Predictive Markers for Late Cervical Lymph Node Metastasis in Patients with N0 Squamous Cell Carcinoma of the Tongue

Predictive Markers for Metastasis of Tongue Carcinoma Asian J Oral Maxillofac Surg. 2006;18:120-6. CLINICAL OBSERVATIONS

Predictive Markers for Late Cervical Lymph Node Metastasis in Patients with N0 Squamous Cell Carcinoma of the Tongue Hideo Kurokawa,1,2 Yoshihiro Yamashita,2 Shinobu Matsumoto,2 Koichi Takamori,1 Kaori Igawa,1 Koji Kashima,1 Min Zhang,3 Hiroshi Fukuyama,3 Tetsu Takahashi,2 Sumio Sakoda1 1 Department of Oral and Maxillofacial Surgery, Miyazaki Medical College, University of Miyazaki, Miyazaki, 2Division of Oral and Maxillofacial Reconstructive Surgery, Department of Oral and Maxillofacial Surgery, and 3Division of Biosciences, Department of Oral Pathology, Kyushu Dental College, Kitakyushu, Japan

Abstract Objective: To find useful markers for predicting late cervical metastasis in patients with N0 squamous cell carcinoma of the tongue. Patients and Methods: The clinicopathological features of 57 consecutive patients with previously untreated N0 squamous cell carcinoma of the tongue were reviewed. Thirty patients had T1 disease, 20 had T2 disease, and 7 had T3 disease. All patients were treated with partial glossectomy without elective neck dissection. Clinicopathological factors were analysed to determine the factors predicting late cervical lymph node metastasis. Results: The overall cervical lymph node metastasis rate was 19.3%. The clinicopathologic factors significantly associated with the development of cervical lymph node metastasis were tumour size (30 mm), tumour depth (4 mm), differentiation (moderate), mode of invasion (G4C, 4D), microvascular invasion (present), muscle invasion (present), and invasive front grading (12 points). In a multivariate logistic regression analysis, invasive front grading ≥12 points in squamous cell carcinoma of the tongue with a tumour depth ≥4 mm had predictive value for late cervical lymph node metastasis. Conclusions: The results indicate that patients with N0 invasive tongue carcinoma with a tumour depth ≥4 mm or invasive front grading ≥12 points should be considered at high risk for late cervical lymph node metastasis. These factors should be considered in the decision to electively treat the neck. Key words: Carcinoma, squamous cell, Lymphatic metastasis, Neoplasm invasiveness, Tongue neoplasms

Introduction Patients with oral squamous cell carcinoma (SCC) can die from failure to control the primary lesion or regional lymph node metastases.1-4 The presence of lymph node metastases is the most important prognostic factor for oral SCC.4-6 There is a high incidence of occult cervical metastases, even with small primary tumours, and late cervical metastases after Correspondence: Hideo Kurokawa, Department of Oral and Maxillofacial Surgery, Miyazaki Medical College, University of Miyazaki, 5200 Kihara, Kiyotake-Cho, Miyazaki 889-1692, Japan. Tel: (81 985) 853 786; Fax: (81 985) 857 190; E-mail: [email protected]

120

surgery for N0 SCC of the tongue.5-11 Postoperative cervical metastases are an adverse prognostic factor for patients with malignancy.5,6,12 Naturally, the survival of these patients is poorer than that of patients without late cervical lymph node metastases.1-12 Many methods have been used to detect cervical lymph node metastases clinically, and the imaging techniques used include computed tomography, magnetic resonance imaging, ultrasound, and positron emission tomography.13-18 However, there are no imaging techniques capable of detecting micrometastases in cervical lymph nodes.17-19 Recently, several studies J Oral of Maxillofac Vol 18, No 2, 2006 © 2006 AsianAsian Association Oral and Surg Maxillofacial Surgeons.

Kurokawa, Yamashita, Matsumoto, et al

have shown that tumour thickness (or depth of invasion)5,7,20-24 and vascular invasion25,26 are risk factors for cervical metastasis in patients with SCC of the head and neck. However, the criteria for elective neck dissection according to predictive factors for late cervical metastasis remain controversial.5,9 Few studies have applied multivariate analysis to the clinicopathological factors associated with cervical metastasis in patients with N0 SCC of the tongue.5,9,12,21,22 This study was a retrospective review of clinical and pathological data of patients with surgically treated tongue carcinoma, and aimed to determine the factors predicting late cervical lymph node metastasis.

