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Relative factors of late cervical lymph node metastasis in patients with stage I or II oral squamous cell carcinoma
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161
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Oral Medicine/Original Research
Relative factors of late cervical lymph node metastasis in patients with stage I or II oral squamous cell carcinoma Yoshifumi Yoshida a,∗ , Kazumichi Sato b , Mira Kin a , Taiki Suzuki a , Hiroki Bessho c , Yoichi Tanaka d , Akira Katakura a a
Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, Japan Oral Cancer Center, Tokyo Dental College, Japan c Oral and Maxillofacial Surgery, Tokyo Dental College, Japan d Division of Surgical Pathology, Clinical Laboratory, Ichikawa General Hospital, Tokyo Dental College, Japan b
a r t i c l e
i n f o
Article history: Received 7 January 2015 Received in revised form 30 May 2015 Accepted 15 July 2015 Available online 19 August 2015 Keywords: Oral squamous cell carcinoma Late cervical lymph node metastasis Prognosis-related factors Logistic regression analysis History of smoking
a b s t r a c t Objectives: Late cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) is a key indicator of prognosis. If the risk of late metastasis can be predicted, closer follow-up can be pursued, including necessary surgery, thus leading to improved outcomes. In this study, we aimed to investigate factors that could predict OSCC metastasis to the lymph nodes. Methods: We reviewed the medical records of 77 patients with stage I or II OSCC at the Oral Cancer Center of Tokyo Dental College between April 2006 and March 2011. Multivariate analysis and logistic regression were conducted, and clinical factors and pathological factors were included. Results: The number of OSCC patients with late cervical lymph node metastasis was 14 (18.2%). The cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patient without such metastasis. Metastasis to cervical lymph nodes was not associated with a significant decrease in survival according to the log-rank test. On multivariate logistic regression analysis of clinical and pathological factors, only a history of smoking was significantly related to late cervical lymph node metastasis. Three of 77 patients had angiolymphatic invasion, and all three patients developed nodal metastasis. Conclusion: Logistic regression analysis showed that a history of smoking was significantly related to late cervical lymph node metastasis. Moreover, nodal metastasis was found in all cases with angiolymphatic invasion. © 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
1. Introduction The presence of late cervical lymph node metastasis is universally recognized as the main factor influencing survival in patients with oral squamous cell carcinoma (OSCC) [1–3]. Numerous studies on factors correlating with late cervical lymph node metastasis and prognosis have been published. Correlative clinical factors include clinical growth pattern [4] and tumor size [5], whereas pathological
夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author. Present address: Department of Oral Surgery, Tokai University School of Medicine 143, Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. Tel.: +81 47 322 0151; fax: +81 47 324 8577. E-mail address: [email protected] (Y. Yoshida).
factors include the histological grade of malignancy [5–7], and mode of invasion [5–7], angiolymphatic invasion [6]. However, the studies that identified these predictive factors were conducted in heterogeneous populations that included patients who did or did not undergo elective neck dissection, patients with different Union for International Cancer Control TNM staging [8], and those with different tissue type cancers. Thus, it is unclear whether these factors are truly predictive of nodal metastasis, and additional examination in unified populations is required to address this question. Accurately defining the factors that can predict late cervical lymph node metastasis can better identify patients who can benefit from better treatment and more robust follow-up. To accurately predict nodal metastasis from among various examination parameters, it is necessary to adjust for confounding factors. This was addressed by employing logistic regression analysis in this study, which was a retrospective study using multivariate analysis to determine the factors that correlated with nodal
http://dx.doi.org/10.1016/j.ajoms.2015.07.005 2212-5558/© 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
Y. Yoshida et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161
metastasis in stage I and II OSCC cases in which local excision was performed.
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2. Methods
or negative. The histological evaluation of the response to preoperative chemotherapy was classified according to preoperative therapy evaluation based on Ohboshi and Shimosato’s classification [13]: grade 0–I and grade IIa–IV.
2.1. Patients
2.3. Statistical methods
We reviewed the medical records of 77 patients (mean age, 67.3 years; range, 24–92 years) treated for OSCC at the Oral Cancer Center of Tokyo Dental College (an arm of the Division of Dentistry and Oral Surgery at Ichikawa General Hospital, Tokyo Dental College) between April 2006 and March 2011. Subjects were patients with stage I or II OSCC who had undergone surgery as the primary treatment without elective neck dissection. This was a case–control study, with patients with late cervical lymph node metastasis serving as the “case” and those without metastasis serving as the “control.” Moreover, this study was limited to patients without regional recurrence. Cervical lymph nodes were evaluated with physical examination and by computed tomography or magnetic resonance imaging every 3 months during the follow-up period. Survival rate analysis was conducted using data obtained as of March 31, 2012.
The ability of clinical and pathological factors to predict late cervical lymph node metastasis was assessed with univariate and multivariate logistic regression analyses. The predictive ability of each clinical and pathological factor was assessed with univariate analysis using nodal metastasis as the dependent variable. Multivariate analysis was conducted using the significant factors extracted from univariate analysis. P < 0.25 was the standard for extracting factors as covariate. Survival curves in patients with and without metastasis were plotted using the Kaplan–Meier method. The correlations between cumulative survival rate (overall survival rate) and late cervical lymph node metastasis were analyzed with the log-rank test. Statistical tests of all data were performed with SPSS software version 19 (IBM, Japan). Results were considered statistically significant when the P value was <0.05.
