Anatomy

The lips are composed of the orbicularis oris muscle, which surrounds the mouth and is covered externally by skin and internally by mucous membrane. The upper and lower lips are attached to the gingiva by raised folds of mucous membrane called the labial frenula. The vascular supply is from the superior and inferior labial branches of the facial arteries. The sensory nerve of the upper lip is the infraorbital nerve; the mental nerve provides sensory innervation for the lower lip.

Lymph vessels from both lips drain into the submandibular lymph nodes. In addition, lymph from the central part of the lower lip drains into the submental lymph nodes. The submental nodes drain either to the submandibular lymph nodes or to the jugulo-omohyoid node. The submandibular lymph nodes drain to the deep cervical chain of lymph nodes.²⁵

Pathology and Patterns of Spread

The most common neoplasms are moderately to well differentiated squamous cell carcinomas; approximately 5% are poorly differentiated.²⁶ Basal cell carcinomas usually arise on the skin above or below the lip and invade the vermilion border, but rarely arise from the vermilion border. Squamous cell carcinomas start on the vermilion of the lower lip, and less commonly on the upper lip. The commissure is rarely the site of origin. Leukoplakia is a common problem on the lower lip and may precede carcinoma by many years.¹⁶

Early lesions can initially invade adjacent skin and the orbicularis oris muscle. Advanced lesions can invade the adjacent commissures of the lip and buccal mucosa, the skin and wet mucosa of the lip, the adjacent mandible, and eventually the mental nerve. The incidence of perineural invasion is approximately 2%.²⁷ Lymph node involvement at presentation occurs in approximately 5% to 10% of patients. An additional 5% to 10% of patients with a clinically negative neck subsequently develop lymph node metastases. The risk of lymph node involvement increases with depth of invasion, poor differentiation, larger lesions, invasion of the commissure, and recurrence after prior treatment.¹⁹

Hendricks and colleagues²⁸ from the Mayo Clinic reported the following incidence of positive cervical lymph nodes by T stage: T1, 2%; T2, 9%; and T3, 30%. The overall incidence of adenopathy was 19% when the commissure was involved.²⁶ De Visscher and associates²⁹ reported a nodal recurrence rate of 5.4% after primary surgical resection in 184 patients with squamous cell carcinoma of the lower lip. Ninety-three percent of lesions were stage I at presentation.

Clinical Manifestations and Staging

Carcinoma of the lip usually presents as a slowly enlarging exophytic lesion with an elevated border. Occasionally, there is minor bleeding. Erythema of the adjacent skin may suggest dermal lymphatic invasion. Anesthesia or paresthesia of the skin indicates perineural invasion.³⁰

The American Joint Committee on Cancer (AJCC) staging for lip cancer applies to lesions arising from the vermilion surface³¹ (Table 30-2).

TABLE 30-2 American Joint Committee on Cancer: Oral Cavity Primary Tumor Staging

Reprinted from American Joint Committee on Cancer: Lip and oral cavity. In Edge SB, Byrd D, Compton CC, et al, editors: AJCC Cancer Staging Handbook, ed 7. Chicago, 2010, Springer, pp 49-61.

Early lip cancers rarely require diagnostic imaging. Locally advanced, deeply infiltrating, or recurrent carcinomas may benefit from a computed tomography (CT) scan or panoramic x-ray film to evaluate possible bony invasion and regional nodal spread.

Treatment

Early Lesions (<2 cm)

The majority of these lesions can be surgically excised with primary closure as an outpatient procedure. Surgery is satisfactory if the lip commissure does not need to be resected and if the resulting aperture of the oral cavity permits the insertion of dentures. Postoperative irradiation is recommended for positive margins or perineural invasion.27,32,33

Tumors that should be treated with radiotherapy include those involving a commissure in order to obtain better cosmesis and improved local control.³⁴ The uncommon, poorly differentiated lesions are also preferably treated by irradiation to cover a more generous treatment volume and the first-echelon lymph nodes. An algorithm for treatment planning is shown in Figure 30-1.

