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Cancer of Oral Cavity Abutting the Mandible; Predictors of Loco-regional Failure.

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TAREK K. SABER, M.D.; HESHAM A. HUSSEIN, M.D.; ALI H. MEBEED, M.D.;
HESHAM I. EL SEBAI, M.D.; IHAB SAMI, M.D. and IMAN G. FARAHAT, M.D.*
The Departments of Surgical Oncology and Pathology*, National Cancer Institute, Cairo University.
Journal of the Egyptian Nat. Cancer Inst., Vol. 21, No. 3, September: 219-227, 2009

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Cancer of Oral Cavity Abutting the Mandible; Predictors of Loco-regional Failure.

  1. 1. ABSTRACT Aim of Work: The purpose of this study is to analyze the causes of Loco-regional failure in 51 patients with tumors of the oral cavity abutting the mandible. Patients and Methods: This cross-sectional study (27 patients were operated upon in the retrospective section and 24 patients in the prospective section of the study) was done in the department of Surgical Oncology, National Cancer Institute, Cairo University, from January 2003 to January 2008. Fifty-one patients, with oral cavity cancerous lesions abutting the mandible, were operated upon by segmental mandibulectomy en-bloc with primary tumor resection in addition to modified radical or selective neck dissection according to the status of the cervical lymph nodes. Results: During a median follow-up of 2 years, 29 patients (56.8%) had local recurrences, the incidence of nodal recurrence after neck dissection was detected in 4 patients (7.8%). On multivariate analysis, tumor depth, tumor grade, oral mucosa, soft tissue and bone surgical margins in addition to metastatic lymphadenopathy were independent prognostic factors of loco-regional failure and disease-free survival. Conclusion: Oral cavity cancers abutting the mandible should be treated with great caution by a multidisciplinary oncology team (resection and reconstruction surgeons) as it has a very aggressive biologic behavior. Negative intraoperative pathological margins should be attempted since this is the critical point for patients with cancers abutting the mandible? Further research on the biologic margin and genetic study is required. Key Words: Oral cavity cancer abutting the mandible – Predictors of loco-regional failure. INTRODUCTION Oral cancer is the sixth most common cancer worldwide, with a high prevalence in south Journal of the Egyptian Nat. Cancer Inst., Vol. 21, No. 3, September: 219-227, 2009 Cancer of Oral Cavity Abutting the Mandible; Predictors of Loco-regional Failure TAREK K. SABER, M.D.; HESHAM A. HUSSEIN, M.D.; ALI H. MEBEED, M.D.; HESHAM I. EL SEBAI, M.D.; IHAB SAMI, M.D. and IMAN G. FARAHAT, M.D.* The Departments of Surgical Oncology and Pathology*, National Cancer Institute, Cairo University. 219 Asia. Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers. Primary site location, size, prox- imity to bone, and depth of infiltration are factors which influence a particular surgical approach. Tumors that approach or involve the mandible require specific understanding of the mechanism of bone involvement. This facilitates the employment of mandible sparing approaches such as marginal mandibulectomy and mandib- ulotomy [1,2]. Standard plain radiographs such as the or- thopantomogram (OPG) are reasonably sensitive in detecting mandibular invasion, but this should be confirmed in doubtful cases with more sen- sitive imaging techniques like CT and MRI [3]. It was found that a malignant tumor does not extend directly through the intact periosteum and cortical bone toward the cancellous part of the mandible since the periosteum acts as a significant protective barrier, instead the tumor advances from the attached gingiva towards the alveolus [4,5]. In patients with teeth, tumor extends through the dental sockets into the cancellous part of the bone and invades the mandible while in edentulous patients the tumor extends up to the alveolar crest and then infiltrates through the dental pores in the alveolar process and extends to the cancellous part of the mandible, Fig. (1) shows the classification of mandible invasion with oral cancer [6,7]. Thus in patients with very early invasion of the alveolar process, marginal mandibulectomy is feasible since the cortical part of the mandible Correspondence: Dr Tarek K. Saber, Department of Surgical Oncology, National Cancer Institute, Cairo University, khairytarek@yahoo.com