Figure 1. Evaluation of tumour depth (A) and deep tumour invasive front (B).

and contained a retrospective portion to determine the histological grade of the malignancy.

Patients and Methods The medical records of 70 patients who were treated for SCC of the tongue at the Departments of Oral and Maxillofacial Surgery, Kyushu Dental College, Kitakyushu, and Miyazaki Medical College, Miyazaki, Japan, were reviewed. This study was limited to patients with N0 SCC of the tongue who underwent partial glossectomy without elective neck dissection. No patients received preoperative or postoperative treatment. Thirteen patients with disseminated disease, other serious illnesses, or poor general condition that made treatment with curative intent impossible were excluded. Fifty seven patients met the criteria for the study. There were 31 men (54.4%) and 26 women (45.6%). Their mean age was 55.7 years (range, 23 to 90 years). Thirty patients had T1 disease, 20 had T2 disease, and 7 had T3 disease.27 Macroscopic appearance (tumour growth type) was classified as exophytic (superficial, papillomatous, and granulomatous) or endophytic (ulcerative and erosive).5 Tumour size was expressed as the maximum tumour diameter. Histopathological Evaluation Paraffin-embedded specimens were retrieved from the files of the Department of Oral Pathology. Serial sections were cut 4 to 6 μm thick. Alternate sections were stained with haematoxylin and eosin. The initial biopsy for histological diagnosis had been undertaken so that the excised specimen included a portion that was as deep as possible, to show tumour-host border, Asian J Oral Maxillofac Surg Vol 18, No 2, 2006

The histological malignancy grade of the deep invasive front areas (invasive front grade, IFG) was determined using the method of Bryne et al.28 For each tumour, the degree of keratinization, nuclear polymorphism, pattern of invasion, and host response (degree of leukocyte infiltration) were graded and given scores between 1 and 4. Tumour depth was measured from the surface of the normal mucosa to the deepest portion of the tumour (Figure 1). The mode of invasion using the classification of Yamamoto et al,29 microvascular invasion, and muscle invasion were also recorded. Two pathologists and 2 oral and maxillofacial surgeons, who were blind to the clinical data, reviewed all of the pathological specimens. The histological assessments were judged by agreement among 3 or more reviewers. Statistical Analysis All data were tabulated and statistical tests were performed using the Statview software package (SAS Institute, Cary, USA). The chi squared test was used to assess the association of late cervical lymph node metastasis with clinicopathological factors, including tumour growth type, tumour size, tumour depth, differentiation in the deep portion, microvascular invasion, muscle invasion, mode of invasion, and IFG. The prognostic significance of clinicopathological factors in late cervical lymph node metastasis (nodal metastasis) was assessed with multivariate logistic regression analysis. Survival curves were plotted using the Kaplan-Meier method,30 and the correlation 121

Predictive Markers for Metastasis of Tongue Carcinoma

between late cervical lymph node metastasis and disease-free survival was analysed using a log-rank test. The results were considered significant when the p value was <0.05.

Results Fifteen of the 57 patients died because of failure to control the primary tumour (5 patients), regional lymph node metastasis (9 patients), or distant metastasis (1 patient). The disease-free survival rate at 5 years was 71.5%. Patients without late cervical lymph node metastases had a significantly better prognosis than those with metastases. The association between clinicopathological factors and late cervical lymph node metastasis is shown in Table 1. Late cervical lymph node metastasis was correlated with tumour size, tumour depth, differentiation, microvascular invasion, muscle invasion, mode of invasion, and IFG. Late cervical lymph node metastasis was not correlated with tumour growth type. The clinicopathological factors correlated with late cervical lymph node metastasis were divided into 4 categories of tumour feature (size and depth), Clinicopathological factors

Number of patients

Number of lymph node metastases (%)

p Value

Growth type Exophytic Endophytic

14 43

2 (14.3) 9 (20.9)

Tumour size <30 mm ≥30 mm

41 16

3 (7.3) 8 (50.0)

0.0002

Tumour depth <4 mm ≥4 mm

36 21

1 (2.8) 10 (47.6)

<0.0001

Differentiation Good Moderate

36 21

4 (11.1) 7 (33.3)

0.0060

Microvascular invasion Absent Present

41 16

3 (7.3) 8 (50.0)

0.0002

Muscle invasion Absent Present

32 25

0 (0) 11 (44)

<0.0001

Mode of invasion G1-3 G4C, 4D

33 24

3 (9.1) 8 (33.3)

