Journal of Cranio-Maxillo-Facial Surgery xxx (2016) 1e5
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Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study Takumi Hasegawa a, *, Yasuyuki Shibuya b, Daisuke Takeda a, Eiji Iwata a, Izumi Saito a, Yasumasa Kakei a, Akiko Sakakibara a, Masaya Akashi a, Tsutomu Minamikawa a, Takahide Komori a a b
Department of Oral and Maxillofacial Surgery (Chief: Prof. T. Komori), Kobe University Graduate School of Medicine, Japan Department of Oral Maxillofacial Surgery (Chief: Prof. Y. Shibuya), Nagoya City University Graduate School of Medical Science, Japan
a r t i c l e i n f o
a b s t r a c t
Article history: Paper received 20 June 2016 Accepted 20 October 2016 Available online xxx
Purpose: The objectives of this study were to retrospectively describe the characteristics and outcomes of patients with oral squamous cell carcinoma (OSCC) with level IV/V metastases, and to evaluate the multivariate relationships among potential risk factors for metastasis and prognosis. Materials and methods: We evaluated 291 patients (178 men and 113 women; mean age, 65.9 ± 13.5 years). Clinicopathological data, time of development of level IV/V metastases, and clinical course were investigated. Results: Twenty-three patients (7.9%) developed level IV/V metastases. The 3-year overall survival rates when level IV/V metastasis first developed were 27.3% upon initial treatment, 57.1% when metachronous neck metastasis developed, and 40.0% when the tumor recurred. Oral tongue tumor subsite, high N staging, neck dissection when metachronous neck metastasis developed, as well as recurrence were independent risk factors for level IV/V metastasis. Conclusion: We demonstrate here the multivariate relationships among the risk factors indicated above for level IV/V metastasis and their prognostic significance for patients with OSCC. Oral tongue tumors, high N staging, and neck dissection upon the occurrence of metachronous neck metastasis or recurrence were risk factors for level IV/V metastasis and positive extracapsular spread, presence of multiple lymph metastases, and moderate or poor differentiation were poor prognostic factors. © 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Keywords: Risk factor Oral cancer Lymph node metastasis Neck level
1. Introduction Surgery, adjuvant chemoradiation, or both for treating patients with oral squamous cell carcinoma (OSCC) have improved locoregional control [Liao et al., 2007, 2008], although the control over distant metastases and overall survival (OS) rates remain low [Bernier et al., 2004; Cooper et al., 2004]. Extracapsular spread (ECS) [Snow et al., 1982; Carter et al., 1987; Richard et al., 1987; Stell PM., 1990; Hirabayashi et al., 1991; Barona de Guzman et al., 1993], multiple lymph metastases (MLM) [Snow et al., 1982; O'Brien et al., 1986; Zhao et al., 1989; Stell PM., 1990; Rapoport and Franco, 1993;
* Corresponding author. Department of Oral and Maxillofacial Surgery, Kobe University Graduate School of Medicine, 7-5-1, Kusunoki-cho, Chuo-ku, Kobe 6500017, Japan. Fax: þ81 78 351 6229. E-mail address:
[email protected] (T. Hasegawa).