Figure 30-1 Treatment algorithm for de novo lip cancer. *Treat neck (neck dissection or radiotherapy); †treat neck if lesion is poorly differentiated or if dermal or commissure involvement is present.26,28

Results

Irradiation Techniques

EBRT is usually delivered with either orthovoltage x-rays or electron beam. The electron beam energy depends on the tumor thickness. Lead shields are placed behind the lip to limit the dose to the oral cavity and mandible. Orthovoltage fractionation schedules range from 40 to 45 Gy in 3 to 4 weeks for smaller lesions, and 50 to 55 Gy in 4 to 6 weeks for moderately advanced lesions. The dose is increased 10% to 15% for electron beam RT to account for differences in the relative biological effectiveness. Orthovoltage x-rays are preferred, if available, because the maximum dose is at the surface and there is less beam constriction compared with electron beam.

An appositional field with a margin of 1 to 1.5 cm is sufficient for most small to moderately advanced lesions if orthovoltage irradiation is used. The field borders are determined by bimanual palpation. Because of beam constriction, 2- to 2.5-cm margins are necessary if an electron beam is employed. A lead shield is used to collimate the beam at the skin/lip surface.

Brachytherapy may be used as the sole treatment or in conjunction with EBRT. Implantation is usually performed under local anesthesia using ¹⁹²Ir sources and a single-plane plastic tube technique. The sources are arranged horizontally 10 to 12 mm apart with crossing sources on the lateral aspects of the implant. Three to five horizontal sources are used depending on the size of the lesion. The advantage of the plastic tube technique is that the volume of the implant is more easily adapted to the extent of the tumor and the commissure is readily included, if necessary. Alternatively, cesium needles mounted in a nylon bar may be employed (Fig. 30-2). The sources are spaced 1 cm apart and the dose is specified 0.5 cm from the plane of the implant. A gauze roll is placed between the lip and gum to increase the distance between the radioactive sources and the alveolar ridge. The recommended dose is 60 to 70 Gy at a dose rate of 0.4 to 0.5 Gy per hour for an implant alone. Large infiltrative lesions may be first treated with EBRT, 30 Gy at 2.5 Gy per fraction to shrink the tumor, followed by an interstitial brachytherapy boost to deliver an additional 35 to 40 Gy. Treatment of lip cancer with high-dose-rate interstitial needles is advocated by some.⁴⁴

Figure 30-2 A 65-year-old man had a T2N0 squamous cell carcinoma of the left lower lip and a T1N0 lesion on the right. A, The left-sided lesion measured 2.5 × 2 × 1.5 cm. Radiation therapy was elected because of the functional deficit likely to result from excision of the larger lesion. He received 30 Gy over 2 weeks, 3 Gy per fraction, 250 kV (0.5 mm³). B, A single-plane cesium needle implant with double crossing needles. A gauze pack was sewn into the gingivolabial gutter to displace the radium from the mandible and upper lip. The implant added 35 Gy at 0.5 cm. C, At 2 years and 5 months, there was no evidence of disease and the lip had completely healed.

T3 and T4 Tumors

Low-volume T3 cancers may be treated with primary irradiation, preferably combining EBRT to the primary lesion and neck followed by a brachytherapy boost. EBRT is administered with parallel opposed fields, including the lip lesion and the level I and II lymph nodes⁵⁵ (Fig. 30-3). A cork is placed in the mouth to displace the maxilla and upper lip and reduce the volume of normal tissue included in the fields. A separate anterior field is used to treat the level III and IV lymph nodes with a tapered midline block over the larynx. The supraclavicular lymph nodes are at low risk and are not included in the fields. Both sides of the neck are treated with irradiation because it is unlikely that T3 and T4 primary lesions would be well lateralized.

Figure 30-3 Parallel opposed fields are used to treat a carcinoma of the lower lip in conjunction with the level I and level II lymph nodes.

