Revista Română de Anatomie funcţională şi clinică, macro- şi microscopică şi de Antropologie

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1 Revista Română de Anatomie funcţională şi clinică, macro- şi microscopică şi de Antropologie Vol. XIV Nr UPDATES D.T. Iancu 1, Roxana Irina Iancu 2 Gr.T. Popa University of Medicine and Pharmacy, Iasi 1. Oncology and Radiotherapy Department 2. General and Oromaxilofacial Pathology Department ORAL CAVITY CANCERS GENERAL REVIEW (Abstract): Head and neck tumors and their treatments can cause complex anatomical and functional deficits. A thorough initial assessment of tumor and patient factors including function, comorbidity and personal preference is essential to choose the optimal treatment pathway. Radiation to the primary site is the preferred treatment in oropharyngeal cancer because of the difficulty in obtaining adequate surgical margins while maintaining good swallowing and speech. Key words: RADIOTHERAPY, ORAL CANCERS, IMRT INTRODUCTION The oral cavity consists of the lips, oral tongue, and floor of the mouth, retromolar trigone, alveolar ridge, buccal mucosa, and hard palate (Fig 1). Classification of tumors by subsite is useful because patterns of spread and clinical outcomes vary by specific subsite, partly reflecting the variable risk of nodal spread by anatomic site of presentation. Cancer of the oral cavity makes up approximately 30% of head and neck region tumors and 3% of all cancers. The incidence rate of oral cancer is more than twice as high in men as in women (1). For all stages, the estimated 1-year survival rate after diagnosis is 84%, while the 5-year and 10-year survival rates are 61% and 51%, respectively. Worldwide, the incidence of oral cancer parallels the tobacco epidemic. Global estimates suggest 263,900 new cases of oral cancer and 128,000 deaths related to oral cancer in 2008(2). Over the past two decades, oral cancer mortality rates appear to be decreasing in most countries. However, mortality rates in several Eastern European countries, including Romania, continue to increase (3). This unfavorable trend may be associated with the increase of tobacco consumption in women in several countries (4). Anatomy - The anterior boundary of the oral cavity is the skin vermilion junction. The superior portion of the oral cavity extends posteriorly to the junction between the hard and soft palate, while the inferior portion extends to the circumvallate papillae. The specific anatomic subsites of this region are listed in the next figure. The epidemiology of oral cancer strongly reflects exposure to certain environmental agents, particularly tobacco and alcohol. Worldwide, the incidence of oral cancer varies considerably. The International Agency for Research on Cancer notes that the age-standardized incidence rate of oral cavity cancer in There is a strong causal relationship between smoking and cancer of the oral cavity. Smoking is identified as an independent risk factor in 80% to 90% of patients(5). Tobacco users have a fivefold to 25-fold higher risk of oral cavity and oropharyngeal cancer. Cessation of smoking is associated with a decline in the risk of cancer of the oral cavity. The oral cavity is the most common site for head and neck cancer in the US. Carcinoma of the oral cavity commonly afflicts patients in the sixth to seventh decades of life (6). Herpes simplex virus (HSV) and human papilloma virus (HPV) have also been implicated in the etiology of oral cavity cancer. The former has been shown to act as a cocarcinogen with tobacco and ultraviolet light in animal models. The relationship between HPV and oropharyngeal cancer has been well established, 610

2 Fig. 1. A: Oral cavity surface anatomy B: Floor of mouth surface anatomy. (From Putz and Pabst. Sobotta atlas of human anatomy, 14th ed. 2008, Elsevier GmbH, Urban & Fischer, Munich) but the association with oral cavity cancer is less clear. Approximately 50% of patients with oropharyngeal cancer and 0% to 20% with oral cavity cancer are positive for HPV 16 DNA (7). Certain syndromes such as Plummer-Vinson (characterized by iron-deficiency anemia, hypopharyngeal webs, weight loss, and dysphagia) have been associated with oral cavity cancer. However, Plummer-Vinson syndrome is rare and accounts for a small number of cancers of the oral cavity. Disorders such as xeroderma pigmentosum, ataxia telangiectasia, Bloom syndrome, and Fanconi s anemia are a result of defective caretaker genes. An increased incidence of second primary malignancies has been reported in this population because such defects result in genetic instability. For instance, an aggressive form of early adulthood head and neck carcinomas, including oral cancer, is seen in patients with Fanconi s anemia. By contrast, with the exception of Li Fraumeni syndrome, abnormalities in gatekeeper genes, which inhibit cell proliferation and/or promote cell death, do not appear to predispose to oral cancer. However, despite such reports, the genetics of oral cavity cancer have not been well delineated (8). 611