0.0220

Invasive front grading <12 points ≥12 points

43 14

3 (7.0) 8 (57.1)

NS

To establish a more effective method for the prediction of late cervical lymph node metastasis, 2 significant factors in the multivariate analysis were combined in a linear discrimination analysis, and the combination of these 2 factors was found to be more predictive of late cervical lymph node metastasis. The 2 factors together had 47.8% sensitivity and 100% specificity, and 47.8% positive predictive value and 100% negative predictive value (Table 3). Clinicopathological factors

Risk ratio

p Value

Tumour size <30 mm vs ≥30 mm

2.300

0.0857

Tumour depth <4 mm vs ≥4 mm

6.444

0.0398

Microvascular invasion Absent vs present

1.863

0.0933

Invasive front grading <12 points vs ≥12 points

9.974

0.0186

Table 2. Multivariate logistic regression analysis of late cervical lymph node metastasis.

Clinicopathological factors

<0.0001

Table 1. Occurrence of late cervical lymph node metastasis.

122

tumour cell population (differentiation in the deep portion), tumour-host relationship (mode of invasion in the deepest portion and microvascular invasion), and histological grade of malignancy (IFG). Four clinicopathological factors that correlated with late cervical lymph node metastasis were selected: tumour size, tumour depth, microvascular invasion, and IFG; IFG was selected because it includes differentiation and mode of invasion. A correlation between late cervical lymph node metastasis and IFG scores ≥12 points was found by Fisher’s exact test, such that patients with IFG scores ≥12 points were significantly more likely to develop late cervical lymph node metastasis. The multivariate logistic regression analysis of the 4 factors showed a correlation between late cervical lymph node metastasis and tumour depth (p = 0.0398) and IFG (p = 0.0186) [Table 2].

Sensitivity (%)

Specificity (%)

Tumour depth ≥4 mm

47.6

97.2

Invasive front grading ≥12 points

57.1

93.0

Tumour depth and invasive front 47.8 grading

100.0

Tumour depth or invasive front grading

89.5

36.8

Table 3. Evaluation of effective methods for the prediction of late cervical lymph node metastasis.

Asian J Oral Maxillofac Surg Vol 18, No 2, 2006

Kurokawa, Yamashita, Matsumoto, et al

Discussion Uncontrolled or recurrent primary lesions and the development of cervical lymph node metastasis affect the prognosis of patients with N0 tongue carcinoma.1,2,4 The treatment of a clinically negative neck is especially important in the management of early carcinoma of the tongue, as metastasis to cervical lymph nodes is associated with a significant decrease in survival.20,21 Treatment decisions for patients without cervical neck lymph node metastasis is based mainly on tumour stage, with minimal treatment for early tongue carcinoma involving simple excision or interstitial radiotherapy.2,31 However, a small percentage of early tongue carcinomas are inexplicably aggressive, with an associated poor prognosis.1,21 Tumour stage alone is not reliable for predicting which patients with N0 carcinoma of the tongue are at the greatest risk for cervical lymph node metastasis. Therefore, an analysis of the risk factors for late cervical lymph node metastasis in N0 tongue carcinoma is important for predicting prognosis and achieving a high survival rate. Several factors related to the development of cervical lymph node metastasis and overall survival have been investigated clinically and pathologically.31-34 Tumour growth type, tumour size, tumour differentiation, mode of invasion, mitotic activity, microvascular invasion, and histological grade of malignancy are all reported to be risk factors for the development of cervical lymph node metastasis and overall survival.20-22,32-34 However, these factors have only a slight effect on prognosis and are not well described. In this study, tumour size, tumour depth, differentiation in the deep portion, microvascular invasion, muscle invasion, mode of invasion, and IFG all showed a statistically significant difference between patients with and without late cervical lymph node metastasis. Moreover, the multivariate logistic regression analysis identified tumour depth and IFG as having a powerful predictive value for postoperative cervical lymph node metastasis. The various histopathological factors reported to be reliable parameters for determining regional metastasis are not available preoperatively and therefore cannot be used to decide the initial treatment.20,22,35-37 Recently, several studies have Asian J Oral Maxillofac Surg Vol 18, No 2, 2006

