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Multivariate Analysis of Risk Factors for Neck Metastases in Surgically Treated Parotid Carcinomas
Izandro Régis de Brito Santos, MD;
Luiz P. Kowalski, MD, PhD;
Vera Cavalcante de Araujo, DDS, PhD;
Angela Flávia Logullo, MD, PhD;
José Magrin, MD, PhD
Arch Otolaryngol Head Neck Surg. 2001;127:56-60.
ABSTRACT
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Objective To analyze risk factors for neck metastases in patients with parotid
carcinomas.
Design Cohort of patients followed up from 1 to 366.2 months at a single institution.
Setting Referral center, private or institutional practice, hospitalized care.
Patients A total of 145 patients with parotid carcinomas with complete clinical
and pathological information. The histological diagnosis was reviewed according
to the World Health Organization classification for salivary gland tumors.
Intervention Patients were treated by surgery alone (62 cases) or with postoperative
radiotherapy (83 cases). A neck dissection was performed in 80 patients.
Main Outcome Measure Rates of neck lymph node metastasis. Univariate and multivariate analyses
were carried out using logistic regression evaluating the significance of
demographic, clinical, and pathological data.
Results The following variables were significantly associated to the risk of
lymph node metastasis by univariate analysis: histological type (P<.001), T stage (P<.001), desmoplasia
(P = .001), facial palsy (P
= .02), perineural invasion (P = .01), extraparotid
tumor extension (P = .02), and necrosis (P = .003). By multivariate analysis, histological type (P<.001), T stage (P = .03), and desmoplasia
(P = .006) had the highest correlation with lymph
node metastasis.
Conclusion The significant risk factors for neck metastasis in parotid carcinoma
were histological type (ie, adenocarcinoma, undifferentiated carcinoma, high-grade
mucoepidermoid carcinoma, squamous cell carcinoma, and salivary duct carcinoma),
T stage (T3 and T4), and desmoplasia (severe).
INTRODUCTION
SALIVARY GLAND tumors are rare and represent 0.3% of all malignant neoplasias.
The vast majority have epithelial origin.1
Seventy percent of all salivary gland neoplasias are at the parotid gland
with a reported percentage of malignancy varying from 17% to 34%. The heterogeneity
and great diversity in histological types along with the rarity of malignant
subtypes have lead to the individualized and controversial treatment of these
patients.2, 3 Tumor extent, neck
metastases, pain at presentation, aged older than 55 to 60 years, and being
male have all been considered poor prognostic indicators,4, 5, 6
as well as the microscopic features of cellular atypia, desmoplasia, and a
high mitotic index.7 Patients with acinic cell
carcinoma and mucoepidermoid carcinoma have a better prognosis when compared
with patients with adenocarcinoma, malignant mixed tumor, adenoid cystic carcinoma,
squamous cell carcinoma, and undifferentiated carcinoma.7
Surgery is the main treatment modality and the type of resection, whether
partial or total parotidectomy, with preservation or sacrifice of the facial
nerve, depends on tumor location, size, and extent.8, 9
The incidence of lymph node metastases in parotid carcinomas at the time of
initial presentation varies from 12.4% to 24%.1, 6, 7, 10
There is no doubt regarding the indications of neck dissection in clinically
positive lymph nodes of the neck. However, the question does remain for patients
with stage N0 neck. Indications for elective neck treatment (neck dissection
or radiotherapy) are unclear.11 Patients with
neck recurrences have a poor prognosis, since treatment in this group is inefficient
and relapse is unlikely to be salvaged.
The specific point of interest in this article is to analyze demographic,
clinical, and histopathological data to determine which were the N0-staged
patients at a high risk for occult metastasis who could potentially benefit
from elective neck treatment.
PATIENTS AND METHODS
All cases of malignant parotid neoplasias treated at the Department
of Head and Neck Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa
Hospital do Câncer A. C. Camargo, São Paulo, Brazil, from November
30, 1965, to March 21, 1992, were reviewed. One hundred forty-five patients
with the diagnosis of primary malignant epithelial tumors of the parotid gland
were eligible for this study. Melanomas, lymphomas, sarcomas, and metastatic
carcinomas were excluded. We also included previously operated on patients
whenever enough demographic, pathological, therapeutic, and clinical information
were recovered. The patients were retrospectively staged according to American
Joint Committee on Cancer classification (1997 version)12
(Table 1). Hematoxylin-eosin–stained
slides were analyzed and histopathological diagnoses reviewed by 2 pathologists
(V.C.A. and A.F.L.) adopting the World Health Organization classification
for salivary gland tumors.13 Whenever there
was disagreement between diagnoses, the slides were analyzed by a third pathologist.