Leemans et al., 1994], and lymphatic metastasis in the lower neck [Ono et al., 1985; Ellis et al., 1989; Zhao et al., 1989] are prognostic indicators of survival. Two recent randomized trials conducted by the European Organization for Research and Treatment of Cancer (EORTC) and the Radiation Therapy Oncology Group (RTOG) demonstrate the benefit of concomitant postoperative chemoradiotherapy (CCRT) in patients with head and neck squamous cell carcinoma (HNSCC) who are at high risk for recurrence and metastasis [Bernier et al., 2004; Cooper et al., 2004]. A subsequent, collaborative analysis of these results found that microscopic tumor-involved resection margins (incomplete resection [ICR]) and ECS from neck lymph nodes are predictors of poor outcome [Bernier et al., 2005]. In the EORTC trial, patients with oral cavity or oropharyngeal tumors with involvement of lymph nodes at level IV or V had a high risk of recurrence [Bernier et al., 2004], although the characteristics and outcomes of
http://dx.doi.org/10.1016/j.jcms.2016.10.011 1010-5182/© 2016 European Association for Cranio-Maxillo-Facial Surgery. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Hasegawa T, et al., Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study, Journal of Cranio-Maxillo-Facial Surgery (2016), http://dx.doi.org/10.1016/j.jcms.2016.10.011
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T. Hasegawa et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2016) 1e5
patients with OSCC with level IV/V metastasis were not reported. Therefore, the aim of the present study was to retrospectively identify significant multivariate relationships among risk factors for level IV/V metastasis and the prognosis of patients with OSCC. 2. Materials and methods We conducted a nonrandomized retrospective study of a cohort of 291 patients with oral cancer who underwent major head and neck surgery at the Department of Oral and Maxillofacial Surgery, Kobe University Hospital, between January 1999 and December 2013. The Institutional Review Board of Kobe University Graduate School of Medicine approved the study. Disease stages of the patients (n ¼ 291) were as follows: 22 (7.6%), stage I; 89 (30.6%), stage II; 54 (18.6%), stage III, and 126 (43.3%), stage IV. All patients underwent wide excision of the primary tumor, neck dissection, or both with modified radical neck dissection or selective neck dissection with or without postoperative adjuvant chemoradiation. Patients underwent neck dissection at the times and for the conditions as follows: initial treatment, 236 (81.1%); 29 (10.0%), occurrence of metachronous neck metastasis; recurrence, 14 (4.8%); and initial treatment and recurrence, 11 (4.1%). Patients were administered a preoperative examination including chest X-rays, computed tomography, and magnetic resonance imaging. We excluded patients with other cancers before their diagnosis of OSCC, a history of palliative treatment because of poor medical condition, refusal of curative surgery, simultaneous second primary cancer, or previous radiotherapy or chemotherapy for head and neck cancer or other diseases. Clinicopathological data for sex, age, anatomic subsite, T and N classification, stage, pathological node status (presence, ECS, number of node metastases, and presence or absence of level IV/V metastasis), histologic grade (well, moderately, or poorly differentiated), and surgical margins (ICR) are summarized in Table 1. The time of development of level IV/V metastases and the clinical course were included in the analyses. Data collection and statistical analyses were performed using SPSS 15.0 software (SPSS Inc., Chicago, IL, USA) and Stat-View-J-4.5 software (Abacus Concepts, Berkeley, CA, USA). The significance of the association of each variable with level IV/V metastasis was evaluated using the ManneWhitney nonparametric test for ordinal variables and Fisher exact test or the chi-squared test for categorical variables. Cumulative OS (presence vs absence of level IV/V metastasis) was calculated using the KaplaneMeier product-limit method. Significant differences among the curves were determined using the log-rank test. P < 0.05 indicated a statistically significant difference. Preoperative variables associated with level IV/V metastasis were analyzed using a multiple logistic regression model. Forward stepwise algorithms were used, and variables associated with differences that were not significant were excluded. Therefore, pathological status and postoperative treatment were excluded. Multivariate odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for the significant variables. All variables, including the presence or absence of level IV/V metastasis, were analyzed using a Cox proportional hazard model to identify independent predictors of prognosis. Multivariate HRs and 95% CIs were calculated for significant variables. P < 0.05 indicated a statistically significant difference. 3. Results The study population (n ¼ 291) included 178 men and 113 women aged 23e96 years (mean 65.9 ± 13.5 years). Twenty-three patients (7.9%) developed level IV/V metastasis. The sex and age of patients with and without level IV/V metastasis were not
