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Nodal Metastasis in Major Salivary Gland Cancer
Predictive Factors and Effects on Survival
Neil Bhattacharyya, MD;
Marvin P. Fried, MD
Arch Otolaryngol Head Neck Surg. 2002;128:904-908.
ABSTRACT
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Objectives To determine how regional nodal metastasis affects survival in patients
with major salivary gland malignancy and to identify clinical predictors for
nodal disease.
Methods Major salivary gland cancer cases with nodal sampling were identified
from the Surveillance, Epidemiology, and End Results cancer database for 1988
through 1998. Kaplan-Meier survival analysis was conducted to compare patients
with and without histopathologic evidence of nodal disease. Multivariate logistic
regression analysis was used to determine the influence of clinical predictors
on the presence of regional nodal disease.
Results A total of 1268 patients with major salivary gland malignancy and regional
node sampling were identified. Mean age at diagnosis was 58.3 years, with
a male-female ratio of 1:4. Mean tumor size was 3.0 cm. Overall mean survival
time was 83 months (95% confidence interval, 80-87 months). Patients with
no evidence of nodal cancer had significantly improved survival over patients
with any pathologically positive nodes (mean survival time, 100 months vs
59 months, respectively; P<.001). Patient age,
tumor histopathologic type, facial nerve involvement, extraglandular involvement,
tumor grade, and tumor size were significant clinical predictors of nodal
disease. Facial nerve involvement, tumor grade, and squamous cell carcinoma
subtype exhibited the highest increased odds ratios for nodal metastasis.
Conclusions Nodal disease significantly decreases survival in patients with major
salivary gland malignancy. Tumor histopathologic type, facial nerve involvement,
extraglandular tumor extension, and tumor grade are the most important predictors
of nodal disease.
INTRODUCTION
MALIGNANT TUMORS of the salivary glands constitute approximately 1%
to 3% of all head and neck malignancies and only 0.3% of all malignant neoplasms.1 Because of their relative rarity, it is often hard
to quantify survival and determine prognostic factors for these tumors. Most
published studies reflect institutional experiences over the course of 2 or
3 decades, with relatively small overall sample sizes.
It is well known that survival in head and neck cancer, especially for
mucosal squamous cell carcinoma, is strongly dependent on the disease status
of the neck. In several series, the finding of positive neck nodes was associated
with a decrease in survival ranging from 30% to 50% compared with patients
with no evidence of metastatic neck disease.2-4
However, for major salivary gland malignancy, management of the neck has received
considerably less attention. Some authors recommend routine neck dissection
for known salivary gland malignancy, whereas others recommend neck dissection
only for obvious nodal disease or for certain tumor histopathologic types.
We sought to determine the effect of nodal metastasis on survival in
patients with major salivary gland malignancy. Furthermore, we sought to determine
clinical factors that would predict the presence or absence of nodal metastasis
from major salivary gland cancer. Identification of such predictive clinical
factors could assist in selecting appropriate patients for planned neck dissection
in the setting of major salivary gland cancer.
SUBJECTS AND METHODS
For our analysis, we used the Surveillance, Epidemiology, and End Results
(SEER) Program Public-Use CD-ROM (1973-1998), National Cancer Institute, Bethesda,
Md, Division of Cancer Control and Population Sciences, Cancer Surveillance
Research Program, Cancer Statistics Branch, released April 2001, based on
the August 2000 submission. We searched the 1988-1998 period to identify all
patients with malignancies of the major salivary glands (parotid gland, submandibular
gland, and/or sublingual gland). From this data set, patients who had evidence
of at least 1 regional node sampled as part of their evaluation and management
were identified. The data were then imported into the Statistical Package
for the Social Sciences version 10.0 (SPSS Inc, Chicago, Ill) for subsequent
processing. Kaplan-Meier survival analysis was used to compare patients in
whom no positive nodes were identified among the sampled nodes and patients
in whom at least 1 positive node was identified. Survival curves were compared
using the log-rank statistic with P<.05 considered
significant.
