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

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1 Journal of the Egyptian Nat. Cancer Inst., Vol. 21, No. 3, September: , 29 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. 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 23 to January 28. 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 Correspondence: Dr Tarek K. Saber, Department of Surgical Oncology, National Cancer Institute, Cairo University, khairytarek@yahoo.com Asia. Surgery is the most well established mode of initial definitive treatment for a majority of oral cancers. Primary site location, size, proximity 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 mandibulotomy [1,2]. Standard plain radiographs such as the orthopantomogram (OPG) are reasonably sensitive in detecting mandibular invasion, but this should be confirmed in doubtful cases with more sensitive 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 219

2 22 inferior to the roots of the teeth remains uninvolved and can be safely spared [8,9]. In edentulous patients, the feasibility of marginal mandibulectomy depends on the vertical 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 primary 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 [1]. PATIENTS AND METHODS This study was conducted in the National Cancer Institute, Cairo University, a tertiary cancer institution, from January 23 to January 28. Statistical analysis was performed on 51 patients who fulfilled our inclusion criteria. These criteria included patients with all T stages, N, 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 presentation, relevant imaging findings, operative details, histopathologic confirmation and followup information is presented. In addition to routine laboratory investigations, 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 primary definitive treatment (apart from two patients who received pre-operative neo-adjuvant chemoradiation therapy due to advanced stage of disease). operation was performed in the form by lateral segmental mandibulectomy en-bloc with excision of the primary 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 Cancer of Oral Cavity Abutting the Mandible 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 specimen: 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 inspection and palpation, and were dissected out from the gross specimen. After fixation in 1% neutral buffered formalin, decalcification of bony sections was done utilizing a solution containing 1% formic acid and 1% Hcl. After decalcification, the specimen was subsequently processed routinely for paraffin embedding 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 evaluated 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 according to the site of primary tumor and stage of disease. RESULTS From a total of fifty-one patients with oral cavity cancer, 31 (6.7%) were male patients

3 Tarek K. Saber, et al. 221 and 2 (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 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 (N) represented 52.94% of the cases followed by N1 (43.13%) (Table 2). Regarding the histology of tumors, squamous cell was the predominant histology found in 47 patients (92.1%) (Table 3). Regarding the grade of the tumor, Intermediate grade (grade 2) was the predominant grade in 38 patients (8.8%) (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, 7/14 patients of retromolar trigone, 3/8 buccal mucosa patients, 2/6 patients of tongue, 1/3 floor of mouth patient and one patient of basal cell. Positive margins recorded high incidence in 9/19 patients with alveolar margin, 3/14 patients with retromolar trigone, 4/7 in buccal mucosa, 3/6 of tongue patients and 1/3 patients with floor of mouth. Close margins were reported in 1/19 patients with of the alveolar margin, 4/14 in retromolar trigone patients, 1/8 of buccal mucosa, 1/6 in tongue and one case of floor of mouth. All results are summarized in Table (6). Figs. (2-5) show radiological 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 and the other one had mucoepdermoid 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 (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 of the tongue (Table 8). In this study, we had 4/5 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 (1). Table (1): Oral cavity cancers abutting the mandible; sites and number of cases. Site of primary tumor Alveolar margin Retromolar trigone Buccal mucosa (gingivo-buccal complex) Floor of mouth Skin of Chin Total No. of cases Table (2): T. N. M stage of 51 patients. T stage T 1 T 2 T 3 T 4 Referred recurrent cases Total no. No. of cases (%) 3 (5.8) 15 (29.4) 16 (31.3) 14 (27.4) 3 (5.8) 51 N stage N N 1 N 2 N 3 Neck Recurrence after treatment T = Tumor. N = Node. M = Metastasis. No. of cases (%) 19 (37.25) 14 (27.45) 8 (15.6) 6 (11.7) 3 (5.8) 1 (1.9) 51 No. of cases (%) 27 (52.94) 22 (43.13) 2 (3.92) None 51 M stage M M M M