Table 1 Patient characteristics and incidence of level IV/V metastasis. Variable
Level IV/V metastasis Absence (n; %)
Sample size 268 (92.1) Sex Male 160 (59.7) Female 108 (40.3) Age, y Range 23e96 Mean ± SD 65.5 ± 13.0 Subsite Oral tongue 104 (38.8) Buccal mucosa 38 (14.2) Floor of the mouth 25 (9.3) Upper gingiva 28 (10.4) Lower gingiva 57 (21.3) Other 16 (6.0) T classification at the initial visiting 1 20 (7.5) 2 144 (53.7) 3 37 (13.8) 4a/b 67 (25.0) N classification at the initial visiting 0 140 (52.2) 1 65 (24.3) 2 63 (23.5) Clinical stage at the initial visiting I 17 (6.3) II 85 (31.7) III 49 (18.3) IV A/B 117 (43.7) Pathological status The status of positive lymph metastasis ECS 219 (81.7) ECSþ 49 (18.3) Number of lymph metastases 1 (MLM) 190 (70.9) More than 2 (MLMþ) 78 (29.1) Surgical margin Negative (ICR) 240 (89.6) Involved margins (ICRþ) 28 (10.4) Histological differentiation Well 157 (58.9) Moderate 89 (33.2) Poor 22 (8.2) The timing of neck dissection Initial treatment 225 (84.0) Metachronous neck metastasis 22 (8.2) Recurrence 12 (4.5) Both initial and recurrence 9 (3.3) Postoperative radiation therapy Yes 80 (29.8) No 188 (70.2) Postoperative chemotherapy Yes 48 (17.9) No 220 (82.1) Treatment outcome Survival 188 (70.2) Tumor-bearing survival 4 (1.5) Death of local failure 19 (7.1) Death of regional failure 12 (4.5) Death of distant metastasis 18 (6.7) Death of other disease 27 (10.1) a b c
P value
Presence (n; %) 23 (7.9) 18 (78.3) 5 (21.7)
0.117a
40e86 63.7 ± 12.7
0.378b
16 (69.6) 1 (4.3) 3 (13.0) 2 (8.7) 3 (13.0) 0 (0)
0.048c
5 (21.7) 11 (47.8) 6 (26.1) 1 (4.3)
0.011c
10 (43.5) 4 (17.4) 9 (39.1)
0.246c
5 4 5 9
0.040c
(21.7) (17.4) (21.7) (39.1)
7 (30.4) 16 (69.6)
<0.001a
1 (4.3) 22 (95.7)
<0.001a
11 (47.8) 12 (52.2)
0.298a
7 (30.4) 15 (65.2) 1 (4.3)
0.009c
11 (47.8) 7 (30.4) 2 (8.7) 3 (13.1)
<0.001c
8 (34.8) 15 (65.2)
0.009a
12 (52.2) 11 (47.8)
0.002a
6 2 3 5 6 1
<0.001c
(26.1) (8.7) (13.0) (21.7) (26.1) (4.3)
Fisher exact test. Mann-Whitney U test. Chi-squared test.
significantly different (Table 1). The most frequent tumor subsite was the tongue, and univariate analysis revealed a significantly higher rate of occurrence of tongue tumors in patients with than without level IV/V metastasis (P < 0.05) (Table 1). Univariate analysis revealed significant relationships between pathological status and level IV/V metastasis. ECS, MLM, and
Please cite this article in press as: Hasegawa T, et al., Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study, Journal of Cranio-Maxillo-Facial Surgery (2016), http://dx.doi.org/10.1016/j.jcms.2016.10.011
T. Hasegawa et al. / Journal of Cranio-Maxillo-Facial Surgery xxx (2016) 1e5
moderate differentiation were significantly more frequent in patients with than without level IV/V metastasis (P < 0.05) (Table 1). However, there was no significant difference in the presence of positive ICR between the two groups. The rates of neck dissection to treat metachronous metastasis and tumor recurrence were significantly higher in patients with than without level IV/V metastasis (P < 0.05) (Table 1). The 3-year cumulative OS rates of patients with and without level IV/V metastasis were significantly different (52.2% and 74.7%, respectively, P < 0.05) (Fig. 1). The characteristics and outcomes of patients with level IV/V metastases are shown in Table 2. The skip metastasis did not occur in patients with level IV/V metastasis, and the 3-year cumulative OS rates for those who underwent neck dissection were 27.3%, as initial treatment; 71.4%, upon occurrence of metachronous neck metastasis; and 80.0%, upon recurrence (Fig. 2). The 3-year cumulative OS rates starting from the development of level IV/V metastasis were 27.3%, initial treatment; 57.1%,
Fig. 1. Cumulative overall survival (OS) rates in patients with and without level IV/V metastasis.