The tumors were categorized into 1 of 8 histologic categories based
on the International Classification of Diseases for Oncology5 as summarized in Table 1. Frequency and descriptive summary data were computed for
each of the potential clinical variables. The following were chosen as predictor
variables for the outcome of at least 1 positive regional node: patient age,
patient sex, tumor grade, tumor histopathologic type, tumor size, facial nerve
involvement, and extraglandular tumor involvement. These variables were selected
as predictor variables because they can often be preoperatively determined
from the physical examination, preoperative radiologic studies, and cytopathologic
analysis and can therefore be used to predict the extent of surgery. To determine
the effects of these predictor variables on regional nodal disease, we conducted
multivariate logistic regression analysis using a backward stepwise likelihood
ratio method with threshold P values of .10 for variable
entry and .05 for variable exclusion. Odds ratios and associated confidence
intervals (CIs) were computed for the statistically significant predictor
variables.
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Table 1. Histopathologic Distribution of Major Salivary Gland Malignancies
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RESULTS
From the SEER database for the 10-year period 1988 through 1998, 1268
patients were identified with malignancy of the major salivary glands and
at least 1 regional node sampled. There were 535 women (42.2%) and 733 men
(57.8%), with a mean age at diagnosis of 58.3 years (SD, 17.9 years). The
mean tumor size at the time of diagnosis was 3.0 cm (SD, 1.9 cm). Patients
had a mean of 10.7 nodes sampled, with a mean of 2.1 nodes pathologically
positive for tumor metastasis. Overall, 748 patients (59.0%) had nodes sampled,
but no positive nodes were found on subsequent pathologic analysis. The mean
Kaplan-Meier survival for the overall group was 83 months (95% CI, 80-87 months).
Among patients with malignancy of the major salivary glands, the presence
or absence of pathologically positive nodal disease was a significant predictor
of survival. Patients with no pathologic evidence of nodal disease exhibited
a mean survival of 100 months (95% CI, 96-104 months), whereas patients with
nodal disease exhibited a mean survival of 59 months (95% CI, 54-64 months; P<.001). These data are graphically depicted in Figure 1. Summaries of the distributions
of histopathologic tumor type and histopathologic grade are given in Table 1 and Table 2. Among squamous cell carcinomas, 12% were well differentiated,
29% were moderately differentiated, 45% were poorly differentiated or undifferentiated,
and the remainder were not graded.
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Kaplan-Meier survival functions for patients with and without positive
nodal disease in major salivary gland malignancy.
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Table 2. Histopathologic Grade of Major Salivary Gland Malignancies
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Logistic regression analysis was conducted to determine predictive factors
associated with positive nodal disease in this patient population. The results
of the logistic regression analysis are given in Table 3. Age at diagnosis, histopathologic tumor type, facial nerve
involvement, extraglandular involvement, tumor grade, and tumor size were
each found to be significant independent predictors for positive nodal disease.
Specifically, adenocarcinoma and squamous cell carcinoma had significantly
increased odds ratios for metastatic nodal disease (increase in odds of 2.0
and 2.2, respectively). Increasing tumor grade, facial nerve involvement,
and extraglandular extension also strongly predicted nodal metastasis. Increasing
age at diagnosis and tumor size were statistically significant but numerically
weak predictors based on their odds ratios. Patient sex showed no effect on
the presence of nodal disease.
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Table 3. Results of Logistic Regression Analysis for the Presence of
Nodal Disease
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COMMENT
Malignant tumors of the major salivary glands are fairly rare, even
among head and neck lesions. Given their relative infrequency, it is difficult
to determine predictors of survival for patients with major salivary gland
malignancy in single-institutional patient series. The SEER database is a
national tumor registry maintained by the National Cancer Institute that samples
several US geographic areas and represents an estimated 10% of the US population.