focused on the tumour depth (thickness) of tongue carcinoma and, although this factor has been found to be an important factor predicting cervical metastasis, the significant depth of invasion ranged from 1.5 to 5 mm.5,7,20-24 It has been demonstrated that a tumour depth of ≥4 mm and moderate differentiation in the deep portion of stage I or II tongue carcinomas are associated with a high rate of late cervical lymph node metastasis.5 In the present study, late cervical lymph node metastasis was also found to be related to tumour depth at a depth of ≥3 mm. The incidence of late cervical lymph node metastasis increased markedly when the tumour depth exceeded 4 mm. The incidence of late cervical lymph node metastasis was 2.8% for tumours <4 mm deep and 47.6% when the tumour depth exceeded 4 mm. These authors concluded that tumour depth is of major importance for predicting cervical lymph node metastasis. Another frequently reported and important factor for the prediction of postoperative cervical lymph node metastasis is the grade of malignancy.5,6,12,38,39 Lim et al6 evaluated correlation between 3 malignancy grading systems (Bryne et al,28 Anneroth et al,40 and Martinez-Gimeno et al41) and late cervical lymph node metastasis, and suggested that both the Bryne et al (IFG) and Anneroth et al scores were significant in the univariate analysis. The authors of this study found an IFG score ≥12 points in N0 tongue carcinoma was significantly correlated with late cervical lymph node metastasis using multivariate logistic regression analysis. Furthermore, tumour depth and IFG were significantly associated with increased risk for late cervical lymph node metastasis; the combination of these 2 independent factors was more predictive than either one alone. The role of elective treatment for a clinically negative neck in the management of tongue carcinoma remains controversial. Three management strategies are commonly used: elective neck dissection, elective neck irradiation, and wait-and-see with treatment reserved for recurrence.3,31,41-44 Several studies have suggested that elective neck dissection should be performed for patients with N0 tongue carcinoma.1,20,31 Elective neck dissection entails low morbidity and allows accurate N staging. The procedure may be necessary for some patients and 123

Predictive Markers for Metastasis of Tongue Carcinoma

adjuvant therapy such as radiation therapy is required if the dissected cervical nodes show metastatic lymphadenopathy.6,9 Elective neck dissection offers the only conclusive method of identifying patients with cervical lymph node metastasis at initial treatment.6,9 However, a recent study showed that patients in the wait-and-see group had better survival than those in the elective neck dissection group.6,45,46 Thus, there is controversy as to whether or not patients with N0 tongue carcinoma should undergo elective neck dissection and definitive indications for elective neck dissection should be established. In this study, a tumour depth ≥4mm or IFG ≥12 points were predictive for late cervical lymph node metastasis in N0 tongue carcinoma, and mortality was associated with metastasis. It therefore seems reasonable to classify patients into high- and low-risk groups and to place patients with a tumour depth ≥4mm or an IFG ≥12 points in the high-risk group. These authors conclude that a tumour depth ≥4mm or an IFG ≥12 points has high predictive value for late cervical lymph node metastasis in tongue carcinoma. The combination of these factors may be a useful marker for deciding on elective neck treatment or salvage treatment during follow-up.

References 1. Cunningham MJ, Johnon JT, Myers EN, Schramm VL Jr, Thearle PB. Cervical lymph node metastasis after local excision of early squamous cell carcinoma of the oral cavity. Am J Surg. 1986;152:361-6. 2. 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 Oncologica. 1993;32:667-3. 3. Weiss, MH, Harrison LB, Isaacs R. Use of decision analysis in planning a management strategy for the stage N0 neck. Arch Otolaryngol Head Neck Surg. 1994;120:699-702. 4. Kurokawa H, Yamashita Y, Murata T, Tokudome S, Miura K, Yosjhikawa T, Kajiyama M. Clinicopathological evaluation of prognostic factors of oral squamous cell carcinoma patients with stage I and II. J Kyushu Dent Soc. 1998;52:399-404. 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 124

