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Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients
Int. J. Oral Maxillofac. Surg. 2007; 36: 507–513 doi:10.1016/j.ijom.2007.01.008, available online at http://www.sciencedirect.com
Clinical Paper Head and Neck Oncology
Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients
R. Gonza´lez-Garcı´a, L. Naval-Gı´as, J. Sastre-Pe´rez, F. J. Rodrı´guez-Campo, M. F. Mun˜oz-Guerra, J.L. Gil-Dı´ez Usandizaga, F. J. Dı´az-Gonza´lez Department of Oral and Maxillofacial Surgery, University Hospital La Princesa, Madrid, Spain
R. Gonza´lez-Garcı´a, L. Naval-Gı´as, J. Sastre-Pe´rez, F. J. Rodrı´guez-Campo, M. F. Mun˜oz-Guerra, J. L. Gil-Dı´ezUsandizaga, F. J. Dı´az-Gonza´lez: Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients. Int. J. Oral Maxillofac. Surg. 2007; 36: 507–513. # 2007 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. Abstract. In primary squamous cell carcinoma (SCC) of the oral cavity, many clinical and histopathological factors have been described as predictive for cervical lymphnode metastasis, but there are no data available on this association for surgical resection of lateral tongue primary SCC. The aim of this study was to analyse factors related to contralateral neck relapse in a series of 203 consecutive patients with SCC of the lateral aspect of the tongue treated by surgery with or without adjuvant radiotherapy. Several clinical features were analyzed. Histological study included pTNM classification, tumour size, surgical margins, extracapsular spread of lymphnode metastasis, perineural infiltration, peritumoural inflammation and bone involvement. The mean duration of follow up for surviving patients was 70.9 49.6 months; 47 patients eventually died of the disease and 116 patients are alive with no evidence of recurrence. The mean disease-specific survival time was 149 7 months. Twenty (9.8%) patients developed ipsilateral and nine (4.4%) contralateral neck recurrence. The mean period of time from surgery to contralateral neck recurrence was 11.4 months (range 3–27 months). Fourteen of the 20 ipsilateral and 8 of the 9 contralateral neck relapse patients eventually died of the disease. Histopathological grading and peritumoural inflammation were found to be statistically significant (P < 0.05). Clinical and pathological lymph neck node status was not found to be associated with the appearance of contralateral lymph neck node relapse. Due to the increased risk of contralateral neck relapse within the first 2 years of surgery, close surveillance is mandatory at this time.
0901-5027/060507 + 07 $30.00/0
Key words: squamous cell carcinoma; oral cavity; tongue; cervical lymph-node relapse; metastasis. Accepted for publication 16 January 2007 Available online 28 February 2007
# 2007 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
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Several clinical and pathological factors have been proposed as prognostic in oral squamous cell carcinoma (SCC), such as site, extension, stage of primary tumour, grade of histological differentiation, thickness and perineural invasion2,15,9. The presence of cervical lymph-node metastasis has been associated with poor prognosis12, and neck failure after radical neck dissection has almost invariably a fatal outcome16. Few studies concerning prognostic factors for specific contralateral lymph neck node relapse (CLNR) in relation to SCC of the lateral aspect of the tongue are available. SCC of the oral cavity extended to the midline has been associated with an increase in bilateral and contralateral cervical lymph-node metastasis18, and this can be extended to carcinomas of the tongue. The study of tumours originally arising in the lateral side of the tongue is essential in order to determine the relationship between primary tumour features and the appearance of CLNR. In these cases, the appearance of CLNR should be explained by factors other than the central location of the tumour. The purpose of this retrospective analytic study was to determine clinical and pathological features that predict CLNR in surgically treated primary SCC of the lateral side of the tongue. This may help in the identification of patients with an elevated risk of CLNR and therefore a poor prognosis. Patients and methods
This study is based upon a series of 203 consecutive patients diagnosed with primary SCC of the anterior two thirds of the tongue who were treated at the Department of Oral and Maxillofacial-Head and Neck Surgery, La Princesa University Hospital, Madrid, Spain, from June 1979 to December 1999. Patients were selected from a prospective database, and none had previously received treatment in any other department. They were treated by means of surgery with or without adjuvant radiotherapy. Surgery was performed in all cases by the same team, composed of two main surgeons. Surgical achievements only were considered for evaluation, so no patients undergoing radiotherapy or chemotherapy as primary treatment were included in this study. Only a small proportion (less than 2%) of the total number of patients with SCC of the tongue were not treated by primary surgery and were not included in the prospective list of patients selected for this study. This was the result of advanced
disease associated with general poor condition due to advanced age at the time of diagnosis. The following exclusion criteria were established: (1) recurrence of the primary tumour (52 of 517 patients); (2) multiple oral and/or head and neck cancer (87 of 517 patients); (3) contraindication for surgery (unresectable tumour or inoperable patient); (4) distant metastasis at the time of diagnosis. Tumours primarily arising from the lateral side of the tongue were selected, including those invading the midline. There was no limitation in TNM staging, and patients with stages I–IV of the tongue were included in the study. The following inclusion criteria were established: (1) presence of histological confirmation of SCC; (2) no prior treatment; (3) surgical treatment as first management method. Extent of tongue involvement was determined by magnetic resonance imaging (MRI) or computed tomography (CT). Neck staging was performed by means of physical examination, CT scan and MRI. Some cases underwent fine needle aspiration biopsy. After examining the records, the following data were analysed for each patient: age, gender, habits, date of diagnosis, performance status, clinical features of the tumour, grade of histological differentiation of the primary tumour, tumour stage according to the TNM classification, number and location of cervical nodes, surgical reconstruction, neck dissection, postoperative radiotherapy, local and distant relapse, post-surgical complications and survival results. Histological study included pTNM classification, size of tumour, surgical margins, perineural infiltration, peritumoural inflammation and bone involvement. All patients underwent surgical resection of the primary tumour with macroscopic margins (more than 1 cm around the tumour). Tumours were classified according to the TNM Staging Classification, and this determined the type of cervical dissection performed: (1) ipsilateral modified type III radical neck dissection in (T2, T3, T4) N0 tumours or tumours with cervical nodes less than 3 cm without extracapsular extension (no fixed nodes); (2) bilateral modified type III radical neck dissection when invasion of the midline of the tongue was present as a result of tumour extension from its lateral aspect in N0 or N1 patients; (3) ipsilateral classical radical neck dissection when nodes equal to or greater than 3 cm, fixed nodes or effect on the spinalis nerve were present; (4) ipsilateral classical radical neck dissection together with contralateral
modified type III radical neck dissection in patients with ipsilateral N2 or N3 and contralateral N0 involvement, but in whom the midline of the tongue was affected as a consequence of extension from the lateral aspect; and (5) contralateral classical radical neck dissection together with ipsilateral modified type III radical neck dissection in a patient with a positive contralateral node more than 3 cm (N2) at the time of diagnosis (despite this aggressive treatment the patient showed recurrence in the contralateral neck during follow up; it was subsequently considered as a true recurrence and included in the study.) According to the Department of Oncology, conventional local adjuvant radiotherapy ranging from 60 to 70 Gy was performed in those patients in whom free margins less than 1 cm were found on histological examination. Tumours classified as pT3 or more also received local adjuvant radiotherapy. Thus, bone invasion (T4 primary) was an indication for postoperative irradiation. Other tumour-related factors such as spidery growth, lymph or blood vessel invasion, perineural invasion and dysplasia in resection margins were considered indications for adjuvant radiotherapy. Regional radiotherapy was also used when more than three cervical nodes or extracapsular extension were demonstrated. Only those patients in whom the contralateral neck was affected were managed by contralateral adjuvant radiotherapy following neck dissection. In summary, postoperative adjuvant radiotherapy was administered to patients with: (1) a positive resection margin in the specimen, (2) multiple pathologic lymph neck nodes and (3) advanced T classification. Patients were selected and analysed in relation to the type of cervical dissection (Table 1). Necks were histologically classified as positive or negative for lymphnode metastasis after surgical specimens were analysed. Ipsilateral and contralateral cervical relapses were referred during the follow-up period. The age, gender, time to diagnosis, clinical T status, clinical N status, pathologic T status, ipsilateral pathologic N (pN) status, tumour staging, histopathological differentiation, surgical margins of primary tumour resection, tumour thickness (<2 mm or >2 mm), type of neck dissection, perineural infiltration, bone involvement, extracapsular spread of lymph-node metastasis, and postoperative radiotherapy were evaluated for association with contralateral neck relapse. The routine method for diagnosing the presence of cervical relapse was physical examination
Contralateral neck relapse in SCC of tongue
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Table 1. Relapse in relation to neck dissection pN0 neck
Ipsilateral modif. type III RND Bilateral modif. type III RND Ipsilateral classical RND Ipsilateral classical RND + contralateral modif. type III RND Ipsilateral modif. type III RND + contralateral classical RND
pN+ neck
No. of patients
Ipsilateral relapse ratio
Contralateral relapse ratio
Ipsilateral relapse ratio
Contralateral relapse ratio
80 49 5 6 1
2/58 1/25 0/0 1/1 0/0
4/58 0/25 0/0 0/1 0/0
0/22 3/24 1/5 1/5 1/1
2/22 0/24 0/5 0/5 1/1*
Patients who did not receive neck dissection are not included. modif., modified; RND, radical neck dissection. * One patient presented with both ipsilateral and contralateral lymph neck node metastasis.