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Table 1. Staging Systems for Major Salivary Gland Malignancy*
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There were 80 male (55.2%) and 65 female patients (44.8%), ranging in
age from 2 to 82 years (median age, 53 years). The presence of a mass in the
parotid region, the most frequent complaint, was reported for 141 patients
(97.2%). Duration of complaint ranged from 1 to 480 months. Regarding tumor
staging, 9 (6.3%) were classified as T1; 28 (19.3%), T2; 47 (32.4%), T3; 36
(24.8%), T4; and 25 (17.2%). TX. Clinical lymph node involvement was present
in 38 (23.5%) of the 145 patients as follows: 18 (12.4%) N1, 15 (10.4%) N2,
1 (0.7%) N3, and 4 (2.7%)NX.
All patients underwent surgical treatment. Total parotidectomy was the
most common resection performed (91 cases [62.8%]), followed by partial parotidectomy
in 37 patients (25.5%) and wider resections (total parotidectomy encompassing
adjacent structures as bone, skin, and muscle), whenever the tumor extended
beyond the parotid confines, in 17 patients (11.7%). Sixty-four patients (44.1%)
submitted to radical (classic or modified) unilateral neck dissection. Supraomohyoid
neck dissection was performed in 15 patients (10.3%) and bilateral radical
neck dissection in 1 (0.7%). Surgical treatment was followed by external beam
radiation therapy in 83 cases (57.2%), with a total dosage ranging from 30
Gy to 70 Gy. The lymphatic drainage was included in the radiation portals
in 50 cases (34.5%) and only the parotid region in 33 cases (22.8%).
The follow-up period ranged from 1 to 366.2 months (median follow-up,
66.2 months) with 77 (53.1%) of the 145 patients being followed up for 60
months and 45 (31.0%) for at least 120 months. Local recurrence alone was
observed in 20 patients (13.8%). Homolateral neck lymph node metastases occurred
in 9 patients (6.2%), within a median period of 37.8 months (range, 34-153.3
months), while contralateral neck nodes were the site of recurrence in only
3 patients (2.0%). Distant metastases were found in 17 patients (11.7%) and
were associated with local recurrence in 2 patients (1.4%) and with neck metastases
in another 2 patients (1.4%).
The following variables were evaluated as candidate risk factors for
lymph node metastases in parotid carcinomas: sex, age, race, T stage, facial
paralysis, extraglandular tumor extent, histological type, vascular and lymphatic
invasion, necrosis, peritumoral lymphocytes, and desmoplasia (inflammatory
reaction). Regarding desmoplasia, we designated the following 3 different
grades based on the proportion of such histopathological features in the tumor
slides reviewed: grade 1, light (14 cases); grade 2, moderate (32 cases);
and grade 3, severe (27 cases) when the proportion of tumor composed of desmoplastic
stromal reaction was less than 25%, between 25% and 50%, and more than 50%,
respectively. Surgical margins were not evaluated in view of the impossibility
to get a precise assessment in a retrospective study like this one. Logistic
regression was used to perform univariate and mulivariate analysis to build
models representing the most parsimonious subset of variables with an independent
predictive value for neck metastases.
RESULTS
Mucoepidermoid carcinoma was the most common histological type (20.0%)
followed by undifferentiated carcinoma (12.4%), malignant mixed tumor (11.?%),
and squamous cell carcinoma (9.7%). Occult metastases were detected in 17
(37.0%) of 46 N0-staged patients who underwent elective neck dissection. Thirteen
patients (76.5%) among the 17 with occult neck metastases had T3 or T4 tumors.12 The histological types observed in such cases were
mucoepidermoid carcinoma, salivary duct carcinoma, squamous cell carcinoma,
undifferentiated carcinoma, malignant mixed tumor, and adenoid cystic carcinoma.
Nine patients had ipsilateral neck recurrences within a median period of 39.6
months. Seven of these patients were initially staged as N0 and elective neck
dissection was performed in 4 of them, followed by radiotherapy in 2 cases.
The histological types were categorized according to the risk of neck
metastases into 3 groups—low, moderate, and high risk, when the percentage
of lymph node involvement by histological type reached, respectively, 0% to
20%, 21% to 50%, and more than 50%. Histological types with a total number
of cases equal to or smaller than 6 were classified as "others" (Table 2).
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Table 2. Histological Types and the Risk for Neck Metastases
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The risk for neck metastases was significantly associated with the following
variables by univariate analysis: histological type (P<.001),
T stage (P<.001), desmoplasia (P = .001), necrosis (P = .003), facial paralysis
(P = .02), perineural infiltration (P = .01), and extraparotid tumor extent (P
= .02) (Table 3). There was a
trend toward lymph node metastases in male patients that, however, failed
to achieve statistical significance. Multivariate analysis identified the
following as independent predictors for neck involvement: the histopathological
type (P<.001), T stage (P
= .033), and desmoplasia (P = .006) (Table 4).