toungue. Head Neck. 2002;24:731-6. 6. Lim SC, Zhang S, Ishii G, Endoh Y, Kodama K, Miyamoto S, Hayashi R, Ebihara S, Cho JS, Ochiai A. 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. 7. Shintani S, Matsuura H, Hasegawa Y, Nakayama B, Fujimoto Y. The relationship of shape of tumor invasion to depth of invasion and cervical lymph node metastasis in squamous cell carcinoma of the tomgue. Oncology. 1997; 54:463-7. 8. Byers RM, El-Naggar AK, Lee YY, Rao B, Fornage B, Terry NH, Sample D, Hankins P, Smith TL, Wolf PJ. Can we detect or predict the presence of occult nodal metastases in patients with squamous cell carcinoma of the oral tongue? Head Neck. 1998;20:138-44. 9. Yii NW, Patel SG, Rhys-Evans PH, Breach NM. Management of the N0 neck in early cancer of the oral tongue. Clin Otolaryngol. 1999;24:75-9. 10. Saparano 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. 11. Pimenta Amaral AM, Da Silva Freire AR, Calvalho AL, Pinto CA, Kowalski LP. Predictive factors of occult metastasis and prognosis of clinical stage I and II squamous cell carcinoma of the tongue and floor of the mouth. Oral Oncol. 2004;40:780-6. 12. Yuen APW, Lam KY, Chan AC. Clinicopathologic analysis of elective neck dissection for N0 neck of early oral tongue carcinoma. Am J Surg. 1999;177:90-2. 13. Shintani S, Nakayama B, Matsuura H, Hasegawa Y. Intraoral ultrasonography is useful to evaluate tumor thickness in tongue carcinoma. Am J Surg. 1997;173: 345-7. 14. Umeda M, Nishimatsu N, Teranobu O, Shimada K. Criteria for diagnosing lymph node metastasis from squamous cell carcinoma of the oral cavity: a study of the relationship between computed tomographic and histologic findings and outcome. J Oral Maxillofac Surg. 1998;56: 585-93. 15. Yusa H, Yoshida H, Ueno E. Ultrasonographic criteria for diagnosis of cervical lymph node metastasis of squamous cell carcinoma in the oral and maxillofacial region. J Oral Maxillofac Surg. 1999;57:41-8. 16. Stuckensen T, Kovacs AF, Adams S, Baum RP. Staging of the neck in patients with oral cavity squamous cell carcinoma: a prospective comparison of PET, ultrasound, CT, Asian J Oral Maxillofac Surg Vol 18, No 2, 2006

Kurokawa, Yamashita, Matsumoto, et al

and MRI. J Cranio Maxillofac Surg. 2000;28:319-24. 17. Kuriakose MA, Loree TR, Hicks WL, Welch JJ, Wang H, DeLacure MD. Tumor volume estimated by computed tomography as a predictive factor in carcinoma of the tongue. Br J Oral Maxillofac Surg. 2000;38:460-5. 18. Shintani S, Yoshihama Y, Ueyama Y, Terakado N, Kamei S, Fujimoto Y, Hasegawa H, Matsuura T. The usefulness of intraoral ultrasonography in the evaluation of oral cancer. Int J Oral Maxillofac Surg. 2001;30:139-43. 19. Hayashi T, Ito J, Taira S, Katsura K, Shingaki S, Hoshina H. The clinical significance of follow-up sonography in the detection of cervical lymph node metastases in patients with stage I or II squamous cell carcinoma of the tongue. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2003;96:112-7. 20. Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous cell carcinoma confined to the tongue and floor of the mouth. Am J Surg. 1986;152:345-50. 21. Fukano H, Matsuura H, Hasegawa Y, Nakamura S. Depth of invasion as a predictive factor for cervical lymph node metastasis in tongue carcinoma. Head Neck. 1997; 19:205-10. 22. Asakage, T, Yokose T, Mukai K, Tsugane S, Tsubono Y, Asai M, Ebihara S. Tumor thickness predicts cervical metastasis in patients with stage I/II carcinoma of the tongue. Cancer. 1998;82:1443-8. 23. Hayashi T, Ito J, Taira S, Kastura K. The relationship of primary tumor thickness in carcinoma of the tongue to subsequent lymph node metastasis. Dentomaxillofac Radiol. 2001;30:242-5. 24. O-charoenrat P, Pillai G, Patel S, Fiser C, Archer D, Eccles S, Rhys-Evans P. Tumor thickness predicts cervical nodal metastases and survival in early oral tongue cancer. Oral Oncol. 2003;39:386-90. 25. Brown B, Barnes L, Mazariegos J, Tylor F, Johnson J, Wagner RL. Prognostic factors in mobile tongue and floor of mouth carcinoma. Cancer. 1989;64:1195-202. 26. Batsakis JG. Invasion of the microcirculation in head and neck. Ann Otol Rhinol Laryngol. 1984;93:646-7. 27. International Union Against Cancer. TNM classification of malignant tumors. 4th ed. Berlin: Springer-Verlag; 1987. p. 1-42. 28. Bryne M, Jenssen N, Boysen M. Histological grading in the deep invasive front of T1 and T2 glottic squamous cell carcinomas has high prognostic value. Virchows Arch. 1995;427:277-81. 29. Yamamoto E, Miyakawa A, Kohama G. Mode of invasion Asian J Oral Maxillofac Surg Vol 18, No 2, 2006

30.