followed by CT scan or MRI. Some cases underwent fine needle aspiration before definitive neck dissection. The aim of the study was to determine those features that predict CLNR in surgically treated primary SCC of the lateral side of the tongue. SPSS 12.0 (SPSS Inc., Chicago, IL, USA) statistical software was used to analyse data. The possible association between different clinical and pathological features and the appearance of CLNR was analysed by means of the x2 test for categorical data and the Student’s t test for parametric data. Survival curves were calculated by the Kaplan–Meier method. A P value 0.05 was considered statistically significant. Results
From a total of 517 patients with SCC of the oral cavity, 203 cases fulfilled the inclusion criteria. The male-to-female ratio was 72:28. The mean age was 59.1 13.7 years (range 18–83 years). The mean duration of follow up for surviving patients was 71.1 months (SD 24.5, median 62 months, range 6–204 months). Time elapsed from first clinical manifestations to diagnosis ranged from 0 to 84 months, with a mean of 4 months and a median of 2 months. Clinicopathological factors and occurrence of contralateral
lymph neck node relapse are shown in Table 2. Forty-seven patients eventually died of the disease, whereas 19 patients died of disease not related to SCC of the tongue. One hundred and sixteen patients are still alive with no evidence of recurrence. The mean disease-specific survival time was 149 7 months (95% confidence interval: 135–166 months) (Fig. 1). The majority of the patients in this series underwent neck dissection (n = 141; 73.1%): (1) 80 (40.6%) underwent an ipsilateral modified type III radical neck dissection; (2) 49 (24.9%) bilateral modified type III radical neck dissection; (3) 5 (2.5%) ipsilateral classical radical dissection; (4) 6 (3%) ipsilateral classical radical dissection together with contralateral modified type III radical neck dissection; and (5) 1 (0.5%) ipsilateral modified type III radical neck dissection together with contralateral classical radical neck dissection. Bilateral neck dissections (groups 2, 4 and 5) were performed in those patients in whom midline involvement or clinical or radiological involvement of both sides of the neck was demonstrated. A mean of 22.6 lymph nodes were analysed in those patients who underwent ipsilateral cervical dissection, whereas a mean of 19.9 lymph nodes were analysed for contralat-
Fig. 1. Disease-specific survival of the whole series.
eral neck dissections. Table 3 summarizes the patient data and the occurrence of CLNR during the follow-up period. Histological confirmation of SCC was obtained postoperatively for all the patients. Seventy-three (37.6%) received adjuvant radiotherapy after the surgical procedure. Twenty-eight (13.7%) developed local relapse after definitive therapy. In relation to cervical relapse, 20 (9.8%) patients developed ipsilateral neck recurrence, whereas 9 (4.4%) developed contralateral neck recurrence. Local–regional relapse was observed in 14 (6.9%) patients and distant metastasis in 15 (7.4%) within the whole series. Fourteen of the 20 ipsilateral and 8 of the 9 contralateral neck relapse patients eventually died of the disease. The mean period of time from surgery to appearance of contralateral neck recurrence was 11.4 months, with a median of 13 months (range 3–27 months). The majority of cases (77.8%) in which CLNR appeared had been managed by means of the modified type III radical neck dissection initially. One of these seven cases had also received contralateral classical radical dissection, due to the absence of ipsilateral neck lymph nodes but the presence of CLNR. One of the nine patients with CLNR did not receive cervical neck dissection either initially or after recurrence, while another only received modified type III radical neck dissection when the CLNR had appeared. In summary, six of the nine patients with CLNR were amenable to further neck dissection. The remaining three patients were not candidates for surgery and only palliative treatment was offered. At the end of the follow-up period only one of the nine patients with CLNR remained alive (Table 4). Histopathological grading and peritumoural imflammation were found to be statistically significant (P < 0.05) in relation to CLNR. Clinical and pathological lymph neck node status was not found to be associated with the appearance of CLNR. Some other features, such as adjuvant radiotherapy (absence of adjuvant
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Table 2. Distribution of clinicopathological factors and occurrence of contralateral lymph-node relapse
Sex Male Female T-stage Tis T1 T2 T3 T4
No. of cases (%)
No. of patients with contralateral lymph node relapse (%)
146 (71.9) 57 (28.1)
6 (4.1) 3 (5.2)
0.71
P value
4 45 89 30 35
(1.9) (22.2) (43.8) (14.8) (17.2)
0 (0) 0 (0) 7 (7.8) 1 (3.3) 1 (2.8)
0.10 (1)
149 34 5 4 7 3
(73.4) (16.7) (2.4) (1.9) (3.4) (1.4)
6 (4.0) 0 (0) 0 (0) 3 (75) 0 (0) 0 (0)
0.62 (2)
178 (87.6) 22 (10.8) 3
9 (4.4) 0 (0) (0)
0.28
1 (1.8) 7 (8.7) 0 (0) 0 (0) 0 (0)
0.26 (3)
N N0 N1 N2a N2b N2c N3 Local surgery Local Local + bone Lost to follow up Cervical dissection None Ipsilateral modified type III radical neck dissection Bilateral modified radical neck dissection type III Ipsilateral classical radical neck dissection Ipsilateral classical radical neck dissection + contralateral modified type III radical neck dissection Ipsilateral classical radical neck dissection + ipsilateral modified type III radical neck dissection Missing data
53 80 49 5 6
(26.9) (40.6) (24.9) (2.4) (2.9)
1 (0.5) 9
1 (100) (0)
Reconstruction Direct closure Microsurgery Pectoralis myocutaneous flap CO2 laser
100 15 34 54
(49.2) (7.3) (16.7) (27.1)
8 (8) 0 (0) 0 (0) 1 (1.8)
0.01 (4)
Adjuvant radiotherapy Yes No
122 (60.1) 81 (30.9)
3 (2.4) 6 (7.4)
0.09
Histopathological grading Well differentiated Moderately differentiated Poorly differentiated Missing data
79 (38.9) 101 (49.8) 21 (10.3) 2
2 (2.5) 4 (3.9) 3 (14.2) (0)
0.02 (5)
pT pTis pT1 pT2 pT3 pT4 Missing data
9 59 77 21 24 13
(4.4) (30.3) (39.5) (10.8) (12.3)
0 (0) 1 (1.6) 6 (7.7) 1 (4.7) 1 (4.1) (0)
0.11 (6)
pN pN0 pN1 pN2a pN2b pN2c pN3
146 16 5 24 10 2
(71.9) (7.8) (2.4) (11.8) (3.4) (0.9)
6 (4.1) 0 (0) 0 (0) 3 (12.5) 0 (0) 0 (0)
0.68 (7)
Surgical margins Correct (1 cm) Microscopical involvement Macroscopical involvement
147 (75.4) 25 (12.8) 3 (1.4)
5 (3.4) 1 (4) 0 (0)
0.11 (8)
Contralateral neck relapse in SCC of tongue
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Table 2 (Continued ) No. of cases (%)
No. of patients with contralateral lymph node relapse (%)
16 (8.2) 4
3 (18.7) (0)
Tumour thickness <2 mm >2 mm Missing data
25 (12.9) 137 (70.6) 32
1 (4) 8 (5.8) (0)
0.71
Peritumoural inflammation None Scarce Moderate Intense Missing data
118 17 30 30 8
(60.5) (8.7) (15.4) (15.4)
9 (7.6) 0 (0) 0 (0) 0 (0) (0)
0.01 (9)
Perineural infiltration Yes No Missing data