  2. 2. 220 inferior to the roots of the teeth remains unin- volved and can be safely spared [8,9]. In edentulous patients, the feasibility of marginal mandibulectomy depends on the ver- tical height of the body of the mandible which is not visible with the age desorption process. Segmental mandibulectomy must be performed when there is extension of tumor to involve the cancellous part of the mandible and may also be required in patients who have massive pri- mary tumors with extensive soft tissue disease surrounding the mandible, and should not be considered to simply gain access for resection as mandibulotomy is a reasonable solution [10]. PATIENTS AND METHODS This study was conducted in the National Cancer Institute, Cairo University, a tertiary cancer institution, from January 2003 to January 2008. Statistical analysis was performed on 51 patients who fulfilled our inclusion criteria. These criteria included patients with all T stages, N0, N1 or N2 patients with exclusion of patients with distant metastases. The patients were staged according to the American Joint Committee of Cancer (AJCC) staging system. Demographic data including clinical presen- tation, relevant imaging findings, operative details, histopathologic confirmation and follow- up information is presented. In addition to routine laboratory investiga- tions, chest X-ray, cardiologic and anesthetic consultations, pre-operative plain X-ray of the mandible (Panorex) was done in 21 patients. Pre-operative CT scan of the head and neck was done in 38 patients. All patients were operated upon as the pri- mary definitive treatment (apart from two pa- tients who received pre-operative neo-adjuvant chemoradiation therapy due to advanced stage of disease). Commando operation was per- formed in the form by lateral segmental man- dibulectomy en-bloc with excision of the pri- mary tumor in addition to modified radical or selective neck dissection in 45 patients. Central mandibulectomy was performed in 4 patients with appropriate mandibular reconstruction, and two patients were operated upon by marginal mandibulectomy with appropriate soft tissue reconstruction. In the majority of patients, a pectoralis major myo-cutaneous flap was done for reconstruction followed by a deltopectoral fascio-cutaneous flap. A free vascularized radial forearm flap was done for three patients for reconstruction of floor of mouth defects and a free vascularized fibular graft was done for two patients for mandibular reconstruction. Pathologic examination of the resected speci- men: The surgical specimens submitted to the Department of Pathology at the National Cancer Institute, Cairo University, were processed in standard fashion after orientation of the mucosal, soft tissue, and bone margins of the resected part of the mandible. Lymph nodes were identified by visual in- spection and palpation, and were dissected out from the gross specimen. After fixation in 10% neutral buffered formalin, decalcification of bony sections was done utilizing a solution containing 10% formic acid and 10% Hcl. After decalcification, the specimen was sub- sequently processed routinely for paraffin em- bedding and staining by haematoxylin and eosin (H&E). After the sections were processed, slides from each section containing the tumor were assessed to determine the extent of mandibular bone invasion, if present. The sections from margins of resection, including bone pathological margins, were eval- uated and classified as negative if there was no evidence of tumor at the margin, close if the tumor was within 2mm distance from the margin or positive if the margin was involved by tumor tissue (microscopic cut-through). Surgical and post-operative treatment done to patients and their results were planned ac- cording to the site of primary tumor and stage of disease. RESULTS From a total of fifty-one patients with oral cavity cancer, 31 (60.7%) were male patients Cancer of Oral Cavity Abutting the Mandible
  3. 3. Tarek K. Saber, et al. 221 and 20 (39.3%) were females whose ages ranged from 22 to 73 years. The median age of all patients was 58 years, while the mean age was 56.3 years. The commonest tumor was alveolar margin carcinoma encountered in 19 patients (37.2%), followed by 14 patients (27.4%) with retromolar tumors, followed by other sites, as shown in Table (1). A.J.C .C staging is shown in Table (2), where T3 was the commonest (31.3%), followed by T2 (29.4%) and T4 (27.4%). Negative nodes (N0) represented 52.94% of the cases followed by N1 (43.13%) (Table 2). Regarding the histology of tumors, squamous cell carcinoma was the predominant histology found in 47 patients (92.1%) (Table 3). Regarding the grade of the tumor, Interme- diate grade (grade 2) was the predominant grade in 38 patients (80.8%) (Table 4). Table (5) shows the number of patients at different primary sites, their stage, tumor grade and histopathological type. The final pathological reports for the surgical pathological margins in different sites came with negative pathological margins in 9/19 patients of alveolar margin carcinoma, 7/14 patients of retromolar trigone, 3/8 buccal mucosa patients, 2/6 patients of tongue carcinoma, 1/3 floor of mouth patient and one patient of basal cell carcinoma. Positive margins recorded high incidence in 9/19 patients with alveolar margin carcinoma, 3/14 patients with retromolar trigone, 4/7 in buccal mucosa, 3/6 of tongue carcinoma patients and 1/3 patients with floor of mouth carcinoma. Close margins were reported in 1/19 patients with carcinoma of the alveolar margin, 4/14 in retromolar trigone patients, 1/8 of buccal mu- cosa, 1/6 in tongue carcinoma and one case of floor of mouth carcinoma. All results are sum- marized in Table (6). Figs. (2-5) show radiolog- ical and intraoperative photographs of oral cavity cancer. In this study, most cases of mandibular bone invasion with tumor were in patients of alveolar margin tumors, this was proved pathologically in 14/19 patients. Bone invasion occurred next in frequency in 8/14 patients with retromolar tumors. Tumors of the buccal mucosa abutting the mandible (gingivo-buccal sulcus tumors) invaded the mandible in 2/8 patients, one of these patients had a grade 2 squamous cell carcinoma and the other one had muco- epdermoid cancer of the gingivo-buccal sulcus (GBC). Both patients had T 4 lesions, but this was not observed in a patient with a locally advanced GBC and another patient with grade 3 squamous cell carcinoma (Table 7). As regards the incidence of local recurrence in this study, the highest rate of local recurrence was found in 5/6 patients (83.3%) with carci- noma of the tongue (Table 8). In this study, we had 4/50 patients (6%) who underwent neck dissection and developed neck recurrence in the neck dissection side. Details of locoregional recurrence and distant metastases according to primary site tumors are shown in Table (9). Results of treatment for the 51 patient with oral cavity cancer abutting the mandible are presented in Table (10). Table (1): Oral cavity cancers abutting the mandible; sites and number of cases. Alveolar margin Retromolar trigone Buccal mucosa (gingivo-buccal complex) Tongue Floor of mouth Skin of Chin Total No. of cases 19 (37.25) 14 (27.45) 8 (15.6) 6 (11.7) 3 (5.8) 1 (1.9) 51 Site of primary tumor No. of cases (%) Table (2): T. N. M stage of 51 patients. T 1 T 2 T 3 T 4 Referred recurrent cases Total no. T stage T = Tumor. N = Node. M = Metastasis. M 0 M 0 M 0 M 0 0 M stage 27 (52.94) 22 (43.13) 2 (3.92) 0 None 51 No. of cases (%) N 0 N 1 N 2 N 3 Neck Recurrence after treatment N stage 3 (5.8) 15 (29.4) 16 (31.3) 14 (27.4) 3 (5.8) 51 No. of cases (%)
  4. 4. 222 Cancer of Oral Cavity Abutting the Mandible Table (3): Histological type of primary tumor. 1 (1.9%) Basal cell carcinoma 1 (1.9%) Verrucous carcinoma 2 (3.9%) Muco-epedermoid carcinoma No. of cases Type of tumor 47 (92.1%) Squamous cell carcinoma Table (6): Pathologic surgical margin according to the site of primary tumor. Negative surgical margin Positive surgical margin Close margin Margin status 1ry Tumor 9 (47.3%) 9 (47.3%) 1 (5.2%) Alveolar margin N=19 7 (50%) 3 (21.4%) 4 (28.5%) Retromolar trigone N=14 3 (37.5%) 4 (57.1%) 1 (12.5%) Buccal mucosa (GBC) N=8 2 (33.3%) 3 (50%) 1 (16.6%) Tongue N=6 1 (33.3%) 1 33.3% 1 33.3% Floor of mouth N=3 1 0 0 Chin N=1 Table (4): Grade of primary tumor. No. of cases Type of tumor 4/47 (8.5%) Squamous cell Ca. Grade 1 38/47 (80.8%) Squamous cell Ca. Grade 2 8/47 (17%) Squamous cell Ca. Grade 3 Gd1 1 case 1/51 (3.9%) Gd3 1 case 1/51 (3.9%) Muco-epedermoid Grade 1,3 1/51 (1.9%) Verrucous carcinoma 1/51 (1.9%) Basal cell carcinoma Table (5): Tumor and nodal stage, histopathology and grade in different sites of oral cavity cancer patients. Alveolar margin (19) 31.5% Retromolar trigone (14) 27.4% Buccal mucosa (8) Tongue (6) Floor of mouth (3) Chin mandible (1) Primary site G3=3 G2=14 G1=2 G3=2 G2=11 G1=1 G3=4 G2=3 G1=1 G3=1 G2=4 G1=1 G2=3 Grade Squamous cell carcinoma. Squamous cell Carcinoma. (13) Mucoepidermoid (1) Verrucous carcinoma (1) Squamous cell carcinoma (6) Mucoepidermoid (1) Squamous cell carcinoma Squamous cell carcinoma Basal cell carcinoma Histopathology N0=9 N1=8 N2=2 N0=7 N1=7 N0=4 N1=4 N0=5 N1=1 N0=3 N0=1 Node T=0 T2=6 T3=6 T4=7 T1=1 T2=5 T3=6 T4=2 T1=0 T2=2 T3=2 T4=4 T1=0 T2=2 T3=4 T4=0 T1=2 T4=1 T4=1 Tumor T = Tumor. N = Node. G = Grade.