2.2. Factors Clinical and pathological factors were examined for their ability to predict late cervical lymph node metastasis. The clinical factors were age, sex, cancer site, tumor size, growth type, operative procedure, presence or absence of preoperative chemotherapy, presence or absence of postoperative chemotherapy or radiation therapy, and histories of smoking, alcohol consumption, and diabetes mellitus (DM). Tumor size was classified as T1 (<20 mm), early T2 (≥20 mm and <30 mm), or late T2 (≥30 mm and <40 mm); previous reports suggested that this stratification correlated with the presence of nodal metastasis [5]. Clinical growth pattern was classified as superficial, exophytic, or endophytic. The operative procedure was classified as surgical treatment after diagnosis by incisional biopsy, or excisional biopsy. Smoking history was stratified as heavy smoking (Brinkman index [9] score >600) and non-smoking/light smoking (Brinkman index score <600). Alcohol consumption was satisfied as heavy drinking and non-drinking/light drinking group. The history of DM was also investigated because past reports suggest that DM affects survival and may predict cervical lymph node metastasis in patients with gingival carcinoma [10]. Pathological factors were differentiation, mode of invasion, surgical margin, angiolymphatic invasion, and histological evaluation of the response to preoperative chemotherapy. The degree of differentiation was classified as well, moderate, or poor differentiation, according to grade (World Health Organization classification) [11]. The mode of invasion was classified into three groups according to the pattern of tumor infiltration (INF) from the criteria of digestive organ carcinoma [12] (esophagus, stomach, and colon carcinoma) used for clinical diagnosis: INFa, INFb and INFc (Table 1). The surgical margin was classified as positive, dysplasia, Table 1 Pattern of tumor infiltration (INF) into the surrounding tissues. Definition INF a INF b INF c
Tumor displays expanding growth with a distinct border from the surrounding tissue. Tumor shows a pattern intermediate between that of INFa and INFc. Tumor displays infiltrative growth with no distinct border with the surrounding tissue.
3. Results 3.1. Univariate analysis Table 2 summarizes the ability of clinical and pathological factors to predict late cervical lymph node metastasis according to univariate logistic regression analysis. The study included 77 patients (mean age, 67.3 years; range, 24–92 years), including 46 males and 31 females (male to female ratio, 1.48:1). Twenty-five patients had stage I disease and 52 patients had stage II disease. Forty (51.9%) patients had tongue cancer, 17 (22.1%) had lower gingival cancer, nine (11.7%) had upper gingival cancer, five (6.5%) had cancer of the floor of the mouth, four (5.2%) had buccal mucosal cancer, and two (2.6%) had lip cancer. On univariate analysis, only a history of smoking correlated with late cervical lymph node metastasis (P < 0.05). Other clinical factors such as age, sex, cancer site, tumor size, clinical growth pattern, operative procedure, preoperative chemotherapy, postoperative chemotherapy or radiation therapy, history of alcohol consumption, and DM did not correlate with nodal metastasis. Furthermore, pathological factors, such as differentiation, mode of invasion, and surgical margin, did not correlate with nodal metastasis. Table 3 summarizes the analysis of angiolymphatic invasion. Logistic regression analysis could not be conducted because all three patients with angiolymphatic invasion had cervical lymph node metastasis. Preoperative chemotherapy evaluation according to Ohboshi and Shimosato’s classification was limited to 30 patients who had received it. These 30 patients included eight with metastasis and 22 without. Stratification of this parameter did not correlate with nodal metastasis (Table 4). 3.2. Multivariate analysis Results of multivariate logistic regression analysis of clinical and pathological factors are shown in Table 5. A history of smoking (P < 0.05; odds ratio [OR], 11.505; 95% confidence interval [CI], 1.607–82.341) was identified as a significant predictor of nodal metastasis. Operative procedure also correlated with nodal metastasis, but this relationship did not reach the level of statistical significance (P = 0.0713; OR, 13.516; 95%CI, 0.921–198.453).
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Y. Yoshida et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161
Table 2 Logistic regression analysis in cervical lymph node metastasis (univariate analysis). Factors
Nodal metastasis
Univariate analysis
Metastasis (14)
No metastasis (63)
Age Sex 7 Male 7 Female Expression site 7 Tongue 1 Upper gingiva 6 Lower gingiva 0 Buccal mucosa 0 Floor of mouth Lip 0 Tumor size T1 3 6 Early 5 Late T2 Clinical growth pattern 0 Exophytic 2 Superficial 12 Endophytic Operative procedure 1 Excisional biopsy Incisional biopsy 13 Preoperative chemotherapy 6 Absent 8 Present Postoperative chemotherapy or radiation therapy Absent 5 9 Present Smoking 9 Non/light-smoking 5 Heavy-smoking Alcohol 9 Non/light-drinking Heavy-drinking 5 DM 12 Absent 2 Present Differentiation 11 Well 2 Moderate Poor 1 Mode of invasion 3 INFa 8 INFb 3 INFc Surgical margin 10 Negative 3 Dysplasia 1 Positive
Odds ratio (95%CI)
P value
0.980 (0.944–1.018)
0.291
39 24
1.739 (0.542–5.584)
0.352
33 8 11 4 5 2
0.889 (0.570–1.386)
0.604
22 27 14
1.618 (0.738–3.545)
0.230
12 8 43
2.625 (0.756–9.047)
0.129
20 43
6.047 (0.739–49.475)
0.093
41 22
2.485 (0.765–8.074)
0.130
27 36
1.350 (0.406–4.490)
0.625
55 8
3.819 (1.019–14.313)
0.047
41 22
1.035 (0.309–3.471)
0.955
52 11
0.788 (0.154–4.030)
0.775
55 6 2
1.608 (0.562–4.606)
0.376
28 27 8
1.918 (0.831–4.430)
0.127
50 11 2
1.484 (0.541–4.072)
0.433
DM: Diabetes Mellitus; 95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio. Table 3 Angiolymphatic invasion. Metastasis
No metastasis
Rate (%)
Positive Negative
3 11
0 63
100 17.5
Rate (%)
27.3
0
Table 4 Histological evaluation of preoperative chemotherapy (Ohboshi and Shimosato’s classification). Preoperative chemotherapy evaluation
Total Odds ratio (95%CI) Metastasis No metastasis
P value
0–I IIa–IV
5 3
6 16
11 19
0.088
Total
8
22
30
0.225 (0.041–1.246)
3.3. Survival rate
95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio.
Among 77 patients in this study, five (two with and three without metastases) died, and three (one with and two without metastases) were transferred to another hospital. Among those that died, the cause of death was cancer in one patient. Calculation of cumulative survival rate included those who died of cancer or of other causes.