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Table 3. Univariate Analysis of Risk Factors for Neck Metastases in
Parotid Carcinomas
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Table 4. Multivariate Analysis of Risk Factors for Neck Metastases
in Parotid Carcinomas
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COMMENT
The treatment of the neck in patients with parotid carcinoma is indicated
whenever there is clinical evidence of lymph node metastases. This is the
only situation in which there is no discussion on the therapeutic approach—usually
a radical neck dissection followed by postoperative external beam radiation.9 The approach of the N0 neck, however, remains controversial;
there is no consensus regarding the need for elective neck dissection or elective
radiotherapy.11 The addition of neck dissection,
to the surgical treatment increases the time required for the surgical procedure,
the risk of postoperative complications, treatment costs, and aesthetic and
functional sequelae. Therefore, it should be avoided in N0-staged patients,
whenever possible. In this series, 25 (31.3%) of 80 patients who underwent
neck dissection had pN0-staged stage. However, clinically N0-staged patients,
with occult metastases who did not undergo treatment of the neck, may evolve
with detrimental outcome, and salvage treatment is frequently inefficient
in such situations.14
The overall incidence of lymph node metastases in our experience was
23.5% and the main histological type was the mucoepidermoid carcinoma (20%),
in accord with the data published in the literature.1, 6, 7, 10, 15, 16
The reported percentage of neck metastases at the time of patients' admission
for undifferentiated carcinoma, squamous cell carcinoma, adenocarcinoma, mucoepidermoid
carcinoma, and malignant mixed tumor is more than 20%.9, 17, 18
In this series, we observed that most of these histological types belong to
the high-risk group for neck spread, ie, undifferentiated carcinoma, high-grade
mucoepidemoid carcinoma, salivary duct carcinoma, adenocarcinoma, and squamous
cell carcinoma. Metastasis in patients with those histological types were
seen in 68%.
The question about N0-staged patients is: what is the exact percentage
of such patients with occult metastases? Or how many patients will have recurrences
in the neck? Are there indications for elective neck dissection in parotid
carcinoma? Several authors have different answers to these questions, nevertheless,
the problem still remains. Fu et al19 observed
the preponderance of undifferentiated carcinomas (3 of 4 patients) in cases
of neck recurrence. All patients had T3 tumors. Frankenthaler et al10 by multivariate analysis showed that extraglandular
tumor extent, being older than 54 years, and lymphatic invasion were significantly
associated with the risk for neck metastasis. In their series, occult metastases
were observed in cases of adenocarcinoma, salivary duct carcinoma, squamous
cell carcinoma, undifferentiated carcinoma, and mucoepidermoid carcinoma.
Kelley and Spiro2 consider clinical stage and
tumor grading as the best predictive factors. Armstrong et al9
have also shown that patients with high-grade tumors, advanced T stage, and
undifferentiated carcinoma (6 of 7 patients), squamous cell carcinoma (6 of
28 patients), adenocarcinoma (11 of 49 patients), and mucoepidermoid carcinoma
(30 of 209 patients) present high-risk for neck metastases and should be considered
candidates to an elective neck dissection. Spiro et al6
reported metastases in 40% and 16% of squamous cell carcinoma and high-grade
mucoepidermoid carcinoma, respectively. The authors suggest elective neck
dissection to be performed in patients with high-grade tumors. Spiro et al6 stated that at least 58% of the patients with undifferentiated
or squamous cell carcinomas will have neck metastases and could benefit from
elective neck dissection. In their series, about 50% of the neck metastases
were detected by this procedure. Califano et al20
found occult lymph node metastases in 17% of the patients with mucoepidermoid
carcinoma and suggested benefit effects of elective neck dissection in such
cases, as well as in undifferentiated and squamous cell carcinomas. In a follow-up
period of 4 years, Poulsen et al16 registered
neck metastases in 24.4% of 237 parotid carcinomas, showing that patients
older than 60 years, with clinically positive lymph nodes at the time of first
presentation and with positive surgical margins, squamous cell carcinoma,
and poorly differentiated tumors, have a higher percentage of neck metastases.
High-risk histological types were observed in 13 (76.5%) of 17 patients
with metastases detected by elective neck dissection in this series, and 13
(76.5%) of those cases had T3 or T4 tumors. The association of high-risk histological
type and T3 or T4 was registered for 9 patients. These figures probably underestimate
the actual percentage of T3 or T4 tumors in this subset of patients because
T stage was undetermined (TX) in 4 of the 13 patients who had high-risk histological
types with occult metastases. Neck recurrences were diagnosed in 7 patients
(4.8%). The advanced T stage (T3 or T4) and the high-risk histological types
were observed in 5 cases (71.4%) and 4 of them were dead of disease at the
end of this study, demonstrating the remarkable and detrimental prognostic
influence of neck recurrence.