39 (20.0) 156 (80.0) 8
4 (10.2) 5 (3.2) (0)
0.06
Bone affected Yes No Missing data
4 (1.9) 191 (97.9) 8
0 (0) 6 (3.1) (3)
0.71
Free insufficient (<1 cm) Missing data
P value
(1) P value is calculated comparing Tis–T1 to T2 and upper. (2) P value is calculated comparing N0 to N+. (3) P value is calculated comparing no cervical dissection to any type of cervical dissection. (4) P value is calculated comparing direct closure to any other reconstruction. (5) P value is calculated comparing well differentiated and moderately differentiated vs. poorly differentiated histopathological grading. (6) P value is calculated comparing pTis–pT1 to pT2 and upper. (7) P value is calculated comparing pN0 to pN+. (8) P value is calculated comparing surgical margins 1 cm to no correct surgical margins. (9) P value is calculated comparing no peritumoural inflammation to peritumoural inflammation.
radiotherapy versus administration of adjuvant radiotherapy, P = 0.09), clinical tumour staging (Tis/T1 versus T2 and upper, P = 0.10), pathological T staging (pTis/pT1 versus pT2 and upper, P = 0.11), surgical margins (incorrect less than 1 cm versus correct 1 cm, P = 0.10) and perineural infiltration (presence of perineural infiltration versus absence of perineural infiltration, P = 0.06), may be demonstrated to be statistically significant in larger series. Discussion
Recurrent primary lesions and cervical lymph-node relapse affect the prognosis and decrease survival rate of patients with
carcinoma of the tongue. A small percentage of early carcinomas of the tongue are aggressive, with associated poor prognosis2,15,9. The unfortunate outcome of patients with oral carcinoma who develop contralateral lymph neck node relapse is also known. Several authors have analysed risk factors for CLNR in tumours of the oral cavity, but few published studies are available concerning the existence of prognostic factors for CLNR in lateral tongue carcinoma. In relation to SCC of the oral cavity, a variable frequency of contralateral metastasis ranging from 0.9% to 34.7% has been referred in the literature12,18. KOWALSKI et al.7 reported an incidence of 14% for CLNR, in concordance with that reported
Table 3. Patients’ follow-up features and occurrence of contralateral lymph neck node relapse No. of cases (%) Relapse Local Ipsilateral neck Contralateral neck Local–cervical Distant metastasis Situation at end of follow up Alive, no evidence of disease Alive with tumour Died of disease Died of other disease Missing data
No. of patients with contralateral lymph-node relapse (%)
28 20 9 14 15
(13.7) (11) (4.4) (7.1) (7.3)
0 0 9 0 0
(0) (0) (100) (0) (0)
116 5 47 19 16
(59.5) (2.6) (24.1) (9.7)
1 0 8 0
(0.8) (0) (17) (0)
by KURITA et al.8 Some features may influence the appearance of CLNR. Location of the primary tumour seems to play an important role. A higher risk of contralateral metastasis in patients with tumours of the floor of the mouth and the anterior third of the tongue compared to the retromolar region or the lateral gum has been reported. The contrasting report of a higher incidence of CLNR in cases of lower gum carcinoma (25%) in comparison to those tumours arising in the mobile tongue (15.4%)8 makes necessary more research to elucidate the influence of the primary tumour location. In relation to tongue carcinomas, the importance of primary tumour invasion across the midline has already been exposed by MARTIN et al.12: 16% of the tumours crossing the midline by less than 1 cm developed CLNR. This value increased to 46% in cases that invaded over the midline by more than 1 cm. KOWALSKI et al.7 showed that clinical staging, tumour crossing the midline and floor of the mouth involvement were the most important predictors of contralateral metastasis. All the present cases involved the lateral side of the tongue, but midline involvement of a tumour primarily located on the lateral side of the tongue was not considered as an exclusion criterion. An increase in percentage of CLNR may be encountered in those cases where the tumour finally reaches the midline of the
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Table 4. Summary of patients with contralateral neck relapse
Primary neck dissection
Postoperative radiation therapy
Relapse time (months)
Ipsilateral modif. type III RND Ipsilateral modif. type III RND
N N
13 5
T1 N0 T2 N0
None Ipsilateral modif. type III RND
N N
13 27
57
T2 N2b
Ipsilateral modif. type III RND+
Y
6
45 46 58 76
T2 T2 T2 T2
Ipsilateral modif. type III RND Ipsilateral modif. type III RND Ipsilateral modif. type III RND None
N Y Y N
10 13 13 3
Age (years)
pTNM
M M
75 46
T3 N0 T4 N0
M M
76 42
M F F M F
Gender
N0 N2b N2b N0
Secondary neck dissection
Outcome
None Ipsilateral modif. type III RND+ Contralateral Classical RND Bilateral modif. type III RND Ipsilateral modif. type III RND+ Contralateral classical RND Contralateral modif. type III RND Contralateral classical RND Contralateral modif. type III RND None None Contralateral modif. type III RND
DOD DOD DOD DOD DOD NED DOD DOD DOD
modif., modified; RND, radical neck dissection; DOD, died of disease; NED, no evidence of disease.
tongue, due to the involvement of contralateral lymphatic drainage. No specific correlation could be established in these cases because other dependent factors such as increased tumour size could have influenced the appearance of CLNR. In an attempt to determine the influence of the location of the primary tumour, a preponderance of CLNR in tumours with radiological evidence of extension over the midline has been shown8. Although this may appear to be an important independent factor, multivariate analysis has elucidated that it is not the only one, and other variables must be globally considered9. The clinical staging and size of the tumour could be considered to be important factors favouring the development of CLNR, at least as important as tumour location and involvement of the midline, but a correlation between earlier cancers (T1–T2) and CLNR was not found. Other authors have suggested similar results, although they considered T1–T3 as earlier cancers7,8. In a recent study by YAO et al.19 concerning intensity-modulated radiation treatment for head and neck SCC, neither T stage nor N stage had a significant effect on local–regional control. Some other factors, such as the histopathological grading, have been related to the frequency of CLNR. In the present study, there was a statistically significant association between histological grading and the appearance of CLNR: poorly differentiated tumours developed CLNR more frequently. A statistically significant association between the absence of peritumoural inflammation and the appearance of CLNR was also observed. A possible explanation for this association could be that a low host immunological response around the primary tumour could allow easier dissemination of cancer cells through lymphatic drainage.