The Kaplan–Meier curves in patients with and without metastasis are shown in Fig. 1. The overall survival rate was 94.6%. The cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patients without such metastasis. Metastasis to cervical lymph nodes was not associated with
Y. Yoshida et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161 Table 5 Logistic regression analysis of factors related to cervical lymph node metastasis (multivariate analysis). Factors
Odds ratio
95%CI
P value
Age Sex Tumor size Clinical growth pattern Operative procedure Preoperative chemotherapy Smoking Mode of invasion
0.974 2.484 2.551 1.749 13.516 1.351 11.505 1.371
0.921–1.030 0.534–11.546 0.916–7.105 0.310–9.881 0.921–198.453 0.220–8.303 1.607–82.341 0.396–4.746
0.350 0.246 0.073 0.527 0.057 0.745 0.015 0.619
95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio.
a significant decrease in survival according to the log-rank test (hazard ratio, 0.3271; 95%CI, 0.0226–2.1875; P = 0.1973). 3.4. Late cervical lymph node metastasis cases The total number of patients with late cervical lymph node metastasis was 14 (18.2%), seven each of males and females. The mean age was 63.5 years (range, 35–87 years). Three patients had stage I disease, and 11 patients had stage II disease. Seven patients had tongue cancer, six had lower gingival cancer, and one had upper gingival cancer. The duration for the development of nodal metastasis was defined as the period of time between local surgery and the radiologic detection of nodal metastasis. The mean duration until the development of nodal metastasis was 387.9 days (range, 37–1597 days). Nodal metastasis developed within 6 months in five (35.7%) patients and within 1 year in 10 (71.4%) patients. 4. Discussion Even if stage I or II OSCC is diagnosed before nodal metastases, late cervical lymph node metastasis can develop and can complicate subsequent management. Although the method of follow-up and the course of treatment are usually decided by clinical and pathological factors, the clinical guidelines are indefinite and vary among institutions. This study investigated the ability of various clinical or pathologic factors to predict nodal metastases in patients with OSCC. In the past, the 2 test and
Fig. 1. Kaplan–Meier survival curve until overall death for the metastasis cases compared with the no metastasis cases (N.S.). Censoring is indicated by tick marks.
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logistic regression analysis were used to report late cervical lymph node metastasis and prognosis-related factors. Reported correlative clinical factors include clinical growth pattern [4] and tumor size [5]; pathological factors include histological degree of malignancy [5–7], pattern of invasion [5–7], and angiolymphatic invasion [6]. In the current study, logistic regression analysis was used to account for confounding factors when evaluating clinical or standard treatment-related pathology. However, a drawback of logistic regression analysis is that the result reflects only the model being analyzed. Although the results are based on a small number of analyzed cases, they could be helpful in determining the follow-up and treatment strategy in our center. Reports suggest that the incidence of nodal metastasis in patients with T1-4N0M0 OSCC cases ranges from 12.1% to 42.4% [5–7,14–17]. In patients who undergo surgical treatment for stage I or II OSCC, the incidence of nodal metastasis is 14.0–35.2% [5,7,16], which is consistent with the incidence of nodal metastases seen in the present study (18.2%). In this study, a history of smoking was the only predictor of late cervical lymph node metastasis according to multivariable analysis. Pytynia et al. [18] studied patients with head and neck cancer and reported that, according to matched-pair analysis, smokers had worse outcomes and a higher risk of recurrence than nonsmokers. Browman et al. [19] reported that smoking concomitant with radiotherapy for head and neck cancer was associated with worse outcomes when compared to patients who had quit smoking. The study has not examined the relationship between smoking and nodal metastasis in patients undergoing surgery for OSCC. However, several studies have reported molecular differences in tumor tissues, including mutation of the p53 tumor-suppressor gene in smokers with head and neck cancer when compared with non-smokers [20,21]. Mutation of p53 is associated with worse outcomes in patients with head and neck cancer [22], which may therefore provide a mechanistic link between smoking and worse outcomes in patients with head and neck cancer. For further investigation, we plan to accumulate more cases in the future. In the present study, three of 77 patients had angiolymphatic and perineural invasion, including two patients with lymphatic invasion and one with vascular invasion. All three patients underwent postoperative chemotherapy but developed late cervical lymph node metastases. These data suggest that postoperative chemotherapy was not sufficient to prevent late nodal metastases in these patients and that they may have benefited from concurrent chemoradiotherapy. Sparano et al. [6] also reported that angiolymphatic invasion was a predictor of nodal metastasis; thus, such patients should be subjected to closer follow-up. Tumor size, growth type, operative procedure, differentiation, mode of invasion, and tumor depth did not significantly correlate with late cervical lymph node metastasis. Although the rate of stage II disease was 65.1% in the non-metastasis group and 78.6% in the metastasis group, this difference did not reach the level of statistical significance. Kurokawa et al. [5] reported that patients in the late T2 (>30 mm and ≤40 mm) group had significantly more nodal metastases than those in the T1 (<20 mm) and early T2 (≥20 mm and <30 mm) group. Lim et al. [7] reported that there was no significant relationship between nodal metastasis and tumor size when stratifying according to T1 (≤20 mm) and T2 (>20 mm and ≤40 mm) stages. In terms of growth type, 20.0% of the tumors were superficial, 0% were exophytic, and 27.9% were endophytic in this study; however, these differences did not reach the level of statistical significance for the prediction of nodal metastasis. The difference between the highest frequency endophytic type and the superficial type was not significant. There is a report that endophytic type tumors are more correlated with nodal metastasis than the exophytic type [5]. A multicenter study reported that the incidence of nodal metastasis was higher for endophytic type tumors (27.6%) than for superficial (12%) or exophytic (15.9%) types [23].