3 D.T. Iancu, Roxana Irina Iancu Fig. 2. Oral cavity; paramedian section depicting regional anatomy. (From Putz and Pabst. Sobotta atlas of human anatomy, 14th ed 2008, Elsevier GmbH, Urban & Fischer, Munich). Premalignant Lesions - Leukoplakia and erythroplakia are gross clinical descriptors that do not always correspond directly to specific pathologic entities. as a white patch or plaque that cannot be rubbed off or characterized clinically or pathologically as any other disease. Homogenous leukoplakia is a uniform white lesion that is prevalent in the buccal mucosa. These lesions represent the most common variety of leukoplakia and have a low malignant potential. Clinically these lesions are nonhomogenous, nodular, speckled, or verrucous, with central ulceration or erosion. Follow-up studies demonstrate that between <1% and 18% of oral leukoplakias develop into oral cancer, with the latter clinical subtype conferring a higher risk of malignant transformation. Erythroplakia describes a chronic, red, generally asymptomatic lesion or patch on the mucosal surface that cannot be attributed to a trau matic, vascular, or inflammatory cause. Erythroplakia, like leukoplakia, is a clinical diagnosis of exclusion that requires the clinician to rule out all other erythematous oral lesions. However, erythroplakia is associated with a higher risk of malignant transformation than leukoplakia (9). The term describes a generalized fibrosis of the oral cavity tissues resulting in marked rigidity and trismus. At early stages these premalignant lesions are characterized by blanching of the mucosa with a marble-like appearance. At more advanced stages, palpable fibrous bands become evident around the buccal mucosa and the mouth opening. Once oral submucous fibrosis reaches advanced stages, approximately 25% of cases biopsied demonstrate epithelial dysplasia in addition to subepithelial alterations. Oral submucous fibrosis is associated with the use of betel quid (with or without tobacco) (10).0 Relative Distribution The most common 612

4 Fig. 3. A: Superficial patches of leukoplakia involving the lateral and ventral surfaces of the oral tongue. B: E xtensive leukoplakia involving the ventral oral tongue, floor of the mouth, and mandibular alveolus. subsite for squamous cell carcinoma of the oral cavity (excluding the lip) is the oral tongue. The floor of the mouth is the second most common subsite where oral cavity carcinomas may arise. Carcinoma of the alveolar ridge accounts for approximately 10% of oral cavity carcinomas. Squamous cell carcinoma of the retromolar trigone and hard palate is rare. Similarly, carcinoma of the buccal mucosa is rare in the United States but is the most common carcinoma of the oral cavity in Southeast Asia because of the widespread use of betel nut (11). Carcinoma from distinct anatomic subsites may exhibit different tendencies for spread based on natural anatomic barriers and location. For instance, the majority of lip cancers are local growths that do not invade deeply into the tissues of the oral cavity or mandible. Squamous cell carcinoma of the floor of the mouth can secondarily involve the ventral tongue, extend along the lingual nerve or submandibular duct, or invade the cortex of the mandible. Tumors in this location can invade deeply, involving the muscles of the floor of the mouth. There is an anatomic gap between the mylohyoid and hyoglossus muscles through which a carcinoma can gain access to submandibular and sublingual areas. Carcinomas of the alveolar ridge and retromolar trigone tend to invade bone early. Tumors of the inferior alveolar ridge may access the mandibular canal and the inferior alveolar nerve, while tumors of the superior alveolar ridge may pass into the maxillary antrum or floor of the nose. Infiltrating lesions of the buccal mucosa can invade the buccinator muscle, extend to the buccal fat pad, and invade the subcutaneous tissue. The hard palate has a relatively dense mucoperiosteum that is relatively resistant to tumor invasion. However, the primary and secondary palates are fused at the incisive fossa, where tumors can gain access into the nasal cavity. The greater palatine foramina can allow tumors to spread posteriorly and enter the pterygopalatine fossa and skull base. The oral cavity has an extensive group of lymphatics that manifest a fairly predictable lymph node drainage pattern based on location (subsite) within the oral cavity. A classical study by Lindberg (12) demonstrated that the superior deep jugular nodes are most frequently involved by cancers of the oral cavity. The oral tongue has an extensive lymphatic drainage. The anterior portion of the tongue drains to the submental nodes (level Ia), and the lateral portion drains to the submandibular (level Ib) and deep jugular nodes (level II). The posterior oral tongue drains into the upper jugulodigastric group of lymph nodes (level II). The lymphatics of the oral tongue also have extensive communication across the midline; thus, carcinomas of the oral tongue can metastasize bilaterally. Studies suggest that some carcinomas of the lateral oral tongue may metastasize to level IV lymph nodes without involving levels I, II, or III. This implies that there may be separate lymphatic channels draining from the oral tongue directly to level IV nodes, allowing for apparent skip metastases (13). The risk of neck metastases depends on several factors including site and size of the primary tumor. Squamous cell cancer of the oral tongue carries the highest risk of nodal metastases. The frequency of neck metastases can 613