The number of ipsilateral metastatic lymph nodes could also be considered an important prognostic factor. Ipsilateral neck lymph-node metastasis has been referred to as a significant predictor for the occurrence of CLNR in tumours of the oral cavity12,18,14, and the appearance of contralateral metastasis was always described in the context of simultaneous ipsilateral metastasis. A possible explanation for these findings is that the performance of elective neck dissection together with primary tumour resection may predispose patients to aberrant migration of in-transit carcinomatous cells to the opposite side of the neck4. In relation to tumours of the oral cavity, CHOW et al.1 in a series of 72 patients, reported a similar incidence of ipsilateral (n = 7) and contralateral (n = 5) neck node relapse. The present results in the tongue do not support these data: contralateral neck failure (4.4%, n = 9) was not as common as ipsilateral relapse (11.0%, n = 20). This difference may be explained by the smaller number of patients in the former study. In contrast to these previous studies, a significant association between ipsilateral clinical or pathological lymph neck node status and CLNR could not be demonstrated in the present study. In this series, bilateral neck dissection was not significantly associated with a decrease in contralateral metastasis. Other authors have failed to demonstrate this association, probably due to the small sample size of their series1. The present results showed a non-statistically significant association between bilateral dissection and decrease in CLNR (P = 0.1). Only 1 of 55 patients undergoing bilateral neck dissection as definitive treatment developed CLNR compared to 7 of 78 patients undergoing ipsilateral neck dissection only. As shown by WEBER et al.17 bilateral neck dissection seems to be extremely
effective in midline primary tumours. The low incidence reported by various authors supports the recommendation for bilateral neck dissection in selected patients with involvement of the midline18,1,5. Concerning the type of modified neck dissection, some authors have considered the possibility of preserving level V lymph-node pads in patients with clinically N+ neck below the nodal stage N2a10, and the performance of a supraomohyoid neck dissection for N0 and a more comprehensive neck dissection (levels I–V) for N+ patients in stage I–II SCC of the tongue and floor of the mouth3. Several authors have thus failed to demonstrate the association of different clinical and histological features with CLNR in the carcinoma of the oral cavity. Some authors have only reported a statistically significant association between pN status and CLNR14, leading to the proposal of aggressive treatment for contralateral necks in cases with positive pN status. In contrast, elective neck dissection for the contralateral N0 neck in early oral tongue carcinoma has not shown any advantage in recent reports11. Although the application of whole neck treatment (surgery or radiotherapy) in cases with ipsilateral clinical nodular involvement could be concluded from other studies, the present results and the small percentage of patients that finally develop CLNR support an individual study of the risks and benefits of bilateral neck treatment for each patient. In recent years a special effort has been made to elucidate which tumour-related factors could influence the appearance of metastasis in SCC of the tongue. Spidery growth, lymph or blood vessel in growth, perineural growth and dysplasia in resection margins have been analysed. In a recent publication13, it was observed that a decrease in E-cadherin and/or P-cadherin expression may contribute to the
Contralateral neck relapse in SCC of tongue invasive potential of early oral SCC. Pcadherin expression may be a potential independent prognostic factor in these patients. HANNEN et al.6 studied the significance of tumour DNA features in SCC of the tongue. They showed an improvement of predictive values with a multiparameter model to predict the process of metastasis more accurately. Future clinical retrospective studies concerning the technique proposed by these authors would be of interest. The present observations confirm the unfavourable prognosis of patients with CLNR, with only one of nine patients surviving. In accordance with other reported series16,17, CLNR occurred within the first 2 years after surgery in 89.9% of the affected patients. Special effort must be made to detect early recurrence, and careful follow up is mandatory during this period of time. In summary, the possibility of collecting clinical information before surgical treatment in an attempt to determine which patients have an increased risk of CLNR may improve prognosis in tongue carcinoma. Surgeons may be encouraged to perform more aggressive treatments in patients with a high risk of CLNR. Clinical and pathological positive node status on the ipsilateral side of the neck is not associated with a higher incidence of contralateral cervical metastasis in SCC of the lateral side of the tongue. Poorly differentiated primary tumours and the absence of peritumoural imflammation are significantly associated with contralateral lymph neck node relapse. Due to the increased risk of CLNR within the first 2 years after surgery, close surveillance is mandatory.
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vical lymph node metastasis after local excision of early squamous cell carcinoma of the oral cavity. Am J Surg 1986: 152: 361–366. Dias FL, Lima RA, Kligerman J, Farias TP, Soares JR, Manfro G, Sa GM. Relevance of skip metastases for squamous cell carcinoma of the oral tongue and the floor of the mouth. Otolaryngol Head Neck Surg 2006: 134: 460–465. Francheschi D, Gupta R, Spiro RH, Shah JP. Improved survival in the treatment of squamous carcinoma of the oral tongue. Am J Surg 1993: 166: 360–365. Godden DR, Ribeiro NF, Hassanein K, Langton SG. Recurrent neck disease in oral cancer. J Oral Maxillofac Surg 2002: 60: 748–753. Hannen EJ, van der Laak JA, Manni JJ, Pahlplatz MM, Freihofer HP, Slootweg PJ, Koole R, de Wilde PC. Improved prediction of metastasis in tongue carcinomas, combining vascular and nuclear tumor parameters. Cancer 2001: 92: 1881–1887. Kowalski LP, Bagietto R, Lara JRL, Santos RL, Tagawa EK, Sandros IRB. Factors influencing contralateral lymph node metastasis from oral carcinoma. Head Neck 1999: 21: 104–110. Kurita H, Koite T, Narikawa J, Sakai H, Nakatsuka A, Uehara S, Kobayashi H, Kurashina K. Clinical predictors for contralateral neck lymph node metastasis from unilateral squamous cell carcinoma in the oral cavity. Oral Oncol 2004: 40: 898–903. Kurokawa H, Yamashita Y, Takeda s. Zhang M, Fukuyama H, Takahashi T. Risk factors for late cervical lymph node metastases in patients with stage I or II carcinoma of the tongue. Head Neck 2002: 24: 731–736. Lim YC, Koo BS, Lee JS, Choi EC. Level V lymph node dissection in oral and oropharyngeal carcinoma patients with clinically node-positive neck: is it absolutely necessary? Laryngoscope 2006: 116: 1232–1235. Lim YC, Lee JS, Koo BS, Kim SH, Kim YH, Choi EC. Treatment of contralateral N0 neck in early squamous cell carcinoma of the oral tongue: elective neck dissection versus observation. Laryngoscope 2006: 116: 461–465.