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An examination of the histological malignancy grade, the Jakobsson classification [24], and the Anneroth classification [7,25] was investigated. However, in Japan, the classification of Yamamoto et al. [5,26] was reported, which provided an additional category for mode of invasion. In this study, the ability of the INF classification (according to the digestive cancer classification used in our institution) to predict nodal metastasis was investigated; the incidence of metastasis was 9.7% for INFa, 22.9% for INFb, and 27.3% for INFc, although these differences were not statistically significant. INF classification is similar to that of the Jakobsson and Anneroth classifications. Sheahan et al. [27] reported that the mode of invasion did not predict survival, which is consistent with the results from the present study. Preoperative chemotherapy may be used in conjunction with surgery with the goal of controlling latent micrometastasis and thereby improving outcomes. However, there is relatively little evidence regarding the efficacy of preoperative chemotherapy in patients with resectable OSCC [28]. In this study, the use of preoperative chemotherapy was not related to the occurrence of nodal metastasis. On the other hand, the preoperative chemotherapy evaluation by Ohboshi and Shimosato’s classification did not reveal a significant correlation, either. In this study, the cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patients without. Metastasis to cervical lymph nodes was not associated with a significant decrease in survival according to the log-rank test. Late cervical lymph node metastasis is associated with poor survival [1–3]. Although five of 77 patients died in this study, only one patient in the metastasis group died of cancer-related causes. Therefore, the possibility that the nodal metastasis was associated with the survival rate was considered when reviewing these cases. Subjects were excluded from this study if they developed local recurrence, and although the cumulative survival rate was 93.3%, this included the whole population including those patients that were excluded. The cumulative survival rate for patients with nodal metastasis in this study was 84.6% compared to 27.2–84.6% [14,16,17,29] seen in other institutions. Our data showed that 10 (71.4%) of 14 patients with late cervical lymph node metastasis were diagnosed within 1 year after surgery. Lim et al. [30] reported that the duration until development of nodal metastasis was 10 months after initial medical treatment. These observations suggest that patients should be followed closely for at least 1 year. The longest reported period from treatment to onset of nodal metastasis was 1597 days (approximately 4.3 years), while the second longest reported period was 755 days, and the average was 387.9 days (approximately 1 year) in this study. Thus, a more appropriate follow-up period for these patients might be of the order of 5 years, which is similar to that recommended by Tewari et al. [31]. Of the pathological factors examined, only angiolymphatic invasion was related to late cervical lymph node metastasis. Previous studies have suggested that the mode of invasion and differentiation were related to outcomes and nodal metastasis in patients with OSCC, which is not consistent with observations from the present study. This may be due to a lack of cases, indicating that additional studies are necessary. Given this result, we predicted a need for a more careful follow-up for angiolymphatic invasion-positive patients of stage I or II early-stage OSCC. Moreover, according to the result of this study, predictors of late metastasis were not derived from other pathological factors. However, past reports suggest that angiolymphatic invasion is a clinically important factor; therefore, it should be taken into account when determining the treatment. Postoperative chemotherapy was conducted for angiolymphatic invasion-positive cases but was ineffective in preventing late cervical lymph node metastasis. Hence, we should consider radiation therapy in addition to chemotherapy, and may also need to consider
treating patients with factors positive for metastatic risk with the same combination as well. The present study showed that a history of smoking was the only clinical factor related to late cervical lymph node metastasis. This is a useful predictive factor, as it can be assessed by a simple clinical interview in most cases. Further studies to identify the mechanisms that link smoking to an increased risk of nodal metastases would be beneficial. 5. Conclusions This study used multivariate analysis to identify predictive factors for late cervical lymph node metastasis in patients with stage I or II OSCC. On multivariate logistic regression analysis of clinical and pathological factors, only a history of smoking was significantly related to late cervical lymph node metastasis (P < 0.05; OR, 11.505; 95%CI, 1.607–82.341). Three of 77 patients had angiolymphatic invasion, all of whom developed nodal metastasis. Conflicts of interest The authors declare no conflicts of interest. References [1] Shear M, Hawkins DM, Farr HW. The prediction of lymph node metastases from oral squamous carcinoma. Cancer 1996;37:1901–7. [2] Kalnins IK, Leonard AG, Sako K, Razack MS, Shedd DP. Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Am J Surg 1977;134:450–4. [3] Leipzig B, Hokanson JA. Treatment of cervical lymph nodes in carcinoma of the tongue. Head Neck Surg 1982;5:3–9. [4] Asakage T, Yokose T, Mukai K, Tsugane S, Tsubono Y, Asai M, et al. Tumor thickness predicts cervical metastasis in patients with stage I/II carcinoma of the tongue. Cancer 1998;82:1443–8. [5] 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;24:731–6. [6] Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 2004;131:472–6. [7] Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10:166–72. [8] Sobin LH, Gospodarowicz MK, Wittekind C. International Union against cancer – TNM classification of malignant tumor. 7th ed. New York: Wiley Blackwell; 2009. [9] Brinkman GL, Coates Jr EO. The prevalence of chronic bronchitis in an industrial population. Am Rev Respir Dis 1962;86:47–54. [10] Ujpál M, Baradás J, Kovalszky I, Szabó G, Németh Z, Gábris K, et al. A preliminary comparative study of the prognostic implications of type 2 diabetes mellitus for patients with primary gingival carcinoma treated with surgery and radiation therapy. J Oral Maxillofac Surg 2007;65:452–6. [11] Kramer IR, Pindborg JJ, Shear M. The World Health Organization histological typing of odontogenic tumours – introducing the second edition. Eur J Cancer B Oral Oncol 1993;29B:169–71. [12] Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101–12. [13] Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinomas. Jpn J Clin Oncol 1971;1:19–35. [14] Kligerman J, Lima RA, Soares JR, Prado L, Dias FL, Freitas EQ, et al. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Am J Surg 1994;168:391–4. [15] Gourin CG, Conger BT, Porubsky ES, Sheils WC, Bilodeau PA, Coleman TA. The effect of occult nodal metastases on survival and regional control in patients with head and neck squamous cell carcinoma. Laryngoscope 2008;118:1191–4. [16] Keski-Säntti H, Atula T, Törnwall J, Koivunen P, Mäkitie A. Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 2006;42:96–101. [17] Yuen AP, Ho CM, Chow TL, Tang LC, Cheung WY, Ng RW, et al. Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma. Head Neck 2009;31:765–72. [18] Pytynia KB, Grant JR, Etzel CJ, Roberts DB, Wei Q, Sturgis EM. Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol 2004;22:3981–8. [19] Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993;328:159–63.