Considering that the identification of risk factors for lymph node metastases,
including preoperative and pathological, could be significant to indicate
elective neck dissection or elective postoperative radiotherapy, with possible
prognostic significance, we decided to undertake this study. Frankenthaler
et al,10 analyzing 11 preoperative and postoperative
variables, found patient's age, extraparotid tumor extent, and perilymphatic
invasion to be the most significant predictive factors for occult lymph node
metastases by multivariate analysis. In our series, histological type, T stage,
facial palsy, extraglandular tumor extent, perineural invasion, necrosis,
and desmoplasia reached statistical significance in univariate analysis. Of
the several candidate prognostic factors, multivariate analysis revealed histological
type, T stage, and severe desmoplasia as the most significant independent
predictors of the risk of neck involvement.
Lewis et al3 studied a group of 90 patients
with acinic cell carcinoma of the parotid gland to determine clinical and
histological features that consistently predicted disease progression. The
presence of desmoplastic reaction (desmoplasia) was 1 of 3 microscopic features
significantly correlated with poor outcome (P<.01).
In different tumors, parenchymal cells stimulate the formation of an abundant
collagenous stroma, characterized by the growth of fibrous tissue, refered
to as desmoplasia,21 which is a fairly common
finding in parotid carcinoma. We tried, however, to estabilish not only a
quantitative but also a qualitative relationship between this finding and
the risk for lymph node metastases, estimating 3 different grades based on
the proportion of the histopathological feature in the tumor slides that were
reviewed. As we have shown, only severe desmoplasia was significantly associated
with the risk for lymph node metastases (P = .001).
Unfortunately, some of this information may be unavailable at the time
of surgical treatment, restricting its applicability to decide on elective
neck dissection or irradiation following primary tumor ressection. Tumor stage
is easily known preoperatively, and histological type is generally known by
intrasurgical evaluation of a tumor specimen (frozen section). Both types
of information can be incorporated in the surgical treatment plan. This is
not the case for desmoplasia. However, all of this information is valuable
to decide whether postoperative radiotherapy should include the lymphatic
drainage area because there is no proven benefit of elective neck dissection
over radiotherapyin treating parotid carcinoma.11
Elective neck dissection is considered in the management of superior
aerodigestive squamous cell carcinomas whenever the percentage of occult lymph
node metastases is between 15% and 20%.22 These
figures are not yet established for parotid carcinomas. Our findings showed
occult metastases in 22.2% of the subset of patients with T3 or T4 and a high-risk
histological type.
Gallo et al,23 studying the expression
of p53 in parotid tumors, observed the association
of neck metastases and decreased survival in patients with high expression
of this suppressor gene. However, as stated by Kelly and Spiro: "the search
for factors at the subcellular level holds much promise for the future, but
as of this writing, the selection of patients for elective lymphadenectomy
involves a judgment based on the relevant clinical findings."2(p697)
Our experience suggests that in the management of parotid carcinomas, patients
with high-risk histological types (ie, adenocarcinoma, undifferentiated carcinoma,
salivary duct carcinoma, squamous cell carcinoma, and high-grade mucoepidermoid
carcinoma) and advanced T stage (T3 or T4) could benefit from elective neck
treatment. In this series, there was neck metastases in 100% of the patients
with tumors at advanced T stage, severe desmoplasia, and high-risk histological
types.
Results of retrospective published series regarding the risk factors
for cervical metastases in parotid carcinoma varies widely. Prospective randomized
trials, however, are virtually infeasible as this is a rare tumor and long-term
follow-up is required.
AUTHOR INFORMATION
Accepted for publication June 29, 2000.
From the Medical School (Drs Régis de Brito Santos and Flávia
Logullo) and the Department of Oral Pathology, School of Dentistry (Dr Cavalcante
de Araujo), University of São Paulo, and the Department of Head and
Neck Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa Hospital
do Câncer A. C. Camargo (Drs Kowalski and Magrin), São Paulo,
Brazil.
Reprints: Luiz P. Kowalski, MD, PhD, Department of Head and Neck
Surgery and Otorhinolaryngology, Centro de Tratamento e Pesquisa Hospital
do Câncer A. C. Camargo, R. Professor Antonio Prudente, 211, 01509-010–São
Paulo-SP, Brazil (e-mail: lp_kowalski{at}uol.com.br).
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