Through active and passive follow-up mechanisms, the database provides high
accuracy and rigorous follow-up on several million cancers. Therefore, the
SEER registry serves as an excellent source for the study of relatively rare
tumors such as major salivary gland malignancies. This registry has been used
to examine incidences, trends, and survival for several head and neck neoplastic
conditions.6-8
Treatment for major salivary gland malignancy in most instances includes
surgery with or without postoperative radiation therapy, depending on the
histopathologic type and grade of the original tumor, status of the surgical
margins, and the presence or absence of regional disease. Based on the Kaplan-Meier
analysis of the survival difference between patients with no pathologically
positive regional adenopathy and patients with positive regional adenopathy,
it is clear that the presence of positive nodal disease has a significant
influence on overall survival in major salivary gland malignancy, regardless
of subsequent additional therapy. The presence of positive nodal disease decreased
mean survival in patients with major salivary gland malignancy by more than
50%. Given this effect, the ability to predict nodal involvement and appropriately
treat patients with positive regional nodal disease could have a significant
effect on survival. Such regional treatment could include either surgery,
usually in the form of a neck dissection, or regional radiotherapy. Ideally,
for most salivary gland malignancy, complete surgical extirpation of local
and regional disease prior to radiotherapy is desirable.
Treatment of the neck in major salivary gland malignancy has been somewhat
controversial. Some investigators recommend neck dissection only for patients
with clinically evident regional disease, whereas others reserve neck dissection
for tumors based on various prognostic factors. Still others recommend routine
elective neck dissection. Several authors have attempted to determine predictive
factors for cervical metastasis in salivary gland malignancy. In a study of
145 patients with parotid gland carcinoma, Regis de Brito Santos and colleagues9 found that histologic tumor type, size of the primary
lesion, and desmoplasia were significant predictors of neck node metastasis.
Similarly, Kelley and Spiro10 found that the
presence of pathologically positive lymph nodes in parotid gland carcinoma
had a significant negative effect on overall survival. Based on their analysis
of neck node metastases in 121 patients with parotid gland carcinoma, they
recommended neck dissection for patients with obvious clinical nodal involvement
or those patients with a large primary tumor size, histologic indications,
or high tumor grade. In a multivariate analysis of patients who had elective
lymph node dissection for parotid gland malignancy, Frankenthaler and associates11 identified facial nerve paralysis, tumor grade, older
patient age, lymphatic invasion, and extraparotid tumor extension as predictors
of occult cervical metastasis. Other authors have confirmed neck node involvement
and tumor size to be major prognostic factors.12-13
For our logistic regression analysis, with the goal of predicting regional
nodal metastatic disease, we selected clinical variables that are often available
to the clinician prior to surgical extirpation of the primary tumor. If the
likelihood of regional nodal disease could be predicted, concurrent neck dissection
might be planned at the time of resection of the primary tumor, which could
provide additional prognostic information and afford improved survival.
Although we identified increasing patient age and size of the primary
tumor to be statistically significant multivariate predictors of positive
nodal disease, their odds ratios indicate that the influence of these variables
is quite small. Only when tumor sizes approach 5.0 cm do the odds for positive
nodal metastasis increase 2-fold. We did not find male sex to be independent
predictor for nodal disease, although other researchers have identified male
sex as a negative overall survival predictor.10
Very often, the histologic type of the salivary gland malignancy can
be determined by preoperative fine-needle aspiration cytologic analysis.14 Our data highlight a significant potential advantage
of using fine-needle aspiration to identify malignant tumors prior to the
initial surgical extirpation. If the histopathologic type can be determined
preoperatively, this information may be used to determine if a neck dissection
is warranted. Our data suggest that adenocarcinomas and squamous cell carcinomas
of the major salivary glands should be considered for neck dissection based
on significantly increased odds ratios for nodal involvement. Although mucoepidermoid
carcinoma alone was not associated with nodal metastasis, high-grade mucoepidermoid
carcinomas should be considered for treatment of the neck because of the independent
influence of tumor grade on nodal metastasis. Increased odds for nodal involvement
in high-grade mucoepidermoid carcinoma have been confirmed by others.15-16 Similarly, the association between
squamous cell carcinoma of the parotid gland and probable nodal metastasis
has also been demonstrated by others, with positive nodal disease rates approximating
40%.17 Our data also indicate that sarcomas,
adenoid cystic carcinoma, and other histologic types are unlikely to involve
nodal disease, and neck dissection may be avoided in these cases in the absence
of obvious clinical disease.18
Tumor grade was found to be a significant independent predictor of nodal
metastasis on multivariate analysis. Each stepwise increase in tumor grade
from grade 1 (well-differentiated) through grade 4 (undifferentiated) conferred
increased odds of positive nodal metastatic disease of almost 2-fold. For
example, a grade 3 tumor has a 4-fold increase in odds of involving nodal
disease over a grade 1 tumor. Our data strongly suggest that tumors with higher
histopathologic grade be considered for treatment of the neck, reinforcing
the recommendations of others.19-21
The likely exceptions to this are adenoid cystic carcinoma and acinic cell
carcinoma, in which the grade of the tumor seems to have limited effect.22 Facial nerve involvement (odds ratio, 2.3) and extraglandular
tumor extent (odds ratio, 1.7) were also found to be very strong predictors
of positive nodal disease, and patients with these clinical factors should
also be strongly considered for treatment of the neck.