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Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology journal homepage: www.elsevier.com/locate/jomsmp
Oral Medicine/Original Research
Relative factors of late cervical lymph node metastasis in patients with stage I or II oral squamous cell carcinoma Yoshifumi Yoshida a,∗ , Kazumichi Sato b , Mira Kin a , Taiki Suzuki a , Hiroki Bessho c , Yoichi Tanaka d , Akira Katakura a a
Department of Oral Medicine, Oral and Maxillofacial Surgery, Tokyo Dental College, Japan Oral Cancer Center, Tokyo Dental College, Japan c Oral and Maxillofacial Surgery, Tokyo Dental College, Japan d Division of Surgical Pathology, Clinical Laboratory, Ichikawa General Hospital, Tokyo Dental College, Japan b
a r t i c l e
i n f o
Article history: Received 7 January 2015 Received in revised form 30 May 2015 Accepted 15 July 2015 Available online 19 August 2015 Keywords: Oral squamous cell carcinoma Late cervical lymph node metastasis Prognosis-related factors Logistic regression analysis History of smoking
a b s t r a c t Objectives: Late cervical lymph node metastasis of oral squamous cell carcinoma (OSCC) is a key indicator of prognosis. If the risk of late metastasis can be predicted, closer follow-up can be pursued, including necessary surgery, thus leading to improved outcomes. In this study, we aimed to investigate factors that could predict OSCC metastasis to the lymph nodes. Methods: We reviewed the medical records of 77 patients with stage I or II OSCC at the Oral Cancer Center of Tokyo Dental College between April 2006 and March 2011. Multivariate analysis and logistic regression were conducted, and clinical factors and pathological factors were included. Results: The number of OSCC patients with late cervical lymph node metastasis was 14 (18.2%). The cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patient without such metastasis. Metastasis to cervical lymph nodes was not associated with a significant decrease in survival according to the log-rank test. On multivariate logistic regression analysis of clinical and pathological factors, only a history of smoking was significantly related to late cervical lymph node metastasis. Three of 77 patients had angiolymphatic invasion, and all three patients developed nodal metastasis. Conclusion: Logistic regression analysis showed that a history of smoking was significantly related to late cervical lymph node metastasis. Moreover, nodal metastasis was found in all cases with angiolymphatic invasion. © 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
1. Introduction The presence of late cervical lymph node metastasis is universally recognized as the main factor influencing survival in patients with oral squamous cell carcinoma (OSCC) [1–3]. Numerous studies on factors correlating with late cervical lymph node metastasis and prognosis have been published. Correlative clinical factors include clinical growth pattern [4] and tumor size [5], whereas pathological
夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author. Present address: Department of Oral Surgery, Tokai University School of Medicine 143, Shimokasuya, Isehara, Kanagawa, 259-1193, Japan. Tel.: +81 47 322 0151; fax: +81 47 324 8577. E-mail address: [email protected] (Y. Yoshida).
factors include the histological grade of malignancy [5–7], and mode of invasion [5–7], angiolymphatic invasion [6]. However, the studies that identified these predictive factors were conducted in heterogeneous populations that included patients who did or did not undergo elective neck dissection, patients with different Union for International Cancer Control TNM staging [8], and those with different tissue type cancers. Thus, it is unclear whether these factors are truly predictive of nodal metastasis, and additional examination in unified populations is required to address this question. Accurately defining the factors that can predict late cervical lymph node metastasis can better identify patients who can benefit from better treatment and more robust follow-up. To accurately predict nodal metastasis from among various examination parameters, it is necessary to adjust for confounding factors. This was addressed by employing logistic regression analysis in this study, which was a retrospective study using multivariate analysis to determine the factors that correlated with nodal
http://dx.doi.org/10.1016/j.ajoms.2015.07.005 2212-5558/© 2015 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
Y. Yoshida et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161
metastasis in stage I and II OSCC cases in which local excision was performed.
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2. Methods
or negative. The histological evaluation of the response to preoperative chemotherapy was classified according to preoperative therapy evaluation based on Ohboshi and Shimosato’s classification [13]: grade 0–I and grade IIa–IV.
2.1. Patients
2.3. Statistical methods
We reviewed the medical records of 77 patients (mean age, 67.3 years; range, 24–92 years) treated for OSCC at the Oral Cancer Center of Tokyo Dental College (an arm of the Division of Dentistry and Oral Surgery at Ichikawa General Hospital, Tokyo Dental College) between April 2006 and March 2011. Subjects were patients with stage I or II OSCC who had undergone surgery as the primary treatment without elective neck dissection. This was a case–control study, with patients with late cervical lymph node metastasis serving as the “case” and those without metastasis serving as the “control.” Moreover, this study was limited to patients without regional recurrence. Cervical lymph nodes were evaluated with physical examination and by computed tomography or magnetic resonance imaging every 3 months during the follow-up period. Survival rate analysis was conducted using data obtained as of March 31, 2012.
The ability of clinical and pathological factors to predict late cervical lymph node metastasis was assessed with univariate and multivariate logistic regression analyses. The predictive ability of each clinical and pathological factor was assessed with univariate analysis using nodal metastasis as the dependent variable. Multivariate analysis was conducted using the significant factors extracted from univariate analysis. P < 0.25 was the standard for extracting factors as covariate. Survival curves in patients with and without metastasis were plotted using the Kaplan–Meier method. The correlations between cumulative survival rate (overall survival rate) and late cervical lymph node metastasis were analyzed with the log-rank test. Statistical tests of all data were performed with SPSS software version 19 (IBM, Japan). Results were considered statistically significant when the P value was <0.05.
2.2. Factors Clinical and pathological factors were examined for their ability to predict late cervical lymph node metastasis. The clinical factors were age, sex, cancer site, tumor size, growth type, operative procedure, presence or absence of preoperative chemotherapy, presence or absence of postoperative chemotherapy or radiation therapy, and histories of smoking, alcohol consumption, and diabetes mellitus (DM). Tumor size was classified as T1 (<20 mm), early T2 (≥20 mm and <30 mm), or late T2 (≥30 mm and <40 mm); previous reports suggested that this stratification correlated with the presence of nodal metastasis [5]. Clinical growth pattern was classified as superficial, exophytic, or endophytic. The operative procedure was classified as surgical treatment after diagnosis by incisional biopsy, or excisional biopsy. Smoking history was stratified as heavy smoking (Brinkman index [9] score >600) and non-smoking/light smoking (Brinkman index score <600). Alcohol consumption was satisfied as heavy drinking and non-drinking/light drinking group. The history of DM was also investigated because past reports suggest that DM affects survival and may predict cervical lymph node metastasis in patients with gingival carcinoma [10]. Pathological factors were differentiation, mode of invasion, surgical margin, angiolymphatic invasion, and histological evaluation of the response to preoperative chemotherapy. The degree of differentiation was classified as well, moderate, or poor differentiation, according to grade (World Health Organization classification) [11]. The mode of invasion was classified into three groups according to the pattern of tumor infiltration (INF) from the criteria of digestive organ carcinoma [12] (esophagus, stomach, and colon carcinoma) used for clinical diagnosis: INFa, INFb and INFc (Table 1). The surgical margin was classified as positive, dysplasia, Table 1 Pattern of tumor infiltration (INF) into the surrounding tissues. Definition INF a INF b INF c
Tumor displays expanding growth with a distinct border from the surrounding tissue. Tumor shows a pattern intermediate between that of INFa and INFc. Tumor displays infiltrative growth with no distinct border with the surrounding tissue.