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12. Martin H, Del Valle B, Ehrlich H, Cahan WG. Neck dissection. Cancer 1951: 4: 441–499. 13. Mun˜oz-Guerra MF, Marazuela EG, Ferna´ndez-Contreras ME, Gamallo C. P-cadherin expression reduced in squamous cell carcinoma of the oral cavity. Cancer 2005: 103: 960–969. 14. Northrop M, Fletcher GH, Jesse RH, Lindberg RD. Evolution of neck disease in patients with primary squamous cell carcinoma of the oral tongue, floor of the mouth, and palatine arch, and clinically positive neck nodes neither fixed nor bilateral. Cancer 1972: 29: 23–30. 15. Nyman J, Mercke C, Lindstroem J. Prognostic factors for local control and survival of cancer of the oral tongue: a retrospective analysis of 230 cases in Western Sweden. Acta Oncol 1993: 32: 667–676. 16. Snow GB, Annyas AA, van Slooten EA, Bartelink H, Hart AA. Prognostic factors of neck node metastasis. Clin Otolaryngol Allied Sci 1982: 7: 185–192. 17. Weber PC, Johnson JT, Myers EN. The impact of bilateral neck dissection on the pattern of recurrence and survival in supraglotic carcinoma. Arch Otolaryngol Head Neck 1994: 120: 703–706. 18. Woolger JA. Histopathological distribution of cervical lymph node metastasis from intraoral/oropharyngeal squamous cell carcinoma. Br J Oral Maxillofac Surg 1999: 37: 175–180. 19. Yao M, Dornfeld KJ, Buatti JM, Skwarchuk M, Tan H, Nguyen T, Wacha J, Bayouth JE, Funk GF, Smith RB, Graham SM, Chang K, Hoffman HT. Intensity-modulated radiation treatment for head-and-neck squamous cell carcinoma-The University of Iowa experience. Int J Radiol Oncol Biol Phys 2005: 63: 410–421. Address: Rau´l Gonza´lez-Garcı´a, MD Calle Los Ye´benes 35, 8C 28047, Madrid, Spain Department of Oral and Maxillofacial Surgery University Hospital La Princesa, Madrid Spain Tel: +34 639129396 Fax: +34 915702259 E-mail: [email protected]
Clinical Paper Head and Neck Oncology
Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients
R. Gonza´lez-Garcı´a, L. Naval-Gı´as, J. Sastre-Pe´rez, F. J. Rodrı´guez-Campo, M. F. Mun˜oz-Guerra, J.L. Gil-Dı´ez Usandizaga, F. J. Dı´az-Gonza´lez Department of Oral and Maxillofacial Surgery, University Hospital La Princesa, Madrid, Spain
R. Gonza´lez-Garcı´a, L. Naval-Gı´as, J. Sastre-Pe´rez, F. J. Rodrı´guez-Campo, M. F. Mun˜oz-Guerra, J. L. Gil-Dı´ezUsandizaga, F. J. Dı´az-Gonza´lez: Contralateral lymph neck node metastasis of primary squamous cell carcinoma of the tongue: a retrospective analytic study of 203 patients. Int. J. Oral Maxillofac. Surg. 2007; 36: 507–513. # 2007 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons. Abstract. In primary squamous cell carcinoma (SCC) of the oral cavity, many clinical and histopathological factors have been described as predictive for cervical lymphnode metastasis, but there are no data available on this association for surgical resection of lateral tongue primary SCC. The aim of this study was to analyse factors related to contralateral neck relapse in a series of 203 consecutive patients with SCC of the lateral aspect of the tongue treated by surgery with or without adjuvant radiotherapy. Several clinical features were analyzed. Histological study included pTNM classification, tumour size, surgical margins, extracapsular spread of lymphnode metastasis, perineural infiltration, peritumoural inflammation and bone involvement. The mean duration of follow up for surviving patients was 70.9 49.6 months; 47 patients eventually died of the disease and 116 patients are alive with no evidence of recurrence. The mean disease-specific survival time was 149 7 months. Twenty (9.8%) patients developed ipsilateral and nine (4.4%) contralateral neck recurrence. The mean period of time from surgery to contralateral neck recurrence was 11.4 months (range 3–27 months). Fourteen of the 20 ipsilateral and 8 of the 9 contralateral neck relapse patients eventually died of the disease. Histopathological grading and peritumoural inflammation were found to be statistically significant (P < 0.05). Clinical and pathological lymph neck node status was not found to be associated with the appearance of contralateral lymph neck node relapse. Due to the increased risk of contralateral neck relapse within the first 2 years of surgery, close surveillance is mandatory at this time.
0901-5027/060507 + 07 $30.00/0
Key words: squamous cell carcinoma; oral cavity; tongue; cervical lymph-node relapse; metastasis. Accepted for publication 16 January 2007 Available online 28 February 2007
# 2007 Published by Elsevier Ltd on behalf of International Association of Oral and Maxillofacial Surgeons.
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Several clinical and pathological factors have been proposed as prognostic in oral squamous cell carcinoma (SCC), such as site, extension, stage of primary tumour, grade of histological differentiation, thickness and perineural invasion2,15,9. The presence of cervical lymph-node metastasis has been associated with poor prognosis12, and neck failure after radical neck dissection has almost invariably a fatal outcome16. Few studies concerning prognostic factors for specific contralateral lymph neck node relapse (CLNR) in relation to SCC of the lateral aspect of the tongue are available. SCC of the oral cavity extended to the midline has been associated with an increase in bilateral and contralateral cervical lymph-node metastasis18, and this can be extended to carcinomas of the tongue. The study of tumours originally arising in the lateral side of the tongue is essential in order to determine the relationship between primary tumour features and the appearance of CLNR. In these cases, the appearance of CLNR should be explained by factors other than the central location of the tumour. The purpose of this retrospective analytic study was to determine clinical and pathological features that predict CLNR in surgically treated primary SCC of the lateral side of the tongue. This may help in the identification of patients with an elevated risk of CLNR and therefore a poor prognosis. Patients and methods
This study is based upon a series of 203 consecutive patients diagnosed with primary SCC of the anterior two thirds of the tongue who were treated at the Department of Oral and Maxillofacial-Head and Neck Surgery, La Princesa University Hospital, Madrid, Spain, from June 1979 to December 1999. Patients were selected from a prospective database, and none had previously received treatment in any other department. They were treated by means of surgery with or without adjuvant radiotherapy. Surgery was performed in all cases by the same team, composed of two main surgeons. Surgical achievements only were considered for evaluation, so no patients undergoing radiotherapy or chemotherapy as primary treatment were included in this study. Only a small proportion (less than 2%) of the total number of patients with SCC of the tongue were not treated by primary surgery and were not included in the prospective list of patients selected for this study. This was the result of advanced