  5. 5. Table (7): Incidence of mandible invasion in different sites of oral cavity cancer. Invasion of Mandible Percentage Site of 1ry tumor 1/1 Chin 2/3 66.6% F.O.M 0/6 0% Tongue 2/8 14.2% Buccal mucosa (GBC) 8/14 57.1% Retromolar trigone 14/19 73.6% Alveolar margin FOM: Floor of mouth. Tarek K. Saber, et al. 223 Table (10): Results of treatment according to site of primary tumor. 11 cases (57.8%) 7 cases (50%) 5 cases (62.5%) 5 cases (83.3%) 1 case No 29/51 cases of locegional failure 56.8% Local recurrence Yes Yes Yes Yes Yes Yes Adjuvant therapy 14 cases 8 cases 2 cases No case of mandibular infiltration 2 cases 1 case 27/51 cases mandibular invasion with tumor 52.9% Positive invasion of mandible Commando N=19 case Commando N=13 cases Marg.mandibulectomy N=1 case Commando N=8 cases Commando N=6 cases Commando N=2 cases Wide excision=1 case Central mandibulectomy N=1 case Primary treatment Alveolar margin Retromolar trigone Buccal mucosa GBC Tongue Floor of mouth Chin Total no. Percentage Site of 1ry tumor Table (8): Incidence of local recurrence in different sites of oral cavity cancer. Local recurrence Percentage Site of 1ry tumor 0/1 0% Chin 1/3 33.3% F.O.M 5/6 83.3% Tongue 5/8 62.5% Buccal mucosa (GBC) 7/14 50% Retromolar trigone 11/19 57.8% Alveolar margin FOM: Floor of mouth. Table (9): Details of loco-regional and distant metastases according to site of primary tumor. Total cases of local recurrence Positive mucosal margin Positive soft tissue margin Positive bone margin Nodal recurrence Distant metastases Site of 1ry tumor 29/51 (56.8%) 16/51 (31.3%) 8/51 (15.6%) 3/51 (5.8%) 4/51 (7.8%) 1/51 (1.9%) Total No. Local, Nodal, Recurrence, Distant metastases 1/3 (33.3%) 1/1 0 0 0 0 Floor of Mouth (F.O.M) 5/6 (83.3%) 2/5 (40%) 1/5 (20%) 0 1/5 (20%) 0 Tongue 5/8 (62.5%) 3/5 (60%) 1/5 (20%) 1/5 (20%) 0 0 Buccal mucosa (GBC) 7/14 (50%) 4/7 (57.1%) 2/7 (28.5%) 1/7 (14.2%) 1/7 (14.2%) 1/7 (14.2%) Retromolar trigone 11/19 (57.8%) 6/11 (54.5%) 4/11 (36.3%) 1/11 (9.1%) 2/11 (18.1%) Alveolar margin
  6. 6. No Bone Invasion T1 Invasion within Alveolar Bone T2 Invasion beyond alveolar bone but above the LMC T3 Invasion including the LMC T4 224 Cancer of Oral Cavity Abutting the Mandible DISCUSSION In this study, we had considerable high rates of loco-regional failure in patients with carci- noma abutting the mandible in different sites of the oral cavity. In comparison, a similar study from Rapidis et al from the Greek Cancer Institute in 2009 included 194 patients with tumors abutting the mandible to whom a com- posite mandibular resection in addition to the appropriate type of neck dissection was carried out. Fig. (1): Classification of mandible invasion with oral cancer. T 1 No Bone Invasion. T 2 Invasion within Alveolar Bone. T 3 Invasion beyond alveolar bone but above the *LMC. T 4 Invasion including the LMC. *LMC: Level of Mandibular Canal (Alexander D.Rapidis) (12). Fig. (2): Carcinoma of floor of mouth abutting the man- dible. Fig. (3): CT of tumor invading the alveolar bone on the lt. side. Fig. (4): Lip splitting, lower cheek flap, marginal man- dibulectomy en-bloc with wide excision of tumor of floor of mouth. Fig. (5): Specimen, en- bloc resection of floor of mouth tumor + marginal mandibulectomy + modified radical neck dissection.