4 222 Cancer of Oral Cavity Abutting the Mandible Table (3): Histological type of primary tumor. Type of tumor Squamous cell Muco-epedermoid Verrucous Basal cell No. of cases 47 (92.1%) 2 (3.9%) 1 (1.9%) 1 (1.9%) Table (4): Grade of primary tumor. Type of tumor Squamous cell Ca. Grade 1 Squamous cell Ca. Grade 2 Squamous cell Ca. Grade 3 Muco-epedermoid Grade 1,3 Verrucous Basal cell No. of cases 4/47 (8.5%) 38/47 (8.8%) 8/47 (17%) Gd1 1 case 1/51 (3.9%) Gd3 1 case 1/51 (3.9%) 1/51 (1.9%) 1/51 (1.9%) Table (5): Tumor and nodal stage, histopathology and grade in different sites of oral cavity cancer patients. Primary site Tumor Node Histopathology Grade Alveolar margin (19) 31.5% T= T2=6 T3=6 T4=7 N=9 N1=8 N2=2 Squamous cell. G3=3 G2=14 G1=2 Retromolar trigone (14) 27.4% T1=1 T2=5 T3=6 T4=2 N=7 N1=7 Squamous cell Carcinoma. (13) Mucoepidermoid (1) G3=2 G2=11 G1=1 Buccal mucosa (8) T1= T2=2 T3=2 T4=4 N=4 N1=4 Verrucous (1) Squamous cell (6) Mucoepidermoid (1) G3=4 G2=3 G1=1 (6) T1= T2=2 T3=4 T4= N=5 N1=1 Squamous cell G3=1 G2=4 G1=1 Floor of mouth (3) T1=2 T4=1 N=3 Squamous cell G2=3 Chin mandible (1) T4=1 N=1 Basal cell T = Tumor. N = Node. G = Grade. Table (6): Pathologic surgical margin according to the site of primary tumor. Margin status 1ry Tumor Alveolar margin N=19 Retromolar trigone N=14 Buccal mucosa (GBC) N=8 N=6 Floor of mouth N=3 Chin N=1 Negative surgical margin Positive surgical margin Close margin 9 (47.3%) 9 (47.3%) 1 (5.2%) 7 (5%) 3 (21.4%) 4 (28.5%) 3 (37.5%) 4 (57.1%) 1 (12.5%) 2 (33.3%) 3 (5%) 1 (16.6%) 1 (33.3%) % % 1

5 Tarek K. Saber, et al. 223 Table (7): Incidence of mandible invasion in different sites of oral cavity cancer. Site of 1ry tumor Alveolar margin Retromolar trigone Buccal mucosa (GBC) F.O.M Chin Invasion of Mandible Percentage 14/ % 8/ % 2/8 14.2% /6 % 2/3 66.6% 1/1 FOM: Floor of mouth. Table (8): Incidence of local recurrence in different sites of oral cavity cancer. Site of 1ry tumor Alveolar margin Retromolar trigone Buccal mucosa (GBC) F.O.M Chin Local recurrence Percentage 11/ % 7/14 5% 5/8 62.5% 5/6 83.3% 1/3 33.3% /1 % FOM: Floor of mouth. Table (9): Details of loco-regional and distant metastases according to site of primary tumor. Site of 1ry tumor Alveolar margin Retromolar trigone Buccal mucosa (GBC) Floor of Mouth (F.O.M) Total No. Local, Nodal, Recurrence, Distant metastases Total cases of local recurrence Positive mucosal margin Positive soft tissue margin Positive bone margin Nodal recurrence Distant metastases 11/19 (57.8%) 6/11 (54.5%) 4/11 (36.3%) 1/11 (9.1%) 2/11 (18.1%) 7/14 (5%) 4/7 (57.1%) 2/7 (28.5%) 1/7 (14.2%) 1/7 (14.2%) 1/7 (14.2%) 5/8 (62.5%) 3/5 (6%) 1/5 (2%) 1/5 (2%) 5/6 (83.3%) 2/5 (4%) 1/5 (2%) 1/5 (2%) 1/3 (33.3%) 1/1 29/51 (56.8%) 16/51 (31.3%) 8/51 (15.6%) 3/51 (5.8%) 4/51 (7.8%) 1/51 (1.9%) Table (1): Results of treatment according to site of primary tumor. Site of 1ry tumor Primary treatment Positive invasion of mandible Adjuvant therapy Local recurrence Alveolar margin N=19 case 14 cases 11 cases (57.8%) Retromolar trigone N=13 cases Marg.mandibulectomy N=1 case 8 cases 7 cases (5%) Buccal mucosa GBC N=8 cases 2 cases 5 cases (62.5%) N=6 cases No case of mandibular infiltration 5 cases (83.3%) Floor of mouth N=2 cases Wide excision=1 case 2 cases 1 case Chin Central mandibulectomy N=1 case 1 case No Total no. 27/51 cases mandibular invasion with tumor 29/51 cases of locegional failure Percentage 52.9% 56.8%