5 D.T. Iancu, Roxana Irina Iancu Fig. 4. A. CT of a primary floor of mouth tumour and lymphadenopathy ct4n2m0. B. Same person (65 years old man) with pelvic floor tumor at primary presentation range from 15% to 75%, depending on the size of the primary lesion. Contralateral metastases are more common in tumors that approach or cross the midline. The majority of oral cavity cancers presents as localized disease and remain localized until late in the course of their development. Distant metastasis occurs in approximately 15% to 20% of patients who eventually die of their disease. The risk of distant metastasis increases with the degree of lymph node involvement (14). The predominant histopathologic type of cancer in the oral cavity is squamous cell carcinoma. There are several variants of squamous cell carcinoma, including basaloid and verrucous carcinoma. Basaloid squamous cell carcinoma is believed to have a worse prognosis than traditional squamous cell carcinoma. Verrucous carcinoma is a less common variant of squamous cell carcinoma. Sarcomatoid carcinomas can be found in the oral cavity and larynx. (15). Less than 10% of neoplasms of the oral cavity have nonsquamous histology. Adenoid cystic carcinoma accounts for approximately 30% to 40% of minor salivary gland cancers of the oral cavity. Other histological types that can occur in the oral cavity include adenocarcinomas, melanoma, ameloblastoma, lymphoma, and Kaposi s sarcoma. Approximately 50% of acquired immunodeficiency syndrome related cases of Kaposi s sarcoma have oral cavity involvement. Most lymphomas in the head and neck arise in Waldeyer s ring (tonsil, base of tongue, and nasopharynx). Fortunately, melanoma of the oral cavity is very rare and represents only 0.2% to 8% of all melanomas (16). The oral cavity is an anatomic region that is readily accessible to visual inspection and palpation. Despite this fact, many patients with oral cavity tumors present with advanced-stage disease as initial symptoms may be vague and painless. Cervical metastases occur early in the natural history of the disease, with 30% to 40% of patients harboring cervical lymph node metastases at diagnosis. Patients with oral cavity cancer should undergo a comprehensive history and physical examination. Detailed examination is particularly important for oral cavity tumors in that much can be learned about cancers that afford opportunity for direct visual inspection and digital palpation. A biopsy of lesions in question should be obtained as well as a thorough dental assessment. A patient s comorbid illnesses must also be taken into account in the treatment plan. Computed tomography (CT) scans, panoramic radiographs, magnetic resonance imaging (MRI), and other imaging studies may also be important for accurate staging of the tumor and in treatment planning. Imaging can complement the physical examination in determining the extent of disease. CT is the modality most commonly used to determine the extent of soft-tissue and bony involvement and occult disease in the neck. CT may be used to determine the extent of invasion into the deep musculature of the tongue and adjacent structures. Moreover, CT is a valuable modality for visualizing invasion of the mandible, palate, and pterygopalatine fossa. 614