From Mendenhall WM: Radiotherapy for cancer of the lip. Treatment technique. In Werning JW, editor: Oral cancer, New York, 2005, Thieme.

The junction between the parallel opposed fields and the low-neck field is at the thyroid notch. The dose fractionation schedule used varies from 38.4 Gy at 1.6 Gy twice daily to 50 Gy at 2 Gy per fraction once daily, followed by a brachytherapy boost. Low-energy photons such as 4-MV or 6-MV beams are recommended.

High-volume T3 and T4 cancers are unlikely to be cured with RT alone and are better treated with surgery and postoperative irradiation. EBRT fields are similar to those used to treat patients with irradiation alone. A petroleum jelly gauze bolus is placed over incisions to ensure that the surface dose is adequate. The fields are extended to the skull base along the course of the third division of the fifth cranial nerve if perineural invasion is present. The dose depends on the surgical margins: negative (R0), 60 Gy; microscopically positive (R1), 66 Gy; and gross residual disease (R2), 70 Gy. Patients are treated once daily at 2 Gy per fraction, 5 days a week, in a continuous course.

Anatomy

The floor of the mouth is a semilunar space overlying the mylohyoid and hyoglossus muscles, extending from the inner surfaces of the mandibular alveolar ridge to the ventral surface of the oral tongue. Its posterior boundary is the base of the anterior tonsillar pillar; it is bisected anteriorly by the frenulum of the tongue. The mylohyoid muscle arises from the mylohyoid ridge of the mandible and is the muscular floor of the oral cavity. The posterior insertion is at the level of the third molars.

The submandibular glands lie along the body of the mandible. The inferior aspect of the gland extends below the inferior edge of the mandibular arch; part of the gland is superficial to the mylohyoid muscle. The submandibular gland is palpable as a soft mass over the posterior portion of the mylohyoid muscle when the muscle is tensed by forcing the tip of the tongue against the maxillary incisor teeth.

The submandibular duct (Wharton’s duct) is approximately 5 cm long and arises from the portion of the gland that lies between the mylohyoid and hyoglossus muscles. The duct passes deep and then superficial to the lingual nerve and exits in the anterior floor of the mouth near the midline.

The sublingual glands are the smallest of the major salivary glands and are the most deeply situated. Each lies in the floor of the mouth between the mandible and the genioglossus muscle.

The first-echelon nodes for the floor of mouth are the submandibular lymph nodes (level IB), which may be stratified into preglandular, intraglandular, and postglandular groups. Lymph may also drain into the submental (level IA) nodes. These lymph nodes eventually drain to the jugulo-omohyoid (level II) nodes.²⁵

The lingual nerve is a branch of the mandibular nerve and provides the sensory innervation to the floor of the mouth. It enters the mouth between the medial pterygoid muscle and the ramus of the mandible and passes anteriorly under the oral mucosa medial to the third mandibular molar.

The hypoglossal nerve (cranial nerve XII) is the motor nerve of the tongue. It passes anterior to the inferior aspect of the hyoglossus muscle and then to the lateral aspect of the genioglossus muscle. Injury to the hypoglossal nerve results in paralysis and atrophy of the ipsilateral oral tongue. The tongue deviates to the paralyzed side upon protrusion because of the unopposed contralateral genioglossus muscle.

Pathology and Patterns of Spread

Most floor of mouth neoplasms are squamous cell carcinomas; most are moderately differentiated. Adenoid cystic and mucoepidermoid carcinomas arise from the minor salivary glands and account for 2% to 3% of floor of mouth malignant tumors.

Most floor of mouth carcinomas are located in the anterior midline adjacent to Wharton’s ducts. Extension toward the gingiva and periosteum occurs early and frequently.