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Fig. 2. Cumulative overall survival (OS) rates and time of neck dissection in patients with level IV/V metastasis.
metachronous neck metastasis; and 40.0%, recurrence (Fig. 3). The OS rates of patients with dissection upon occurrence of metachronous neck metastasis were longer compared with those of patients who underwent dissection upon initial treatment. However, the OS rates did not differ significantly among groups (Figs. 2 and 3). A logistic regression model using forward stepwise algorithms determined that oral tumors of the tongue (OR, 2.91), high N staging (OR, 2.34), and neck dissection at metachronous neck metastasis or recurrence (OR, 9.28) were significantly associated with the risk of level IV/V metastasis (Table 3). A Cox proportional hazard model that included all study variables determined that positive ECS (HR, 2.52) and MLM (HR, 1.96) as well as moderate or poor differentiation (HR, 1.62) were independent predictors of prognosis (Table 4). However, multivariate analysis did identify level IV/V metastasis as an independent predictor of prognosis.
Table 2 Characteristics and outcomes of patients with level IV/V metastasis. Patient No.
Timing of neck dissection
MLM
Contralateral metastasis
ECS
Treatment modality
Prognosis
Duration until level IV/V metastasis (mo)
Disease-free survival (mo)
Overall survival (mo)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23
IT IT IT IT IT IT IT IT IT IT IT MNM MNM MNM MNM MNM MNM MNM NR NR NR PR þ NM PR þ NM
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ
þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ þ
S þ RT S þ CRT SþC S S þ CRT S S þ RT S þ CRT S S S þ RT S þ RT S þ RT S þ RT/Ca S S S S þ CRT S CRT S S S þ RT
Regional failure Distant failure Regional failure Regional failure Distant failure Regional failure Survival Tumor-bearing Local failure Regional failure Distant failure Survival Distant failure Survival Survival Survival Other disease Distant failure Regional failure Tumor-bearing Survival Distant failure Local failure
0 0 0 0 0 0 0 0 0 0 0 6 16 4 3 18 17 4 33 37 5 1 24
12 31 6 13 4 9 73 53 5 3 7 102 33 81 74 55 23 7 36 42 36 6 26
15 37 11 15 10 14 73 63 13 7 25 102 47 81 74 55 23 9 43 125 36 6 41
MLM: multiple lymph metastasis, ECS: extracupsular spread, IT: initial treatment, MNM: metachronous neck metastasis, NR: neck recurrence, PR þ NM: primary recurrence and neck metastasis, S: surgery, RT: postoperative radiotherapy, C: postoperative chemotherapy, CRT: concomitant chemoradiotherapy. a Adjuvant chemotherapy after postoperative radiotherapy.
Please cite this article in press as: Hasegawa T, et al., Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study, Journal of Cranio-Maxillo-Facial Surgery (2016), http://dx.doi.org/10.1016/j.jcms.2016.10.011
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Fig. 3. Cumulative overall survival (OS) rates starting from the development of level IV/V metastasis and time of neck dissection in patients with level IV/V metastasis.