6 MRI may be used in case of contrast allergy or a lesion that is not well visualized on CT. For instance, MRI may be used if a patient has significant dental artifact that obscures visualization of the primary tumor on CT. MRI provides excellent definition of tumor involving the tongue and is a good modality for evaluating the possibility of perineural spread. Ultrasound may be used to screen for enlarged lymph nodes that are not clinically detectable. In experienced hands, the accuracy of ultrasound when combined with fine needle aspiration may be superior to CT or MRI for staging the neck (17). Positron emission tomography (PET) and PET/CT have been used increasingly in head and neck cancer evaluation for staging disease in the neck, evaluation of perineural and skull base involvement, identification of distant metastases, and detection of recurrence. Despite the improved overall accuracy, clinical application of PET/CT is limited by the suboptimal detection of small metastases. Therefore, the decision to pursue a neck dissection should not be based solely on PET/CT findings (18). The choice of treatment modality, either singly or in combination, depends on the stage and size of the tumor and relevant patient factors such as toxicity, performance status, comorbid disease, and convenience. A multidisciplinary approach is paramount in the management of oral cancer patients. It is important and valuable for patients to undergo evaluation by relevant members of the multidisciplinary team, including head and neck surgery, radiation and medical oncology, nursing, dentistry, dietary, speech pathology, and social work, before treatment is delivered. Surgery is most commonly the treatment of choice. Surgical resection is expeditious, effective, and often associated with modest morbidity and good functional outcome particularly for patients with small to moderate-size lesions. Radiation therapy can be considered for patients with early-stage disease who either are not surgical candidates or refuse surgical management. For patients with advanced lesions of the oral cavity, a combined-modality approach is generally recommended. In patients with highrisk pathologic features, the addition of concurrent chemotherapy during the postoperative radiation treatment course may further augment tumor control rates provided the chemotherapy can be tolerated. High-risk features commonly include extracapsular tumor spread and positive resection margins (19). Surgical approaches to cancers of the oral cavity may either be transoral, transcervical (pull-through), or, alternatively, via mandibulectomy, which is sometimes necessary to obtain the exposure required to achieve adequate margins. In cases where the mental or alveolar nerve is involved with tumor, the nerve should be proximally resected and analyzed microscopically. A tracheotomy is often necessary to maintain a patent airway because of the large amount of oral edema resulting from extensive resection and placement of myocutaneous flaps in the oral cavity. Lymphadenectomy in the presence of known neck disease can be therapeutic as well as provide prognostic information (i.e., presence of extracapsular extension). Generally, in patients with nodal disease 6 cm (N3), extracapsular extension, or clinically evident disease in levels IV or V, the most common approach is a modified radical nodal dissection (MRND). Evidence-based practice guidelines in oncology published by the National Comprehensive Cancer Network (NCCN) recommend singlemodality treatment (i.e., surgery or radiation) for early staget1 or T2 lesions; however, a primary surgical approach is generally preferred. For more advanced lesions, NCCN guidelines recommend a combined-modality approach involving surgery followed by adjuvant radiation or chemoradiation. The outcomes for advanced lesions of the oral cavity (T3 and T4) are less than satisfactory with either surgery or radiation alone. In most advanced-stage cancers singlemodality therapy is inferior to combined-modality therapy. Adjuvant radiation therapy can be delivered preoperatively or postoperatively. Although surgery is the preferred initial treatment approach for the majority of patients with tumors of the oral cavity, adjuvant radiation is commonly recommended to enhance the likelihood of locoregional tumor control (20). Carcinoma of the oral cavity has traditionally been treated with opposed lateral fields, using either two-dimensional or threedimensional (CT-based) techniques. In recent years, there has been increasing use of intensitymod- 615

7 D.T. Iancu, Roxana Irina Iancu Fig. 5. IMRT solution for a pelvic floor cancer ct4n2m0 for a 65 years old person Fig. 6. RapidArc solution for an oral cancer ct4n3m0 for a 73 years old person ulated radiation therapy (IMRT) for the treatment of head and neck region tumors. With respect to oral cavity cancer, IMRT offers the opportunity to diminish normal-tissue toxicities, including damage to major salivary glands (xerostomia) and to the mandible (osteoradionecrosis). Dosimetric analysis of radiation dose to the parotid glands with evaluation of resultant salivary function suggests that limiting mean parotid dose to <25 to 30Gy is associated with improved postradiation salivary function. In light of the steep dose gradients that often accompany IMRT plans, successful delivery is dependent on accurate and reproducible localization and immobilization. The use of IMRT results in a more conformal dose distribution compared to conventional techniques. However, IMRT may be more sensitive to intertreatment setup variations than conventional radiation therapy. Daily imaging and strict immobilization protocols may decrease setup error and improve the fidelity of treatment delivery (21). More recently, there has been some inte rest in0 arc-based or rotational therapies in an attempt to overcome some of the limitations associated with fixed field IMRT. The basic concept of arc therapy is the delivery of radiation from a continuous rotation of the radiation source and allows the patient to be treated from a full 360 beam angle. Arc therapies have the ability to achieve highly conformal dose distributions and are essentially an alternative form of IMRT. However, a major advantage over fixed gantry IMRT is the improvement in treatment delivery efficiency as a result of the reduction in treatment delivery time and the reduction in MU us age with subsequent reduction of integral radiation dose to the rest of the body. In addition to the subsequent advantages from the shorter treatment delivery time,0 a further 616