Small to moderate-size (stage T1 and T2) lesions are associated with metastases to the ipsilateral regional lymph nodes in 15% to 38% of cases, depending on the size and depth of invasion of the primary tumor.57,58,59

Mohit-Tabatabai and colleagues⁶⁰ reviewed 84 patients with squamous cell carcinoma of the floor of the mouth and concluded that lesion thickness was related to the probability of subclinical cervical metastases in clinically node negative (N0) patients (Table 30-5). Patients with a primary lesion more than 1.5 mm thick had a 20% or higher risk of lymph node metastases.⁶⁰ Histologic grade and configuration of the primary lesion did not have a statistically significant correlation with subsequent development of neck node metastases. O’Brien and associates⁵⁸ analyzed the impact of tumor thickness on the incidence of regional lymph node metastases and found that the risk increased significantly for lesions of 4 mm or more in thickness. The reported incidence of recurrence in the untreated clinically negative neck varies from 20% to 35%.^59,61 Histologic grade and extent of vascular and perineural invasion have been implicated as predictors of lymph node spread.⁶²

TABLE 30-5 Floor of Mouth Carcinomas: Correlation of Primary Tumor Thickness with Neck Failure*

* Number of treatment failures/total number of patients.

Reprinted from Mohit-Tabatabai MA, Sobel HJ, Rush BF, Mashberg A: Relation of thickness of floor of mouth stage I and II cancers to regional metastasis, Am J Surg 152:351-353, 1986.

Figure 30-4 shows the distribution of clinically positive neck nodes at diagnosis,⁶³ and Figure 30-5 depicts the distribution of pathologically positive nodes after elective neck dissection in 62 patients with carcinoma of the floor of the mouth.⁶⁴ The incidence of positive lymph nodes was 19% for those with T1 or T2 lesions and 26% for patients with T3 or T4 cancers.

Figure 30-4 Carcinoma of the floor of the mouth. Nodal distribution on admission, M.D. Anderson Hospital, 1948 to 1965.

From Lindberg RD: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts, Cancer 29:1448, 1972.

Figure 30-5 The distribution of involved neck nodes in the N0 neck when elective dissection was done in 62 patients with carcinoma of the floor of the mouth.

From Byers RM, Wolf PF, Ballantyne AJ: Rationale for elective modified neck dissection, Head Neck Surg 10:162, 1988.

Clinical Manifestations, Patient Evaluation, and Staging

Floor of mouth carcinomas usually present as slightly elevated mucosal lesions with well-defined borders. A background of leukoplakia may be present. The lesions are often diagnosed by a dentist or physician during a routine physical examination.

T1 and T2 tumors may be noted initially when the patient feels a lump in the floor of the mouth with the tip of the tongue. Advanced lesions tend to produce pain, bleeding, foul breath, loose teeth, and change in speech as the result of fixation of the tongue.

Bimanual palpation is necessary to accurately determine the extent of induration and degree of fixation to the periosteum. Extensive lesions may exhibit invasion into the soft tissues of the neck or skin.

The AJCC staging system⁶⁵ (see Table 30-2) is based on tumor size and invasion of adjacent structures such as bone or soft tissue of the neck. Radiographic studies may facilitate staging with reference to (1) the status of the mandible and teeth, (2) the deep extent of the tumor, and (3) the evaluation of the regional lymph nodes. CT scans should be obtained in essentially all patients. The mandible may be evaluated by panoramic x-ray films, dental films, and CT scanning. Magnetic resonance imaging (MRI) is useful to evaluate marrow space invasion and perineural involvement.⁶⁶

The role of PET scanning as part of the initial staging workup for oral cavity cancers has not gained widespread acceptance. It may, however, be useful in early detection of recurrences and in prediction of which patients may benefit from elective neck dissection after chemoradiation.^67–69

Treatment

Early Lesions (T1 and Superficial T2)

Surgery and radiation therapy produce equal cure rates for T1 and superficial T2 lesions. The risk of irradiation-induced bone and soft tissue necrosis is significant. Therefore, surgery is usually the treatment of choice. The neck is also treated with an elective neck dissection,⁷⁰ although some advocate observation of the neck in select patients with clinically negative nodes (cN0).⁷¹ A treatment algorithm is shown in Figure 30-6.