Table 3 Multivariate logistic regression analysis of risk factors for level IV/V metastasis. Variable
Oral tumors of the tongue High N staging Neck dissection at metachronous neck metastasis or recurrence
P value
0.031 0.006 <0.001
Odds ratio
2.91 2.34 9.28
95% Confidence interval Lower
Upper
1.10 1.28 3.10
7.65 4.28 27.74
Table 4 Multivariate analysis of prognostic variables. Variable
The ECSþ The MLMþ Moderate or poor differentiation
P value
<0.001 0.007 0.002
Hazard ratio
2.52 1.96 1.62
95% Confidence interval Lower
Upper
1.56 1.21 1.19
4.08 3.18 2.22
4. Discussion Pathological confirmation of lymph node metastasis predicts poor prognosis of patients with OSCC [Kowalski et al., 2000; Woolgar et al., 2003; Garzino-Demo et al., 2006; Gil et al., 2009; Rogers et al., 2009]. Lymph node involvement, MLM, ECS, and level of cervical lymph node metastasis indicate poor patient prognosis [Snow et al., 1982; Ono et al., 1985; O'Brien et al., 1986; Carter et al., 1987; Richard et al., 1987; Ellis et al., 1989; Zhao et al., 1989; Stell PM., 1990; Hirabayashi et al., 1991; Barona de Guzman et al., 1993; Rapoport and Franco, 1993; Stell PM., 1990; Leemans et al., 1994]. A recent randomized trial conducted by the EORTC found that patients with tumors of the oral cavity or oropharyngeal tumors with involved lymph nodes at level IV or V are at high risk for recurrence [Bernier et al., 2004]. However, the study cited did not report the characteristics and outcomes of OSCC patients with level IV/V metastases. Using multivariate analysis, the present study identified independent risk factors for level IV/V metastasis and demonstrated their prognostic value in OSCC patients. It is generally assumed that lymph node metastasis of oral cancer occurs at level IV/V secondary to metastasis at levels I to III [Haagensen CD., 1972]. Furthermore, the rates of level IV metastasis in OSCC are 0% and 9% for cN0 and cN þ cases, respectively [Mishra and Sharma, 2010]. However, at level III or IV, it is anatomically
possible for lymph to flow directly to the lymph nodes from the anterior of the tongue after first passing through the level I or II nodes [Haagensen CD., 1972]. The rate of single lymph node metastasis at level IV was 9.9% for patients with oral tumors of the tongue [Byers, 1985]. However, in the present study, single lymph node metastases were not detected at level IV at the time of initial treatment. Conversely, level V metastases were present in 2.0%e5.5% of patients with cN2b or cN2c disease [Davidson et al., 1993; Dias et al., 2006; Rapoport et al., 2009] and occurred secondarily to lymph node metastasis in other regions [Skolnik et al., 1976; Davidson et al., 1993]. MLM may thus increase the risk of level IV/V metastasis, which is consistent with findings that multiple involved nodes are a significant risk €hler and Kowalski, 2012]. In the factor for level IV/V metastasis [Ko present study, oral tongue tumor, high N stage, and neck dissection to treat metachronous neck metastasis or recurrence were significant risk factors for level IV/V metastasis. The finding here that high N stage was a risk factor is consistent with previous reports [Skolnik et al., 1976; Davidson et al., 1993; Dias et al., 2006; Rapoport et al., €hler and Kowalski, 2012]. To our 2009; Mishra and Sharma, 2010; Ko knowledge, there are no published reports of the association between the time of neck dissection and occurrence of IV/V metastasis. The spread of lymph node metastasis beyond the sentinel nodes is an important prognostic factor [Jones et al., 1994; Mamelle et al., 1994]. For example, MLM and positive nodes beyond the sentinel node area predict poor prognosis, and the rate of distant metastasis is increased when positive nodes occur outside the sentinel node area (41%) [Mamelle et al., 1994] or when they number 4 (43%) [Jones et al., 1994]. Moreover, the number of lymph node metastases is the most important predictive factor for disease-free interval and OS [Kowalski et al., 2000]. In the present study, the 3year cumulative OS rate of patients with level IV/V metastasis was worse compared with those without level IV/V metastasis (Fig. 1). These results are consistent with those of previous reports [Jones et al., 1994; Mamelle et al., 1994; Kowalski et al., 2000], although level IV/V metastases were not independently associated with prognosis. The multivariate analysis conducted here revealed that ECS, the presence of MLM, and moderate or poor differentiation were significantly associated with prognosis vs level IV/V metastasis. The RTOG trial found that positive ICR, ECS, MLM, or both indicated poor prognosis [Cooper et al., 1998]. In the present study, ECS and MLM indicated poor prognosis, although ICR was not significantly associated with