8 potential benefit is the availability of extra time within a set treatment appointment time slot to employ image-guided radiotherapy (IGRT). The application of chemotherapy to the treatment of head and neck cancer dates back to the 1960s. Over the decades the role of chemotherapy has advanced from initial use only in the recurrent or metastatic setting to active current use in the definitive treatment setting. The advantage of concurrent chemotherapy with radiation has been further examined in the context of several meta-analyses. Prior to the initiation of head and neck radiation, a careful oral and dental evaluation, including a panoramic radiograph, should be performed. Dentition in poor condition should be identified and considered for extraction to minimize the subsequent risk of osteoradionecrosis. Specifically, those teeth that will reside within the high-dose radiation volume that demonstrate significant periodontal disease, advanced caries, or abscess formation or are otherwise in a state of disrepair should be extracted. In addition, impacted teeth, unopposed teeth, and teeth that could potentially oppose a segment of a resected jawbone should be considered for extraction if they are anticipated to reside within the high-dose radiation treatment volume. Extraction of marginal teeth should also be considered in patients who are deemed unable to maintain adequate oral hygiene (21). Radiation can induce several chronic effects in the oral cavity that warrant routine surveillance. Radiation can impair bone healing and diminish the capacity for successful recovery following trauma or oral surgery. For this reason, elective oral surgical procedures including extractions must be very carefully considered after radiation. Escalation of dental caries deriving from xerostomia following radiation is well recognized. Radiation of the major salivary glands changes the nature of salivary secretions, which can increase the accumulation of plaque and debris, reduce salivary ph, and reduce the buffering ability of saliva. This creates an environment in the oral cavity, which predisposes patients to caries. During a course of radiation to the oral cavity, simple techniques such as the use of custom molds to absorb electron backscatter can diminish hot-spot mucositis from dental fillings and improve treatment tolerance. Attention to oral hygiene with frequent dental follow-up examinations and cleanings, daily fluoride therapy, flossing, and brushing should be an integral component of the education and postradiation care of patients who undergo radiation to the oral cavity. REFERENCES 1. Greenlee RT, et al. Cancer statistics, CA Cancer J Clin 2000;50(1): Jemal A, et al. Cancer statistics, CA Cancer J Clin 2010;60(5): American Cancer Society. Cancer facts and figures Atlanta: American Cancer Society Patel SC, et al. Increasing incidence of oral tongue squamous cell carcinoma in young white women, age 18 to 44 years. J Clin Oncol 2011; 29(11): Garavello W, et al. The oral cancer epidemic in central and eastern Europe. Int J Cancer 2010;127(1): Lambert R, et al. Epidemiology of cancer from the oral cavity and oropharynx. Eur J Gastroenterol Hepatol 2011; 23(8): Fakhry C, Gillison ML. Clinical implications of human papillomavirus in head and neck cancers. J Clin Oncol 2006; 24 (17): Hobbs CG, et al. Human papillomavirus and head and neck cancer: a systematic review and metaanalysis. Clin Otolaryngol 2006;31(4): Salem A. Dismissing links between HPV and aggressive tongue cancer in young patients. Ann Oncol 2010; 21(1): Prime SS, et al. A review of inherited cancer syndromes and their relevance to oral squamous cell carcinoma. Oral Oncol 2001; 37(1): Chen AY, Myers JN. Cancer of the oral cavity. Dis Mon 2001; 47(7): Lindberg R. Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts. Cancer 1972; 29(6): Byers RM, et al. Frequency and therapeutic implications of skip metastases in the neck from squamous carcinoma of the oral tongue. Head Neck 1997; 19(1):

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