Figure 30-6 Treatment algorithm for de novo floor of mouth cancer. *Treat neck with neck dissection or radiotherapy in any patient with a primary lesion that is more than 1.5 mm thick.⁶⁰ † Concomitant chemotherapy may be used.¹⁵⁴

Sentinel lymph node biopsy is being investigated for possible use in oral cavity cancers.^72,73 However, a recent study showed that this procedure was less sensitive for floor of mouth cancers (80%) compared with other oral sites (100%).⁷⁴

Some patients present after excisional biopsy of the primary tumor. If the margins are either close or involved and there is no evidence of visible or palpable residual tumor, an interstitial implant alone to the primary site is a good alternative provided that the depth of invasion is less than 1.5 mm. Re-excision may not be feasible, because the surgeon does not know exactly what to remove. An additional advantage of RT is the ability to treat a larger area. Six patients were treated in this manner at M.D. Anderson Hospital⁷⁵ and seven patients at the University of Florida.⁷⁶ All had disease locally controlled, and none of the patients developed regional lymph node metastases. Conversely, Sessions and colleagues⁷¹ have recommended re-excision rather than irradiation if close or positive margins are found on permanent sections.

Results

Outcomes after radiation therapy alone vary with the stage of disease and treatment technique. The irradiation schedules used at the University of Florida are shown in Table 30-6.⁸² EBRT alone results in lower local control rates compared with brachytherapy alone or combined with EBRT.⁸³ Table 30-7 provides the M.D. Anderson Hospital experience with RT alone.⁸⁴ The failure rates range from 2% for T1 lesions to 23% and 79% for T3 and T4 lesions, respectively. For T2 and T3 lesions, brachytherapy with or without EBRT appears to result in better local control rates than EBRT alone.

Sessions and colleagues⁷¹ reported on 280 patients who were treated with surgery alone, RT alone, or combined surgery and RT. Tumor extent was T1, 106 patients; T2, 107 patients; T3, 40 patients; and T4, 27 patients. The local recurrence rate was 41%. The 5-year CSS by treatment modality are shown in Table 30-8.

One hundred sixty patients with T1 (79 patients) and T2 (81 patients) floor of mouth cancers were treated at the Institut Gustave-Roussy with low-dose-rate ¹⁹²Ir brachytherapy.⁸⁵ One hundred twenty-seven patients had a clinically negative neck and 33 patients (21%) had N1 neck disease. Patients with T2 and/or N1 lesions underwent a neck dissection. With a minimum follow-up of 9 years, local control rates were 93% for T1 cancers and 88% for T2 tumors.

Pernot and associates⁸⁶ reported on 207 patients with floor of mouth carcinomas treated with EBRT and ¹⁹²Ir brachytherapy (105 patients) or brachytherapy alone (102 patients). Tumor stages were 41%, Tl; 48%, T2; 8%, T3; 2%, T4; and 1%, TX. Neck stages were 83%, N0; 12%, Nl; 3%, N2; and 2%, N3. The 5-year local control rates were 97%, 72%, and 51% for Tl, T2, and T3 tumors, respectively. The 5-year CSS were T1, 88%; T2, 47%; and T3, 36%.

Rodgers and associates⁸⁷ reviewed 194 patients treated at the University of Florida. Patients with advanced lesions (T3 or T4) had lower control rates when treated with RT or surgery alone compared with those treated with combined surgery and RT (Table 30-9). The 5-year CSS were stage I, 96%; stage II, 70%; stage III, 67%; and stage IVA, 44%.

Irradiation Techniques

Because of the proximity of the gingival ridge, which is vulnerable to high-dose irradiation-induced soft tissue injury or osteoradionecrosis, the floor of the mouth has a lower radiation therapy tolerance than other portions of the oral cavity. Therefore preirradiation and postirradiation oral care is critical.