  7. 7. Tarek K. Saber, et al. 225 Local recurrence in alveolar margin carci- noma was found in 61.9% (26/42 patients), in 50% of patients with retromolar carcinoma (5/10 patients), in 42.6% of patients with tongue cancer (20/47 patients), in 41.9% of patients with floor of mouth carcinoma (13/31 patients) in a total of 64/194 patients (32.6%). The overall rate of loco-regional failure in our study was 29/51 patients (56.8%), where alveolar margin cancer recurrence was detected in 11/19 patients (57.6%), in carcinoma of the tongue, in 5/6 patients (83.3%) with local re- currence, retromolar trigone in 7/14 patients (50%), carcinoma of the buccal mucosa or the gingivo-buccal complex in 5/8 patients (62.5%), while in floor of mouth carcinoma, we had 1/3 patient (33.3%) with local recurrence [12]. This high incidence of local recurrence in our study could be explained by the high number of positive resection margins which were exam- ined pathologically after surgery, as presented in Table (6). Jones et al. [13], in an attempt to identify those patients most at risk for recurrence, ret- rospectively determined the clinical and histo- logical factors that was associated with recur- rence in 49 patients with stage I and II oral cavity cancer. Multiple regression analysis re- vealed that when various interactions between variables were controlled for, only the presence of a positive surgical margin or a tumor depth greater than 5mm was significantly associated with recurrence. Each-individually-increased the likelihood of recurrence almost threefold [14]. Again, this high rate of local recurrence in our study could be explained by the high inci- dence of positive margins, although most of these cases were operated upon by segmental mandibulectomy to be sure of negative margins but results came with positive soft tissue margins as shown in Table (6). O`Brien et al. [15] prospectively documented patients who were treated with marginal or segmental resection for oral (n=110) and oropha- ryngeal (n=17) cancers. Among patients with bone invasion, the local control rate was higher following segmental resection when compared to marginal resections (87% Vs. 75%), but this was not statistically significant. Survival was significantly influenced by positive soft tissue margins but not bone invasion or the type of resection. They concluded that bone invasion alone did not predict for local control or survival rates among patients with oral and oropharyn- geal cancers. Involved soft tissue margins were highly predictive of local recurrence and de- creased survival. Conservative resection of the mandible is safe as long as marginal mandibulec- tomy does not lead to compromise of soft tissue margins. Segmental resection should be reserved for patients with extensive bone invasion or those with limited invasion in a thin atrophic mandible. The need for intra-operative frozen section confirmation cannot be over-emphasized in order to obtain adequate local control for these potentially curable tumors which were inade- quately treated. However, despite apparently adequate local resection of oral cancer, recurrence rates of 25-48% have been re- ported [16]. Recurrent oral cancer tends to appear at the primary site, perhaps because of the persistence of malignant cells within local lym- phatics or field cancerization, and is usually seen within 36 months after the initial treatment. Surgery and radiotherapy may cause tissue hypoxia, hypocellularity, and fibrosis, the last of which can encase persistent malignant cells, making detection difficult. These processes may eventually result in local recurrence. One of the most important causes of local recurrence is the persistence of tumor cells at the resection margin [17]. Slootweg et al. [18] examined the resection margins of 394 patients who underwent tumor resection and found a much lower incidence of local recurrence in patients with negative (3.9%) than positive (21.9%) margins. Unfortunately, locally recurrent cancer de- velops even when resection margins are histo- logically tumor-free. It is believed that the relatively small number of cancer cells that remains in the patient at the margin is the main source of local recurrence. This limited number of cells has been designated local minimal residual cancer (MRC) [19-22].
