disease seen radiologically was treated surgically with postoperative iodine 131 ablation.

Stage I disease was controlled over the long-term in all patients. Three patients with stage 2 disease died eventually of their disease: 2 of distant metastases and 1 of local disease. In the analysis of overall survival, the presence of neck disease at presentation had an adverse effect on overall survival (P = .005, log-rank test) (Figure 1, C). The effect was lost on multivariate analysis (P = 0.73, Cox regression) owing to the small number of deaths in this series.

COMMENT

The ability of papillary carcinoma of the thyroid to spread to regional lymph nodes is well known. Patients may present because of an enlarged neck node rather than because of the primary tumor itself. The present study demonstrates that patients with neck node metastases are more likely to have multifocal disease, suggesting that these cancers may have increased metastatic potential. Although on univariate analysis the age of the patients with neck disease was significantly younger than those without neck disease, this difference is not clinically relevant and is a result of the large number of patients who were included in the series; the statistical significance was lost on multivariate analysis. There was no significant difference in nodal metastases when the patients' sex, family history of thyroid disease, or history of radiation exposure was considered.

This study also shows that the presence of neck node metastases in patients with well-differentiated thyroid carcinoma who are treated with total thyroidectomy and routine postoperative iodine 131 ablation carries an approximately 6-fold risk of recurrence, with most recurrences occurring in the neck. This effect is significant only in patients with regional disease at a distance from the thyroid, eg, those with disease in the mediastinum or lateral neck area. On univariate analysis, the presence of neck disease also appeared to have a significant impact on overall survival in these patients, but the number of patients who died was small, making the analysis unreliable, and the effect was lost on multivariate analysis.

These findings contrast with the results of McConahey et al10 and Shah et al,11 but they agree with those of Mazzaferri and Jhiang,9 whose patients were treated in a similar way, ie, with total thyroidectomy and postoperative iodine 131 ablation. Some of the differences observed between series may be attributable to the different treatment approaches used in the various institutions. Hannequin et al5 noted that it was not possible to apply prognostic indexes from one population to another in cases involving thyroid carcinoma.

The results from our study suggest that if neck node metastases are found outside the central compartment of the neck in patients with well-differentiated thyroid carcinoma, particular attention should be paid to the detection of recurrent disease. In our hospital, this is done with 6 monthly clinical examinations and annual serum thyroglobulin measurement. In those patients with an undetectable serum thyroglobulin level, a 3-week thyroxine withdrawal–thyroglobulin stimulation test is performed. Whether this follow-up regimen has a significant impact on survival is unknown and will require continued examination of this series of patients over a longer period of time.

Back to top
Article Information

Accepted for publication November 30, 2001.

We are grateful to Temmy Latner/Dynacare, Toronto, Ontario, for financial support.

This study was presented in part at the 55th Annual Meeting of the Canadian Society of Otolaryngology, Vancouver, British Columbia, May 29, 2001.

Corresponding author and reprints: Jeremy L. Freeman, MD, Department of Otolaryngology, Mount Sinai Hospital, Toronto, Ontario, Canada M5G 1X5 (e-mail: jfreeman@mtsinai.on.ca).

References
1.
Akslen  LAMyking  AOSalvesen  HVarhaug  JE Prognostic importance of various clinicopathological features in papillary thyroid carcinoma. Eur J Cancer.1992;29A:44-51.
2.
Bacourt  FAsselain  BSavoie  JC  et al Multifactorial study of prognostic factors in differentiated thyroid carcinoma and a re-evaluation of the importance of age. Br J Surg.1986;73:274-277.
3.
Bellantone  RLombardi  CPBoscherini  M  et al Prognostic factors in differentiated thyroid carcinoma: a multivariate analysis of 234 consecutive patients. J Surg Oncol.1998;68:237-241.
4.
Cunningham  MPDuda  RBRecant  WChmiel  JSSylvester  JAFremgen  A Survival discriminants for differentiated thyroid cancer. Am J Surg.1990;160:344-347.
5.
Hannequin  PLiehn  JCDelisle  MJ Multifactorial analysis of survival in thyroid cancer: pitfalls of applying the results of published studies to another population. Cancer.1986;58:1749-1755.
6.
Hughes  CJShaha  ARShah  JPLoree  TR Impact of lymph node metastasis in differentiated carcinoma of the thyroid: a matched-pair analysis. Head Neck.1996;18:127-132.
7.
Kerr  DJBurt  ADBoyle  PMacFarlane  GJStorer  AMBrewin  TB Prognostic factors in thyroid tumours. Br J Cancer.1986;54:475-482.
8.
Lerch  HSchober  OKuwert  TSaur  HB Survival of differentiated thyroid carcinoma studied in 500 patients. J Clin Oncol.1997;15:2067-2075.
9.
Mazzaferri  ELJhiang  SM Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med.1994;97:418-428.
10.
McConahey  WMHay  IDWoolner  LBvan Heerden  JATaylor  WF Papillary thyroid cancer treated at the Mayo Clinic, 1946 through 1970: initial manifestations, pathologic findings, therapy, and outcome. Mayo Clin Proc.1986;61:978-996.
11.
Shah  JPLoree  TRDharker  DStrong  EWBegg  CVlamis  V Prognostic factors in differentiated carcinoma of the thyroid gland. Am J Surg.1992;164:658-661.
12.
Sellers  MBeenken  SBlankenship  A  et al Prognostic significance of cervical lymph node metastases in differentiated thyroid cancer. Am J Surg.1992;164:578-581.
13.
Steinmuller  TKlupp  JRayes  N  et al Prognostic factors in patients with differentiated thyroid carcinoma. Eur J Surg.2000;166:29-33.
14.
Tennvall  JBiorklund  AMoller  TRanstam  JAkerman  M Is the EORTC prognostic index of thyroid cancer valid in differentiated thyroid carcinoma? retrospective multivariate analysis of differentiated thyroid carcinoma with long follow-up. Cancer.1986;57:1405-1414.
×