31.

32. 33.

34.

35.

36.

37.

38.

39.

40.

41.

and lymph node metastasis in squamous cell carcinoma of the oral cavity. Head Neck Surg. 1984;6:938-47. Kaplan E, Meier P. Non-parametric estimation from incomplete observations. J Am Stat Assoc. 1958;53: 457-81. Lee JG, Krause CJ. Radical neck dissection: elective, therapeutic and secondary. Arch Otolaryngol. 1975;101: 656-9. Tytor M, Olofsson J. Prognostic factors in oral cavity carcinoma. Acta Otolaryngol. 1992;112:75-8. Lydiatt DD, Robbins T, Byers RM, Wolf PF. Treatment of stage I and II oral tongue cancer. Head Neck. 1993;15: 308-12. Kurokawa H, Zhang M, Matsumoto S, Yamashita Y, Tomoyose T, Tanaka T, Fukuyama H, Takahashi T. The relationship prognostic value of the histologic grade at the deep invasive front of tongue squamous cell carcinoma. J Oral Pathol Med. 2005;34:329-33. Fakih AR, Rao RS, Borges AM, Patel AR. Elective versus therapeutic neck dissection in early carcinoma of the tongue. Am J Surg. 1989;158:309-13. Gluckman JL, Pavelic ZP, Welkoborsky HJ. Prognostic indicators for squamous cell carcinoma of the oral cavity: a clinicopathologic correlation. Laryngoscope. 1997;107: 1239-44. Kurokawa H, Zhang M, Matsumoto S, Yamashita Y, Tanaka T, Tomoyose T, Takano H, Funaki K, Fukuyama H, Takahashi T, Sakoda S. The relationship of the histologic grade at the deep invasive front and the expression of ki67 antigen and p53 protein in oral squamous cell carcinoma. J Oral Pathol Med. 2005;34:602-7. Osaki T, Hirota J, Yoneda K, Yamamoto T, Ueta E. Clinical and histopathologic characteristics of tongue and gingiva carcinoma with occult and clinically evident cervical lymph node metastasis. Int J Oral Maxillofac Surg. 1996; 25:274-8. Hiratsuka H, Miyakawa A, Nakamori K, Kido Y, Sunakawa H, Kohama G. Multivariate analysis of ocult lymph node metastasis as a prognostic indicator for patients with squamous cell carcinoma of the oral cavity. Cancer. 1997; 80:351-6. Anneroth G, Batsakis J, Lunna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinoma. Scand J Dent Res. 1987;95: 229-49. Martinez-Gimeno C, Moro Rodriguez E, Navarro Vila C, Lopez Varela C. Squamous cell carcinoma of the oral cavity: a clinicopathologic scoring system for evaluating 125

Predictive Markers for Metastasis of Tongue Carcinoma

risk of cervical lymph node metastases. Laryngoscope. 1995:105:728-33. 42. Mendenhall WM, Million RR, Cassisi NJ. Elective neck irradiation in squamous cell carcinoma of the head and neck. Head Neck Surg. 1980;3:15-32. 43. Vandenbrouck C, Sancho-Garnier H, Chassagne D, Saravane D, Cachin Y, Micheau C. Elective versus therapeutic radical neck dissection in epidermoid carcinoma of the oral cavity. Cancer. 1980;46:386-90. 44. Levendag P, Vikram B. The problem of neck relapse in early stage supraglottic cancer: results of different treatment modalities for the clinically negative neck. Int J Radiat

126

Oncol Biol Phys. 1987;13:1621-4. 45. Nieuwenhuis EJ, Castelijins JA, Pijpers R, van der Brekel MW, Brakenhoff RH, van der Waal I, Snow GB, Leemans CR. Wait-and-see policy for the N0 neck in early stage oral and oropharyngeal squamous cell carcinoma using ultrasonography-guided cytology: is there a role for identification of the sentinel node? Head Neck. 2002;24: 282-9. 46. Khafif RA, Gelbfish GA, Tepper P, Attie JN. Elective radical neck dissection in epidermoid cancer of the head and neck. A retrospective analysis of 853 cases of mouth, pharynx, and larynx cancer. Cancer. 1991;67:67-71.

Asian J Oral Maxillofac Surg Vol 18, No 2, 2006