This study has several limitations. First, the patient population in
this study is likely to be biased toward more severe overall disease because
one of the selection criteria for cases was operative sampling of locoregional
nodes. Given that most clinicians perform neck dissection or sample the local
nodes when they suspect more severe disease, based on either the tumor histologic
findings or the extent of the primary tumor, these patients are likely to
represent a more diseased population. Therefore, the data likely represent
a "worst-case scenario" for patients with major salivary gland malignancy.
Second, because the SEER database is a national tumor registry, there
is probably variability in the extent of treatment assessment it records.
For example, the nodal sampling may have arisen from a selective upper jugular
neck dissection (eg, regions I-III) in one patient and a comprehensive neck
dissection (eg, regions I-V) in another. Other authors have shown that the
extent of the neck dissection is directly related to the number of overall
nodes and positive nodes recovered, and that supraomohyoid neck dissections
recover on average approximately 10 nodes.23
Given that the overall mean number of nodes sampled was approximately 11,
we believe that most of the patients in this series had relatively thorough
regional lymphadenectomies rather than simple isolated nodal sampling.
Because cervical metastases from major salivary gland malignancy significantly
influence survival, treatment of the neck deserves consideration in each newly
diagnosed case. The neck may be treated with postoperative radiation therapy,
or it may be addressed with neck dissection at the time of primary site surgery.
The decision to subject patients to the potential (but likely limited) morbidity
of neck dissection in treatment of major salivary gland cancer depends on
the ability to predict which patients are likely to have pathologically positive
nodal disease. Our data may be helpful in determining whether to perform a
neck dissection as part of the surgical treatment of major salivary gland
malignancy. For example, based on our data, patients who are deemed to have
extraglandular extension or high tumor grade should be considered for neck
dissection at the time of surgery for the primary site. Similarly, patients
with adenocarcinoma or squamous cell carcinoma, especially with poor grade,
should undergo neck dissection because they are significantly more likely
than patients with other types of cancer to have nodal disease in the neck.
Patients who have no pathologic evidence of nodal metastasis after neck dissection
may then be spared subsequent radiation therapy to the neck and its attendant
morbidities.
In conclusion, the presence of positive nodal disease confers a greater
than 50% decrease in mean survival in patients with major salivary gland malignancy.
Therefore, patients in whom facial nerve involvement, extraglandular tumor
extension, and high tumor grade are identified should be considered for neck
dissection. Similarly, patients with histologically diagnosed squamous cell
carcinoma or adenocarcinoma of the major salivary glands should also be considered
for surgical treatment of the neck, whereas patients with adenoid cystic carcinoma
or sarcomas may be able to avoid neck dissection and their conditions managed
by close observation.
AUTHOR INFORMATION
Accepted for publication February 13, 2002.
Corresponding author: Neil Bhattacharyya, MD, Division of Otolaryngology,
333 Longwood Ave, Boston, MA 02115.
From the Division of Otolaryngology, Brigham & Women's Hospital,
Harvard Medical School, Boston, Mass (Dr Bhattacharyya); and Department of
Otolaryngology, Montefiore Medical Center, Albert Einstein College of Medicine,
New York, NY (Dr Fried).
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