3. Results 3.1. Univariate analysis Table 2 summarizes the ability of clinical and pathological factors to predict late cervical lymph node metastasis according to univariate logistic regression analysis. The study included 77 patients (mean age, 67.3 years; range, 24–92 years), including 46 males and 31 females (male to female ratio, 1.48:1). Twenty-five patients had stage I disease and 52 patients had stage II disease. Forty (51.9%) patients had tongue cancer, 17 (22.1%) had lower gingival cancer, nine (11.7%) had upper gingival cancer, five (6.5%) had cancer of the floor of the mouth, four (5.2%) had buccal mucosal cancer, and two (2.6%) had lip cancer. On univariate analysis, only a history of smoking correlated with late cervical lymph node metastasis (P < 0.05). Other clinical factors such as age, sex, cancer site, tumor size, clinical growth pattern, operative procedure, preoperative chemotherapy, postoperative chemotherapy or radiation therapy, history of alcohol consumption, and DM did not correlate with nodal metastasis. Furthermore, pathological factors, such as differentiation, mode of invasion, and surgical margin, did not correlate with nodal metastasis. Table 3 summarizes the analysis of angiolymphatic invasion. Logistic regression analysis could not be conducted because all three patients with angiolymphatic invasion had cervical lymph node metastasis. Preoperative chemotherapy evaluation according to Ohboshi and Shimosato’s classification was limited to 30 patients who had received it. These 30 patients included eight with metastasis and 22 without. Stratification of this parameter did not correlate with nodal metastasis (Table 4). 3.2. Multivariate analysis Results of multivariate logistic regression analysis of clinical and pathological factors are shown in Table 5. A history of smoking (P < 0.05; odds ratio [OR], 11.505; 95% confidence interval [CI], 1.607–82.341) was identified as a significant predictor of nodal metastasis. Operative procedure also correlated with nodal metastasis, but this relationship did not reach the level of statistical significance (P = 0.0713; OR, 13.516; 95%CI, 0.921–198.453).
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Table 2 Logistic regression analysis in cervical lymph node metastasis (univariate analysis). Factors
Nodal metastasis
Univariate analysis
Metastasis (14)
No metastasis (63)
Age Sex 7 Male 7 Female Expression site 7 Tongue 1 Upper gingiva 6 Lower gingiva 0 Buccal mucosa 0 Floor of mouth Lip 0 Tumor size T1 3 6 Early 5 Late T2 Clinical growth pattern 0 Exophytic 2 Superficial 12 Endophytic Operative procedure 1 Excisional biopsy Incisional biopsy 13 Preoperative chemotherapy 6 Absent 8 Present Postoperative chemotherapy or radiation therapy Absent 5 9 Present Smoking 9 Non/light-smoking 5 Heavy-smoking Alcohol 9 Non/light-drinking Heavy-drinking 5 DM 12 Absent 2 Present Differentiation 11 Well 2 Moderate Poor 1 Mode of invasion 3 INFa 8 INFb 3 INFc Surgical margin 10 Negative 3 Dysplasia 1 Positive
Odds ratio (95%CI)
P value
0.980 (0.944–1.018)
0.291
39 24
1.739 (0.542–5.584)
0.352
33 8 11 4 5 2
0.889 (0.570–1.386)
0.604
22 27 14
1.618 (0.738–3.545)
0.230
12 8 43
2.625 (0.756–9.047)
0.129
20 43
6.047 (0.739–49.475)
0.093
41 22
2.485 (0.765–8.074)
0.130
27 36
1.350 (0.406–4.490)
0.625
55 8
3.819 (1.019–14.313)
0.047
41 22
1.035 (0.309–3.471)
0.955
52 11
0.788 (0.154–4.030)
0.775
55 6 2
1.608 (0.562–4.606)
0.376
28 27 8
1.918 (0.831–4.430)
0.127
50 11 2
1.484 (0.541–4.072)
0.433
DM: Diabetes Mellitus; 95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio. Table 3 Angiolymphatic invasion. Metastasis
No metastasis
Rate (%)
Positive Negative
3 11
0 63
100 17.5
Rate (%)
27.3
0
Table 4 Histological evaluation of preoperative chemotherapy (Ohboshi and Shimosato’s classification). Preoperative chemotherapy evaluation
Total Odds ratio (95%CI) Metastasis No metastasis
P value
0–I IIa–IV
5 3
6 16
11 19
0.088
Total
8
22
30
0.225 (0.041–1.246)
3.3. Survival rate
95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio.
Among 77 patients in this study, five (two with and three without metastases) died, and three (one with and two without metastases) were transferred to another hospital. Among those that died, the cause of death was cancer in one patient. Calculation of cumulative survival rate included those who died of cancer or of other causes.
The Kaplan–Meier curves in patients with and without metastasis are shown in Fig. 1. The overall survival rate was 94.6%. The cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patients without such metastasis. Metastasis to cervical lymph nodes was not associated with
Y. Yoshida et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology 28 (2016) 156–161 Table 5 Logistic regression analysis of factors related to cervical lymph node metastasis (multivariate analysis). Factors
Odds ratio
95%CI
P value
Age Sex Tumor size Clinical growth pattern Operative procedure Preoperative chemotherapy Smoking Mode of invasion
0.974 2.484 2.551 1.749 13.516 1.351 11.505 1.371
0.921–1.030 0.534–11.546 0.916–7.105 0.310–9.881 0.921–198.453 0.220–8.303 1.607–82.341 0.396–4.746
0.350 0.246 0.073 0.527 0.057 0.745 0.015 0.619
95%CI: 95% Confidence interval. The first line of each factor is set to referent of odds ratio.