disease associated with general poor condition due to advanced age at the time of diagnosis. The following exclusion criteria were established: (1) recurrence of the primary tumour (52 of 517 patients); (2) multiple oral and/or head and neck cancer (87 of 517 patients); (3) contraindication for surgery (unresectable tumour or inoperable patient); (4) distant metastasis at the time of diagnosis. Tumours primarily arising from the lateral side of the tongue were selected, including those invading the midline. There was no limitation in TNM staging, and patients with stages I–IV of the tongue were included in the study. The following inclusion criteria were established: (1) presence of histological confirmation of SCC; (2) no prior treatment; (3) surgical treatment as first management method. Extent of tongue involvement was determined by magnetic resonance imaging (MRI) or computed tomography (CT). Neck staging was performed by means of physical examination, CT scan and MRI. Some cases underwent fine needle aspiration biopsy. After examining the records, the following data were analysed for each patient: age, gender, habits, date of diagnosis, performance status, clinical features of the tumour, grade of histological differentiation of the primary tumour, tumour stage according to the TNM classification, number and location of cervical nodes, surgical reconstruction, neck dissection, postoperative radiotherapy, local and distant relapse, post-surgical complications and survival results. Histological study included pTNM classification, size of tumour, surgical margins, perineural infiltration, peritumoural inflammation and bone involvement. All patients underwent surgical resection of the primary tumour with macroscopic margins (more than 1 cm around the tumour). Tumours were classified according to the TNM Staging Classification, and this determined the type of cervical dissection performed: (1) ipsilateral modified type III radical neck dissection in (T2, T3, T4) N0 tumours or tumours with cervical nodes less than 3 cm without extracapsular extension (no fixed nodes); (2) bilateral modified type III radical neck dissection when invasion of the midline of the tongue was present as a result of tumour extension from its lateral aspect in N0 or N1 patients; (3) ipsilateral classical radical neck dissection when nodes equal to or greater than 3 cm, fixed nodes or effect on the spinalis nerve were present; (4) ipsilateral classical radical neck dissection together with contralateral
modified type III radical neck dissection in patients with ipsilateral N2 or N3 and contralateral N0 involvement, but in whom the midline of the tongue was affected as a consequence of extension from the lateral aspect; and (5) contralateral classical radical neck dissection together with ipsilateral modified type III radical neck dissection in a patient with a positive contralateral node more than 3 cm (N2) at the time of diagnosis (despite this aggressive treatment the patient showed recurrence in the contralateral neck during follow up; it was subsequently considered as a true recurrence and included in the study.) According to the Department of Oncology, conventional local adjuvant radiotherapy ranging from 60 to 70 Gy was performed in those patients in whom free margins less than 1 cm were found on histological examination. Tumours classified as pT3 or more also received local adjuvant radiotherapy. Thus, bone invasion (T4 primary) was an indication for postoperative irradiation. Other tumour-related factors such as spidery growth, lymph or blood vessel invasion, perineural invasion and dysplasia in resection margins were considered indications for adjuvant radiotherapy. Regional radiotherapy was also used when more than three cervical nodes or extracapsular extension were demonstrated. Only those patients in whom the contralateral neck was affected were managed by contralateral adjuvant radiotherapy following neck dissection. In summary, postoperative adjuvant radiotherapy was administered to patients with: (1) a positive resection margin in the specimen, (2) multiple pathologic lymph neck nodes and (3) advanced T classification. Patients were selected and analysed in relation to the type of cervical dissection (Table 1). Necks were histologically classified as positive or negative for lymphnode metastasis after surgical specimens were analysed. Ipsilateral and contralateral cervical relapses were referred during the follow-up period. The age, gender, time to diagnosis, clinical T status, clinical N status, pathologic T status, ipsilateral pathologic N (pN) status, tumour staging, histopathological differentiation, surgical margins of primary tumour resection, tumour thickness (<2 mm or >2 mm), type of neck dissection, perineural infiltration, bone involvement, extracapsular spread of lymph-node metastasis, and postoperative radiotherapy were evaluated for association with contralateral neck relapse. The routine method for diagnosing the presence of cervical relapse was physical examination
Contralateral neck relapse in SCC of tongue
509
Table 1. Relapse in relation to neck dissection pN0 neck
Ipsilateral modif. type III RND Bilateral modif. type III RND Ipsilateral classical RND Ipsilateral classical RND + contralateral modif. type III RND Ipsilateral modif. type III RND + contralateral classical RND
pN+ neck
No. of patients
Ipsilateral relapse ratio
Contralateral relapse ratio
Ipsilateral relapse ratio
Contralateral relapse ratio
80 49 5 6 1
2/58 1/25 0/0 1/1 0/0
4/58 0/25 0/0 0/1 0/0
0/22 3/24 1/5 1/5 1/1
2/22 0/24 0/5 0/5 1/1*
Patients who did not receive neck dissection are not included. modif., modified; RND, radical neck dissection. * One patient presented with both ipsilateral and contralateral lymph neck node metastasis.
followed by CT scan or MRI. Some cases underwent fine needle aspiration before definitive neck dissection. The aim of the study was to determine those features that predict CLNR in surgically treated primary SCC of the lateral side of the tongue. SPSS 12.0 (SPSS Inc., Chicago, IL, USA) statistical software was used to analyse data. The possible association between different clinical and pathological features and the appearance of CLNR was analysed by means of the x2 test for categorical data and the Student’s t test for parametric data. Survival curves were calculated by the Kaplan–Meier method. A P value 0.05 was considered statistically significant. Results
From a total of 517 patients with SCC of the oral cavity, 203 cases fulfilled the inclusion criteria. The male-to-female ratio was 72:28. The mean age was 59.1 13.7 years (range 18–83 years). The mean duration of follow up for surviving patients was 71.1 months (SD 24.5, median 62 months, range 6–204 months). Time elapsed from first clinical manifestations to diagnosis ranged from 0 to 84 months, with a mean of 4 months and a median of 2 months. Clinicopathological factors and occurrence of contralateral
lymph neck node relapse are shown in Table 2. Forty-seven patients eventually died of the disease, whereas 19 patients died of disease not related to SCC of the tongue. One hundred and sixteen patients are still alive with no evidence of recurrence. The mean disease-specific survival time was 149 7 months (95% confidence interval: 135–166 months) (Fig. 1). The majority of the patients in this series underwent neck dissection (n = 141; 73.1%): (1) 80 (40.6%) underwent an ipsilateral modified type III radical neck dissection; (2) 49 (24.9%) bilateral modified type III radical neck dissection; (3) 5 (2.5%) ipsilateral classical radical dissection; (4) 6 (3%) ipsilateral classical radical dissection together with contralateral modified type III radical neck dissection; and (5) 1 (0.5%) ipsilateral modified type III radical neck dissection together with contralateral classical radical neck dissection. Bilateral neck dissections (groups 2, 4 and 5) were performed in those patients in whom midline involvement or clinical or radiological involvement of both sides of the neck was demonstrated. A mean of 22.6 lymph nodes were analysed in those patients who underwent ipsilateral cervical dissection, whereas a mean of 19.9 lymph nodes were analysed for contralat-
Fig. 1. Disease-specific survival of the whole series.
