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Impact of Nodal Metastases on Prognosis in Patients With Well-Differentiated Thyroid Cancer
Nigel J. P. Beasley, FRCS;
John Lee, BSc;
Spiro Eski, MD;
Paul Walfish, MD;
Ian Witterick, MD;
Jeremy L. Freeman, MD
Arch Otolaryngol Head Neck Surg. 2002;128:825-828.
ABSTRACT
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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.
INTRODUCTION
THE IMPACT of neck node metastases on the prognosis of patients with
well-differentiated thyroid carcinoma is uncertain.1-14
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  2
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 2) (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 2) (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).
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Demographics, by Stage, of Patients With Well-Differentiated Thyroid
Carcinoma
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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).
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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).
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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 2). 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.
AUTHOR 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{at}mtsinai.on.ca).
From the Departments of Otolaryngology, (Drs Beasley, Eski, Witterick,
and Freeman and Mr Lee) and Medicine (Dr Walfish), Mount Sinai Hospital, Toronto,
Ontario.
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