a significant decrease in survival according to the log-rank test (hazard ratio, 0.3271; 95%CI, 0.0226–2.1875; P = 0.1973). 3.4. Late cervical lymph node metastasis cases The total number of patients with late cervical lymph node metastasis was 14 (18.2%), seven each of males and females. The mean age was 63.5 years (range, 35–87 years). Three patients had stage I disease, and 11 patients had stage II disease. Seven patients had tongue cancer, six had lower gingival cancer, and one had upper gingival cancer. The duration for the development of nodal metastasis was defined as the period of time between local surgery and the radiologic detection of nodal metastasis. The mean duration until the development of nodal metastasis was 387.9 days (range, 37–1597 days). Nodal metastasis developed within 6 months in five (35.7%) patients and within 1 year in 10 (71.4%) patients. 4. Discussion Even if stage I or II OSCC is diagnosed before nodal metastases, late cervical lymph node metastasis can develop and can complicate subsequent management. Although the method of follow-up and the course of treatment are usually decided by clinical and pathological factors, the clinical guidelines are indefinite and vary among institutions. This study investigated the ability of various clinical or pathologic factors to predict nodal metastases in patients with OSCC. In the past, the 2 test and
Fig. 1. Kaplan–Meier survival curve until overall death for the metastasis cases compared with the no metastasis cases (N.S.). Censoring is indicated by tick marks.
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logistic regression analysis were used to report late cervical lymph node metastasis and prognosis-related factors. Reported correlative clinical factors include clinical growth pattern [4] and tumor size [5]; pathological factors include histological degree of malignancy [5–7], pattern of invasion [5–7], and angiolymphatic invasion [6]. In the current study, logistic regression analysis was used to account for confounding factors when evaluating clinical or standard treatment-related pathology. However, a drawback of logistic regression analysis is that the result reflects only the model being analyzed. Although the results are based on a small number of analyzed cases, they could be helpful in determining the follow-up and treatment strategy in our center. Reports suggest that the incidence of nodal metastasis in patients with T1-4N0M0 OSCC cases ranges from 12.1% to 42.4% [5–7,14–17]. In patients who undergo surgical treatment for stage I or II OSCC, the incidence of nodal metastasis is 14.0–35.2% [5,7,16], which is consistent with the incidence of nodal metastases seen in the present study (18.2%). In this study, a history of smoking was the only predictor of late cervical lymph node metastasis according to multivariable analysis. Pytynia et al. [18] studied patients with head and neck cancer and reported that, according to matched-pair analysis, smokers had worse outcomes and a higher risk of recurrence than nonsmokers. Browman et al. [19] reported that smoking concomitant with radiotherapy for head and neck cancer was associated with worse outcomes when compared to patients who had quit smoking. The study has not examined the relationship between smoking and nodal metastasis in patients undergoing surgery for OSCC. However, several studies have reported molecular differences in tumor tissues, including mutation of the p53 tumor-suppressor gene in smokers with head and neck cancer when compared with non-smokers [20,21]. Mutation of p53 is associated with worse outcomes in patients with head and neck cancer [22], which may therefore provide a mechanistic link between smoking and worse outcomes in patients with head and neck cancer. For further investigation, we plan to accumulate more cases in the future. In the present study, three of 77 patients had angiolymphatic and perineural invasion, including two patients with lymphatic invasion and one with vascular invasion. All three patients underwent postoperative chemotherapy but developed late cervical lymph node metastases. These data suggest that postoperative chemotherapy was not sufficient to prevent late nodal metastases in these patients and that they may have benefited from concurrent chemoradiotherapy. Sparano et al. [6] also reported that angiolymphatic invasion was a predictor of nodal metastasis; thus, such patients should be subjected to closer follow-up. Tumor size, growth type, operative procedure, differentiation, mode of invasion, and tumor depth did not significantly correlate with late cervical lymph node metastasis. Although the rate of stage II disease was 65.1% in the non-metastasis group and 78.6% in the metastasis group, this difference did not reach the level of statistical significance. Kurokawa et al. [5] reported that patients in the late T2 (>30 mm and ≤40 mm) group had significantly more nodal metastases than those in the T1 (<20 mm) and early T2 (≥20 mm and <30 mm) group. Lim et al. [7] reported that there was no significant relationship between nodal metastasis and tumor size when stratifying according to T1 (≤20 mm) and T2 (>20 mm and ≤40 mm) stages. In terms of growth type, 20.0% of the tumors were superficial, 0% were exophytic, and 27.9% were endophytic in this study; however, these differences did not reach the level of statistical significance for the prediction of nodal metastasis. The difference between the highest frequency endophytic type and the superficial type was not significant. There is a report that endophytic type tumors are more correlated with nodal metastasis than the exophytic type [5]. A multicenter study reported that the incidence of nodal metastasis was higher for endophytic type tumors (27.6%) than for superficial (12%) or exophytic (15.9%) types [23].