prognosis. Patients with level III, IV, or V metastases were found to have a significantly increased risk of recurrence and death (2.5 times greater compared with patients without metastasis) [Kowalski et al., 2000]. Moreover, level IV/V metastasis incurred increased risk of neck recurrence and indicated poor prognosis [Davidson et al., 1993; Dias et al., 2006]. In the present study, regional failure and distant metastases occurred in 11/23 (47.8 %) patients with level IV/V metastases and in 30/268 patients (11.2 %) without level IV/V metastasis. Despite previous neck dissection, neck recurrence and treatment failure occur in patients with level IV/V metastasis, which may be explained by implantation of cancer cells at the time of surgery, which subsequently spread beyond the regional lymph nodes and infiltrate the skin or other tissues [Kalnins et al., 1977]. We agree with this view because of the manner that neck recurrence and treatment failure occurred in patients with level IV/V metastasis in the present study. The 3-year cumulative OS rate from the time of development of level IV/V metastases was 27.3% for patients who underwent neck dissection upon initial treatment. Although the difference was not
Please cite this article in press as: Hasegawa T, et al., Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study, Journal of Cranio-Maxillo-Facial Surgery (2016), http://dx.doi.org/10.1016/j.jcms.2016.10.011
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significant, 3-year OS was longer (57.1%) in patients with metachronous neck metastasis, which suggests the poor prognosis of patients with level IV/V metastasis upon initial treatment. Therefore, improved treatment selection criteria for patients with OSCC with level IV/V metastasis are required. However, we must carefully consider this possibility because of the small population analyzed here. 5. Conclusion Here we show that multivariate analysis demonstrates significant relationships among certain risk factors with level IV/V metastasis and prognosis of patients with OSCC. Specifically, oral tongue tumors, high N staging, and neck dissection upon the occurrence of metachronous neck metastasis or recurrence were significantly associated with the development of level IV/V metastases. Furthermore, we determined that positive ECS, presence of MLM, and moderate or poor differentiation were independent predictors of prognosis, although the presence of level IV/V metastasis did not predict prognosis. Clinicians should therefore consider these risk factors and pay close attention to the management of patients with OSCC with level IV/V metastasis. Funding None. Conflict of interest The authors declare that there is no conflict of interest. References Barona de Guzman R, Martorell MA, Basterra J, Armengot M, Montoro A, Montoro J: Analysis of DNA content in supraglottic epidermoid carcinoma. Otolaryngol Head Neck Surg 108: 706e710, 1993 bvre JL, Greiner RH, et al: Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefe Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350: 1945e1952, 2004 Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, et al: Defining risk levels in locally advanced head and neck cancers: a comparative analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27: 843e850, 2005 Byers RM: Modified neck dissection. A study of 967 cases from 1970 to 1980. Am J Surg 150: 414e421, 1985 Carter RL, Bliss JM, Soo KC, O'Brien CJ: Radical neck dissections for squamous carcinomas: pathological findings and their clinical implications with particular reference to transcapsular spread. Int J Radiat Oncol Biol Phys 13: 825e832, 1987 Cooper JS, Pajak TF, Forastiere A, Jacobs J, Fu KK, Ang KK, et al: Precisely defining high-risk operable head and neck tumors based on RTOG #85-03 and #88-24: targets for postoperative radiochemotherapy? Head Neck 20: 588e594, 1998 Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, et al: Postoperative concurrent radiotherapy and chemotherapy for high-risk squamouscell carcinoma of the head and neck. N Engl J Med 350: 1937e1944, 2004 Davidson BJ, Kulkarny V, Delacure MD, Shah JP: Posterior triangle metastases of squamous cell carcinoma of the upper aerodigestive tract. Am J Surg 166: 395e398, 1993 Dias FL, Lima RA, Kligerman J, Farias TP, Soares JR, Manfro G, et al: Relevance of skip metastases for squamous cell carcinoma of the oral tongue and the floor of the mouth. Otolaryngol Head Neck Surg 134: 460e465, 2006
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Please cite this article in press as: Hasegawa T, et al., Prognosis of oral squamous cell carcinoma patients with level IV/V metastasis: An observational study, Journal of Cranio-Maxillo-Facial Surgery (2016), http://dx.doi.org/10.1016/j.jcms.2016.10.011