6 Cancer of Oral Cavity Abutting the Mandible 224 No Bone Invasion T1 Invasion within Alveolar Bone T2 Fig. (1): Classification of mandible invasion with oral cancer. Invasion beyond alveolar bone but above the LMC T3 Invasion including the LMC T4 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 mandible. Fig. (3): CT of tumor invading the alveolar bone on the lt. side. Fig. (4): Lip splitting, lower cheek flap, marginal mandibulectomy 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. DISCUSSION study from Rapidis et al from the Greek Cancer Institute in 29 included 194 patients with tumors abutting the mandible to whom a composite mandibular resection in addition to the appropriate type of neck dissection was carried out. In this study, we had considerable high rates of loco-regional failure in patients with abutting the mandible in different sites of the oral cavity. In comparison, a similar

7 Tarek K. Saber, et al. 225 Local recurrence in alveolar margin was found in 61.9% (26/42 patients), in 5% of patients with retromolar (5/1 patients), in 42.6% of patients with tongue cancer (2/47 patients), in 41.9% of patients with floor of mouth (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 of the tongue, in 5/6 patients (83.3%) with local recurrence, retromolar trigone in 7/14 patients (5%), of the buccal mucosa or the gingivo-buccal complex in 5/8 patients (62.5%), while in floor of mouth, 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 examined pathologically after surgery, as presented in Table (6). Jones et al. [13], in an attempt to identify those patients most at risk for recurrence, retrospectively determined the clinical and histological factors that was associated with recurrence in 49 patients with stage I and II oral cavity cancer. Multiple regression analysis revealed 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 incidence 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=11) and oropharyngeal (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 oropharyngeal cancers. Involved soft tissue margins were highly predictive of local recurrence and decreased survival. Conservative resection of the mandible is safe as long as marginal mandibulectomy 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 inadequately treated. However, despite apparently adequate local resection of oral cancer, recurrence rates of 25-48% have been reported [16]. Recurrent oral cancer tends to appear at the primary site, perhaps because of the persistence of malignant cells within local lymphatics 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 develops even when resection margins are histologically 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].

8 226 Recent molecular genetic studies provide evidence that the majority of, if not all, head and neck squamous cell s (HNSCCs) develop within a contiguous field of preneoplastic cells and genetic alterations associated with the process of carcinogenesis. A subclone in a field gives rise to an invasive. An important implication of this knowledge is that, after surgery of the initial, 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, 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. 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 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. 2, 6: Sankaranarayanan R. Oral cancer in India: An epidemiological and clinical review. Oral Surg Oral Med Oral Pathol. 199, 69: Paul Lam, Kai Ming Au Yeung, Pui Wai Cheng, William Ignace Wei, Anthony Po-Wing Yuen, Nigel Trendell-Smith, Jimmy HC Li, Raymond Li. Correlating MRI and Histologic Tumor Thickness in the Assessment of Oral Cancer, American Journal of Roentgenology, AJR. 24, 182: Shah JP, Patel SG. Head and neck Surgery and Oncology. 3 rd ed. London, New York, Edinburgh, Mosby. 23. Cancer of Oral Cavity Abutting the Mandible 5- Shah JP. Patterns of cervical lymph node metastasis from squamous s of the upper aerodigestive tract. Am J Surg. 199, 16 (4): Spiro RH, Huvos AG, Wong GY, Spiro JD, Gnecco CA, Strong EW. Predictive value of tumor thickness in squamous confined to the tongue and floor of the mouth. Am J Surg. 1986, 152 (4): Jun MY, Strong EW, Saltzman EI, Gerold FP. Head and neck cancer in the elderly. Head Neck Surg. 1983, 5 (5): Friedlander PL, Schantz SP, Shaha AR, Yu G, Shah JP. Squamous cell of the tongue in young patients: A matched-pair analysis. Head Neck. 1998, 2 (5): McGregor AD, MacDonald DG. Routes of entry of squamous cell to the mandible. Head Neck Surg. 1988, 1 (5): Shah JP, Johnson NW, Batsakis JG. Oral Cancer. London: Martin Dunitz. 23, p Marchetta FC, Sako K, Murphy JB. The periosteum of the mandible and intraoral. Am J Surg. 1971, 122 (6): Rapidis AD. Management of the Mandible in Cancer of the Oral Cavity. 27 th. Alexandria Combined ORL Congress, April 8-1, 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 May, 118 (5): 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 of the oral tongue. Clin Cancer Res. 24, 1 (1 Pt 1): 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. 23, 32 (5): Pearlman NW. Treatment outcome in recurrent head and neck cancer. Arch Surg. 1979, 114: 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: evaluation of histopathologic variables. Arch Otolaryngol Head Neck Surg. 1996, 122: 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. 22, 38: Braakhuis BJ, Brakenhoff RH, Leemans CR. Second Field Tumors: A New Opportunity for Cancer Prevention? Oncologist. 25, 1:

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