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An examination of the histological malignancy grade, the Jakobsson classification [24], and the Anneroth classification [7,25] was investigated. However, in Japan, the classification of Yamamoto et al. [5,26] was reported, which provided an additional category for mode of invasion. In this study, the ability of the INF classification (according to the digestive cancer classification used in our institution) to predict nodal metastasis was investigated; the incidence of metastasis was 9.7% for INFa, 22.9% for INFb, and 27.3% for INFc, although these differences were not statistically significant. INF classification is similar to that of the Jakobsson and Anneroth classifications. Sheahan et al. [27] reported that the mode of invasion did not predict survival, which is consistent with the results from the present study. Preoperative chemotherapy may be used in conjunction with surgery with the goal of controlling latent micrometastasis and thereby improving outcomes. However, there is relatively little evidence regarding the efficacy of preoperative chemotherapy in patients with resectable OSCC [28]. In this study, the use of preoperative chemotherapy was not related to the occurrence of nodal metastasis. On the other hand, the preoperative chemotherapy evaluation by Ohboshi and Shimosato’s classification did not reveal a significant correlation, either. In this study, the cumulative survival rate was 84.6% for patients with late cervical lymph node metastasis and 95.1% for patients without. Metastasis to cervical lymph nodes was not associated with a significant decrease in survival according to the log-rank test. Late cervical lymph node metastasis is associated with poor survival [1–3]. Although five of 77 patients died in this study, only one patient in the metastasis group died of cancer-related causes. Therefore, the possibility that the nodal metastasis was associated with the survival rate was considered when reviewing these cases. Subjects were excluded from this study if they developed local recurrence, and although the cumulative survival rate was 93.3%, this included the whole population including those patients that were excluded. The cumulative survival rate for patients with nodal metastasis in this study was 84.6% compared to 27.2–84.6% [14,16,17,29] seen in other institutions. Our data showed that 10 (71.4%) of 14 patients with late cervical lymph node metastasis were diagnosed within 1 year after surgery. Lim et al. [30] reported that the duration until development of nodal metastasis was 10 months after initial medical treatment. These observations suggest that patients should be followed closely for at least 1 year. The longest reported period from treatment to onset of nodal metastasis was 1597 days (approximately 4.3 years), while the second longest reported period was 755 days, and the average was 387.9 days (approximately 1 year) in this study. Thus, a more appropriate follow-up period for these patients might be of the order of 5 years, which is similar to that recommended by Tewari et al. [31]. Of the pathological factors examined, only angiolymphatic invasion was related to late cervical lymph node metastasis. Previous studies have suggested that the mode of invasion and differentiation were related to outcomes and nodal metastasis in patients with OSCC, which is not consistent with observations from the present study. This may be due to a lack of cases, indicating that additional studies are necessary. Given this result, we predicted a need for a more careful follow-up for angiolymphatic invasion-positive patients of stage I or II early-stage OSCC. Moreover, according to the result of this study, predictors of late metastasis were not derived from other pathological factors. However, past reports suggest that angiolymphatic invasion is a clinically important factor; therefore, it should be taken into account when determining the treatment. Postoperative chemotherapy was conducted for angiolymphatic invasion-positive cases but was ineffective in preventing late cervical lymph node metastasis. Hence, we should consider radiation therapy in addition to chemotherapy, and may also need to consider
treating patients with factors positive for metastatic risk with the same combination as well. The present study showed that a history of smoking was the only clinical factor related to late cervical lymph node metastasis. This is a useful predictive factor, as it can be assessed by a simple clinical interview in most cases. Further studies to identify the mechanisms that link smoking to an increased risk of nodal metastases would be beneficial. 5. Conclusions This study used multivariate analysis to identify predictive factors for late cervical lymph node metastasis in patients with stage I or II OSCC. On multivariate logistic regression analysis of clinical and pathological factors, only a history of smoking was significantly related to late cervical lymph node metastasis (P < 0.05; OR, 11.505; 95%CI, 1.607–82.341). Three of 77 patients had angiolymphatic invasion, all of whom developed nodal metastasis. Conflicts of interest The authors declare no conflicts of interest. References [1] Shear M, Hawkins DM, Farr HW. The prediction of lymph node metastases from oral squamous carcinoma. Cancer 1996;37:1901–7. [2] Kalnins IK, Leonard AG, Sako K, Razack MS, Shedd DP. Correlation between prognosis and degree of lymph node involvement in carcinoma of the oral cavity. Am J Surg 1977;134:450–4. [3] Leipzig B, Hokanson JA. Treatment of cervical lymph nodes in carcinoma of the tongue. Head Neck Surg 1982;5:3–9. [4] Asakage T, Yokose T, Mukai K, Tsugane S, Tsubono Y, Asai M, et al. Tumor thickness predicts cervical metastasis in patients with stage I/II carcinoma of the tongue. Cancer 1998;82:1443–8. [5] 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;24:731–6. [6] Sparano A, Weinstein G, Chalian A, Yodul M, Weber R. Multivariate predictors of occult neck metastasis in early oral tongue cancer. Otolaryngol Head Neck Surg 2004;131:472–6. [7] Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, et al. Predictive markers for late cervical metastasis in stage I and II invasive squamous cell carcinoma of the oral tongue. Clin Cancer Res 2004;10:166–72. [8] Sobin LH, Gospodarowicz MK, Wittekind C. International Union against cancer – TNM classification of malignant tumor. 7th ed. New York: Wiley Blackwell; 2009. [9] Brinkman GL, Coates Jr EO. The prevalence of chronic bronchitis in an industrial population. Am Rev Respir Dis 1962;86:47–54. [10] Ujpál M, Baradás J, Kovalszky I, Szabó G, Németh Z, Gábris K, et al. A preliminary comparative study of the prognostic implications of type 2 diabetes mellitus for patients with primary gingival carcinoma treated with surgery and radiation therapy. J Oral Maxillofac Surg 2007;65:452–6. [11] Kramer IR, Pindborg JJ, Shear M. The World Health Organization histological typing of odontogenic tumours – introducing the second edition. Eur J Cancer B Oral Oncol 1993;29B:169–71. [12] Japanese Gastric Cancer Association. Japanese classification of gastric carcinoma: 3rd English edition. Gastric Cancer 2011;14:101–12. [13] Shimosato Y, Oboshi S, Baba K. Histological evaluation of effects of radiotherapy and chemotherapy for carcinomas. Jpn J Clin Oncol 1971;1:19–35. [14] Kligerman J, Lima RA, Soares JR, Prado L, Dias FL, Freitas EQ, et al. Supraomohyoid neck dissection in the treatment of T1/T2 squamous cell carcinoma of oral cavity. Am J Surg 1994;168:391–4. [15] Gourin CG, Conger BT, Porubsky ES, Sheils WC, Bilodeau PA, Coleman TA. The effect of occult nodal metastases on survival and regional control in patients with head and neck squamous cell carcinoma. Laryngoscope 2008;118:1191–4. [16] Keski-Säntti H, Atula T, Törnwall J, Koivunen P, Mäkitie A. Elective neck treatment versus observation in patients with T1/T2 N0 squamous cell carcinoma of oral tongue. Oral Oncol 2006;42:96–101. [17] Yuen AP, Ho CM, Chow TL, Tang LC, Cheung WY, Ng RW, et al. Prospective randomized study of selective neck dissection versus observation for N0 neck of early tongue carcinoma. Head Neck 2009;31:765–72. [18] Pytynia KB, Grant JR, Etzel CJ, Roberts DB, Wei Q, Sturgis EM. Matched-pair analysis of survival of never smokers and ever smokers with squamous cell carcinoma of the head and neck. J Clin Oncol 2004;22:3981–8. [19] Browman GP, Wong G, Hodson I, Sathya J, Russell R, McAlpine L, et al. Influence of cigarette smoking on the efficacy of radiation therapy in head and neck cancer. N Engl J Med 1993;328:159–63.
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