eral neck dissections. Table 3 summarizes the patient data and the occurrence of CLNR during the follow-up period. Histological confirmation of SCC was obtained postoperatively for all the patients. Seventy-three (37.6%) received adjuvant radiotherapy after the surgical procedure. Twenty-eight (13.7%) developed local relapse after definitive therapy. In relation to cervical relapse, 20 (9.8%) patients developed ipsilateral neck recurrence, whereas 9 (4.4%) developed contralateral neck recurrence. Local–regional relapse was observed in 14 (6.9%) patients and distant metastasis in 15 (7.4%) within the whole series. Fourteen of the 20 ipsilateral and 8 of the 9 contralateral neck relapse patients eventually died of the disease. The mean period of time from surgery to appearance of contralateral neck recurrence was 11.4 months, with a median of 13 months (range 3–27 months). The majority of cases (77.8%) in which CLNR appeared had been managed by means of the modified type III radical neck dissection initially. One of these seven cases had also received contralateral classical radical dissection, due to the absence of ipsilateral neck lymph nodes but the presence of CLNR. One of the nine patients with CLNR did not receive cervical neck dissection either initially or after recurrence, while another only received modified type III radical neck dissection when the CLNR had appeared. In summary, six of the nine patients with CLNR were amenable to further neck dissection. The remaining three patients were not candidates for surgery and only palliative treatment was offered. At the end of the follow-up period only one of the nine patients with CLNR remained alive (Table 4). Histopathological grading and peritumoural imflammation were found to be statistically significant (P < 0.05) in relation to CLNR. Clinical and pathological lymph neck node status was not found to be associated with the appearance of CLNR. Some other features, such as adjuvant radiotherapy (absence of adjuvant
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Table 2. Distribution of clinicopathological factors and occurrence of contralateral lymph-node relapse
Sex Male Female T-stage Tis T1 T2 T3 T4
No. of cases (%)
No. of patients with contralateral lymph node relapse (%)
146 (71.9) 57 (28.1)
6 (4.1) 3 (5.2)
0.71
P value
4 45 89 30 35
(1.9) (22.2) (43.8) (14.8) (17.2)
0 (0) 0 (0) 7 (7.8) 1 (3.3) 1 (2.8)
0.10 (1)
149 34 5 4 7 3
(73.4) (16.7) (2.4) (1.9) (3.4) (1.4)
6 (4.0) 0 (0) 0 (0) 3 (75) 0 (0) 0 (0)
0.62 (2)
178 (87.6) 22 (10.8) 3
9 (4.4) 0 (0) (0)
0.28
1 (1.8) 7 (8.7) 0 (0) 0 (0) 0 (0)
0.26 (3)
N N0 N1 N2a N2b N2c N3 Local surgery Local Local + bone Lost to follow up Cervical dissection None Ipsilateral modified type III radical neck dissection Bilateral modified radical neck dissection type III Ipsilateral classical radical neck dissection Ipsilateral classical radical neck dissection + contralateral modified type III radical neck dissection Ipsilateral classical radical neck dissection + ipsilateral modified type III radical neck dissection Missing data
53 80 49 5 6
(26.9) (40.6) (24.9) (2.4) (2.9)
1 (0.5) 9
1 (100) (0)
Reconstruction Direct closure Microsurgery Pectoralis myocutaneous flap CO2 laser
100 15 34 54
(49.2) (7.3) (16.7) (27.1)
8 (8) 0 (0) 0 (0) 1 (1.8)
0.01 (4)
Adjuvant radiotherapy Yes No
122 (60.1) 81 (30.9)
3 (2.4) 6 (7.4)
0.09
Histopathological grading Well differentiated Moderately differentiated Poorly differentiated Missing data
79 (38.9) 101 (49.8) 21 (10.3) 2
2 (2.5) 4 (3.9) 3 (14.2) (0)
0.02 (5)
pT pTis pT1 pT2 pT3 pT4 Missing data
9 59 77 21 24 13
(4.4) (30.3) (39.5) (10.8) (12.3)
0 (0) 1 (1.6) 6 (7.7) 1 (4.7) 1 (4.1) (0)
0.11 (6)
pN pN0 pN1 pN2a pN2b pN2c pN3
146 16 5 24 10 2
(71.9) (7.8) (2.4) (11.8) (3.4) (0.9)
6 (4.1) 0 (0) 0 (0) 3 (12.5) 0 (0) 0 (0)
0.68 (7)
Surgical margins Correct (1 cm) Microscopical involvement Macroscopical involvement
147 (75.4) 25 (12.8) 3 (1.4)
5 (3.4) 1 (4) 0 (0)
0.11 (8)
Contralateral neck relapse in SCC of tongue
511
Table 2 (Continued ) No. of cases (%)
No. of patients with contralateral lymph node relapse (%)
16 (8.2) 4
3 (18.7) (0)
Tumour thickness <2 mm >2 mm Missing data
25 (12.9) 137 (70.6) 32
1 (4) 8 (5.8) (0)
0.71
Peritumoural inflammation None Scarce Moderate Intense Missing data
118 17 30 30 8
(60.5) (8.7) (15.4) (15.4)
9 (7.6) 0 (0) 0 (0) 0 (0) (0)
0.01 (9)
Perineural infiltration Yes No Missing data
39 (20.0) 156 (80.0) 8
4 (10.2) 5 (3.2) (0)
0.06
Bone affected Yes No Missing data
4 (1.9) 191 (97.9) 8
0 (0) 6 (3.1) (3)
0.71
Free insufficient (<1 cm) Missing data
P value
(1) P value is calculated comparing Tis–T1 to T2 and upper. (2) P value is calculated comparing N0 to N+. (3) P value is calculated comparing no cervical dissection to any type of cervical dissection. (4) P value is calculated comparing direct closure to any other reconstruction. (5) P value is calculated comparing well differentiated and moderately differentiated vs. poorly differentiated histopathological grading. (6) P value is calculated comparing pTis–pT1 to pT2 and upper. (7) P value is calculated comparing pN0 to pN+. (8) P value is calculated comparing surgical margins 1 cm to no correct surgical margins. (9) P value is calculated comparing no peritumoural inflammation to peritumoural inflammation.
radiotherapy versus administration of adjuvant radiotherapy, P = 0.09), clinical tumour staging (Tis/T1 versus T2 and upper, P = 0.10), pathological T staging (pTis/pT1 versus pT2 and upper, P = 0.11), surgical margins (incorrect less than 1 cm versus correct 1 cm, P = 0.10) and perineural infiltration (presence of perineural infiltration versus absence of perineural infiltration, P = 0.06), may be demonstrated to be statistically significant in larger series. Discussion
Recurrent primary lesions and cervical lymph-node relapse affect the prognosis and decrease survival rate of patients with
carcinoma of the tongue. A small percentage of early carcinomas of the tongue are aggressive, with associated poor prognosis2,15,9. The unfortunate outcome of patients with oral carcinoma who develop contralateral lymph neck node relapse is also known. Several authors have analysed risk factors for CLNR in tumours of the oral cavity, but few published studies are available concerning the existence of prognostic factors for CLNR in lateral tongue carcinoma. In relation to SCC of the oral cavity, a variable frequency of contralateral metastasis ranging from 0.9% to 34.7% has been referred in the literature12,18. KOWALSKI et al.7 reported an incidence of 14% for CLNR, in concordance with that reported
Table 3. Patients’ follow-up features and occurrence of contralateral lymph neck node relapse No. of cases (%) Relapse Local Ipsilateral neck Contralateral neck Local–cervical Distant metastasis Situation at end of follow up Alive, no evidence of disease Alive with tumour Died of disease Died of other disease Missing data
No. of patients with contralateral lymph-node relapse (%)
28 20 9 14 15
(13.7) (11) (4.4) (7.1) (7.3)
0 0 9 0 0
(0) (0) (100) (0) (0)
116 5 47 19 16
(59.5) (2.6) (24.1) (9.7)
1 0 8 0
(0.8) (0) (17) (0)
by KURITA et al.8 Some features may influence the appearance of CLNR. Location of the primary tumour seems to play an important role. A higher risk of contralateral metastasis in patients with tumours of the floor of the mouth and the anterior third of the tongue compared to the retromolar region or the lateral gum has been reported. The contrasting report of a higher incidence of CLNR in cases of lower gum carcinoma (25%) in comparison to those tumours arising in the mobile tongue (15.4%)8 makes necessary more research to elucidate the influence of the primary tumour location. In relation to tongue carcinomas, the importance of primary tumour invasion across the midline has already been exposed by MARTIN et al.12: 16% of the tumours crossing the midline by less than 1 cm developed CLNR. This value increased to 46% in cases that invaded over the midline by more than 1 cm. KOWALSKI et al.7 showed that clinical staging, tumour crossing the midline and floor of the mouth involvement were the most important predictors of contralateral metastasis. All the present cases involved the lateral side of the tongue, but midline involvement of a tumour primarily located on the lateral side of the tongue was not considered as an exclusion criterion. An increase in percentage of CLNR may be encountered in those cases where the tumour finally reaches the midline of the
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Table 4. Summary of patients with contralateral neck relapse
Primary neck dissection
Postoperative radiation therapy
Relapse time (months)
Ipsilateral modif. type III RND Ipsilateral modif. type III RND
N N
13 5
T1 N0 T2 N0
None Ipsilateral modif. type III RND
N N
13 27
57
T2 N2b
Ipsilateral modif. type III RND+
Y
6
45 46 58 76
T2 T2 T2 T2
Ipsilateral modif. type III RND Ipsilateral modif. type III RND Ipsilateral modif. type III RND None
N Y Y N
10 13 13 3
Age (years)
pTNM
M M
75 46
T3 N0 T4 N0
M M
76 42
M F F M F
Gender
N0 N2b N2b N0
Secondary neck dissection
Outcome
None Ipsilateral modif. type III RND+ Contralateral Classical RND Bilateral modif. type III RND Ipsilateral modif. type III RND+ Contralateral classical RND Contralateral modif. type III RND Contralateral classical RND Contralateral modif. type III RND None None Contralateral modif. type III RND
DOD DOD DOD DOD DOD NED DOD DOD DOD
modif., modified; RND, radical neck dissection; DOD, died of disease; NED, no evidence of disease.