  8. 8. 226 Recent molecular genetic studies provide evidence that the majority of, if not all, head and neck squamous cell carcinomas (HNSCCs) develop within a contiguous field of pre- neoplastic cells and genetic alterations associ- ated with the process of carcinogenesis. A sub- clone in a field gives rise to an invasive carci- noma. An important implication of this knowledge is that, after surgery of the initial carcinoma, part of the field may remain in the patient. A field with preneoplastic cells that share genetic alterations with cells of the excised tumor has been detected in the resection margins of at least 25% of patients, indicating that this frequently occurs. Fields can be much larger than the actual carcinoma, sometimes having a diameter >7cm [19]. Still further research is ongoing to accurately predict and, therefore, have an implication on early prediction and treatment of patients most susceptible to have recurrences based on genetic and biologic examination of the surgical margin in patients with oral cavity squamous cell car- cinoma. Conclusion: Oral cavity cancers abutting the mandible should be treated with great caution by a mul- tidisciplinary oncology team (resection and reconstruction surgeons) as it has a very aggres- sive biologic behavior. Negative intraoperative pathological margins should be attempted since this is the critical point for patients with cancers abutting the mandible. Further research on the biologic margin with genetic studies is required. REFERENCES 1- Moore SR, Johnson NW, Pierce AM, Wilson DF. The epidemiology of mouth cancer: A review of global incidence. Oral Dis. 2000, 6: 65-74. 2- Sankaranarayanan R. Oral cancer in India: An epide- miological and clinical review. Oral Surg Oral Med Oral Pathol. 1990, 69: 325-30. 3- Paul Lam, Kai Ming Au–Yeung, Pui Wai Cheng, William Ignace Wei, Anthony Po-Wing Yuen, Nigel Trendell-Smith, Jimmy HC Li, Raymond Li. Corre- lating MRI and Histologic Tumor Thickness in the Assessment of Oral Tongue Cancer, American Journal of Roentgenology, AJR. 2004, 182: 803-808. 4- Shah JP, Patel SG. Head and neck Surgery and Oncol- ogy. 3rd ed. London, New York, Edinburgh, Mosby. 2003. 5- Shah JP. Patterns of cervical lymph node metastasis from squamous carcinomas of the upper aerodigestive tract. Am J Surg. 1990, 160 (4): 405-9. 6- Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous carcinoma confined to the tongue and floor of the mouth. Am J Surg. 1986, 152 (4): 345- 50. 7- Jun MY, Strong EW, Saltzman EI, Gerold FP. Head and neck cancer in the elderly. Head Neck Surg. 1983, 5 (5): 376-82. 8- Friedlander PL, Schantz SP, Shaha AR, Yu G, Shah JP. Squamous cell carcinoma of the tongue in young patients: A matched-pair analysis. Head Neck. 1998, 20 (5): 363-8. 9- McGregor AD, MacDonald DG. Routes of entry of squamous cell carcinoma to the mandible. Head Neck Surg. 1988, 10 (5): 294-301. 10- Shah JP, Johnson NW, Batsakis JG. Oral Cancer. London: Martin Dunitz. 2003, p. 387-94. 11- Marchetta FC, Sako K, Murphy JB. The periosteum of the mandible and intraoral carcinoma. Am J Surg. 1971, 122 (6): 711-3. 12- Rapidis AD. Management of the Mandible in Cancer of the Oral Cavity. 27th. Alexandria Combined ORL Congress, April 8-10, 2009. 13- Jones KR, Lodge-Rigal RD, Reddick RL, Tudor GE, Shockley WW. Prognostic factors in the recurrence of stage I and II squamous cell cancer of the oral cavity. Arch Otolaryngol Head Neck Surg. 1992 May, 118 (5): 483-5. 14- 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 (1 Pt 1): 166-72. 15- O'Brien CJ, Adams JR, McNeil EB, Taylor P, Laniewski P, Clifford A, et al. Influence of bone invasion and extent of mandibular resection on local control of cancers of the oral cavity and oropharynx. Int J Oral Maxillofac Surg. 2003, 32 (5): 492-7. 16- Pearlman NW. Treatment outcome in recurrent head and neck cancer. Arch Surg. 1979, 114: 39-42. 17- Van Es RJ, van Nieuw Amerongen N, Slootweg PJ, Egyedi P. Resection margin as a predictor of recurrence at the primary site for T1 and T2 oral cancers: evalu- ation of histopathologic variables. Arch Otolaryngol Head Neck Surg. 1996, 122: 521-5. 18- Slootweg PJ, Hordijk GJ, Schade Y, van Es RJ, Koole R. Treatment failure and margin status in head and neck cancer: A critical view on the potential value of molecular pathology. Oral Oncol. 2002, 38: 500-3. 19- Braakhuis BJ, Brakenhoff RH, Leemans CR. Second Field Tumors: A New Opportunity for Cancer Preven- tion? Oncologist. 2005, 10: 493-500. Cancer of Oral Cavity Abutting the Mandible
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