tongue, due to the involvement of contralateral lymphatic drainage. No specific correlation could be established in these cases because other dependent factors such as increased tumour size could have influenced the appearance of CLNR. In an attempt to determine the influence of the location of the primary tumour, a preponderance of CLNR in tumours with radiological evidence of extension over the midline has been shown8. Although this may appear to be an important independent factor, multivariate analysis has elucidated that it is not the only one, and other variables must be globally considered9. The clinical staging and size of the tumour could be considered to be important factors favouring the development of CLNR, at least as important as tumour location and involvement of the midline, but a correlation between earlier cancers (T1–T2) and CLNR was not found. Other authors have suggested similar results, although they considered T1–T3 as earlier cancers7,8. In a recent study by YAO et al.19 concerning intensity-modulated radiation treatment for head and neck SCC, neither T stage nor N stage had a significant effect on local–regional control. Some other factors, such as the histopathological grading, have been related to the frequency of CLNR. In the present study, there was a statistically significant association between histological grading and the appearance of CLNR: poorly differentiated tumours developed CLNR more frequently. A statistically significant association between the absence of peritumoural inflammation and the appearance of CLNR was also observed. A possible explanation for this association could be that a low host immunological response around the primary tumour could allow easier dissemination of cancer cells through lymphatic drainage.
The number of ipsilateral metastatic lymph nodes could also be considered an important prognostic factor. Ipsilateral neck lymph-node metastasis has been referred to as a significant predictor for the occurrence of CLNR in tumours of the oral cavity12,18,14, and the appearance of contralateral metastasis was always described in the context of simultaneous ipsilateral metastasis. A possible explanation for these findings is that the performance of elective neck dissection together with primary tumour resection may predispose patients to aberrant migration of in-transit carcinomatous cells to the opposite side of the neck4. In relation to tumours of the oral cavity, CHOW et al.1 in a series of 72 patients, reported a similar incidence of ipsilateral (n = 7) and contralateral (n = 5) neck node relapse. The present results in the tongue do not support these data: contralateral neck failure (4.4%, n = 9) was not as common as ipsilateral relapse (11.0%, n = 20). This difference may be explained by the smaller number of patients in the former study. In contrast to these previous studies, a significant association between ipsilateral clinical or pathological lymph neck node status and CLNR could not be demonstrated in the present study. In this series, bilateral neck dissection was not significantly associated with a decrease in contralateral metastasis. Other authors have failed to demonstrate this association, probably due to the small sample size of their series1. The present results showed a non-statistically significant association between bilateral dissection and decrease in CLNR (P = 0.1). Only 1 of 55 patients undergoing bilateral neck dissection as definitive treatment developed CLNR compared to 7 of 78 patients undergoing ipsilateral neck dissection only. As shown by WEBER et al.17 bilateral neck dissection seems to be extremely
effective in midline primary tumours. The low incidence reported by various authors supports the recommendation for bilateral neck dissection in selected patients with involvement of the midline18,1,5. Concerning the type of modified neck dissection, some authors have considered the possibility of preserving level V lymph-node pads in patients with clinically N+ neck below the nodal stage N2a10, and the performance of a supraomohyoid neck dissection for N0 and a more comprehensive neck dissection (levels I–V) for N+ patients in stage I–II SCC of the tongue and floor of the mouth3. Several authors have thus failed to demonstrate the association of different clinical and histological features with CLNR in the carcinoma of the oral cavity. Some authors have only reported a statistically significant association between pN status and CLNR14, leading to the proposal of aggressive treatment for contralateral necks in cases with positive pN status. In contrast, elective neck dissection for the contralateral N0 neck in early oral tongue carcinoma has not shown any advantage in recent reports11. Although the application of whole neck treatment (surgery or radiotherapy) in cases with ipsilateral clinical nodular involvement could be concluded from other studies, the present results and the small percentage of patients that finally develop CLNR support an individual study of the risks and benefits of bilateral neck treatment for each patient. In recent years a special effort has been made to elucidate which tumour-related factors could influence the appearance of metastasis in SCC of the tongue. Spidery growth, lymph or blood vessel in growth, perineural growth and dysplasia in resection margins have been analysed. In a recent publication13, it was observed that a decrease in E-cadherin and/or P-cadherin expression may contribute to the
Contralateral neck relapse in SCC of tongue invasive potential of early oral SCC. Pcadherin expression may be a potential independent prognostic factor in these patients. HANNEN et al.6 studied the significance of tumour DNA features in SCC of the tongue. They showed an improvement of predictive values with a multiparameter model to predict the process of metastasis more accurately. Future clinical retrospective studies concerning the technique proposed by these authors would be of interest. The present observations confirm the unfavourable prognosis of patients with CLNR, with only one of nine patients surviving. In accordance with other reported series16,17, CLNR occurred within the first 2 years after surgery in 89.9% of the affected patients. Special effort must be made to detect early recurrence, and careful follow up is mandatory during this period of time. In summary, the possibility of collecting clinical information before surgical treatment in an attempt to determine which patients have an increased risk of CLNR may improve prognosis in tongue carcinoma. Surgeons may be encouraged to perform more aggressive treatments in patients with a high risk of CLNR. Clinical and pathological positive node status on the ipsilateral side of the neck is not associated with a higher incidence of contralateral cervical metastasis in SCC of the lateral side of the tongue. Poorly differentiated primary tumours and the absence of peritumoural imflammation are significantly associated with contralateral lymph neck node relapse. Due to the increased risk of CLNR within the first 2 years after surgery, close surveillance is mandatory.
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