T1 and T2 Cancers

Patients with superficial (≤4 mm thick), well-differentiated squamous cell carcinomas of the floor of the mouth may be treated either with brachytherapy alone or, when accessible, with intraoral cone irradiation. Brachytherapy is not feasible if the tumor abuts or extends onto the mandibular alveolar ridge because of the risk of bone exposure. Brachytherapy may be performed with either rigid cesium needles mounted in a customized template or with iridium using the plastic tube technique. The rigid needles are preferable because although the needles are active, the implant can be accomplished rapidly because the needles are mounted in a rigid template^88,89 (Figs. 30-7 and 30-8). An additional advantage of this technique is that the geometry of the implant is optimal and dosimetry can be obtained before the implant. The vertical needles are spaced approximately 1 cm apart with a crosser to ensure an adequate surface dose. The implant is anchored in place by a suture placed through the submentum into the floor of the mouth.

Figure 30-7 Custom-made implant device for T1 to T2 cancers of the floor of the mouth. Note the single crossing needle through the center of the device (arrowheads). The device is now machined from nylon. Cesium needles have replaced the radium needles.

Adapted from Marcus RB Jr, Million RR, Mitchell TA: A preloaded, custom-designed implantation device for stage T1 to T2 carcinoma of the floor of the mouth, Int J Radiat Oncol Biol Phys 6:111-113, 1980; Figure 2, p 112.

Figure 30-8 Squamous cell carcinoma of the floor of the mouth (T2N0) (arrows). A, The lesion measured 2.5 × 2.5 cm, including the induration, and was tethered to the periosteum in the midline. The treatment plan was 50 Gy over 5 weeks with parallel opposed portals that included the submaxillary and subdigastric lymph nodes. The midjugular lymph nodes were treated with an anterior portal. An implant was planned to add 15 Gy. B, Cardboard template used for design of radium needle holder. C, Implant in position. Device was secured with two sutures from the submental skin. There were five 2-cm active length, full-intensity needles without crossers. D, Sagittal isodose distribution. The 0.5-Gy-per-hour isodose line was selected for specification of dose, and the implant remained in place for 30 hours. Stippled area represents the implant device. E, Midplane isodose distribution. The 0.5-Gy-per-hour isodose line is approximately 1 mm outside the needles. The highest dose rate to the anterior lingual gingiva would be about 0.3 to 0.35 per hour or at least 4.5 Gy lower than the minimum tumor dose. F, Patient was free of disease at 4 years and 8 months with no complications.

From Million RR, Cassisi NJ, Mancuso AA: Oral cavity. In Million RR, Cassisi NJ, editors: Management of head and neck cancer: a multidisciplinary approach, ed 2. Philadelphia, 1994, Lippincott, pp 321-400; Figure 16-25, pp 352-353.

Intraoral cone irradiation is administered with either orthovoltage x rays or electrons. Orthovoltage x rays are preferred because there is less beam constriction and the surface dose is higher. Before each treatment, it is necessary for the radiation oncologist to verify the position of the tumor relative to the intraoral cone. Because a small volume of tissue is included in the intraoral cone field, the dose per fraction may be increased to 2.5 to 3 Gy once daily.

Cancers thicker than 4 mm and those that are poorly differentiated have an increased risk of subclinical disease in the regional nodes. The first-echelon nodes for the floor of the mouth are the level I and II nodes. EBRT is delivered with either 4-MV or 6-MV x-rays using parallel opposed fields that encompass the primary tumor as well as the first-echelon nodes. An intraoral stent is placed in the mouth to displace the maxilla and upper lip out of the fields⁵⁵ (Fig. 30-9). The EBRT fields are treated to 46 Gy in 23 fractions once daily or 38.4 Gy at 1.6 Gy per fraction twice daily. Brachytherapy follows the EBRT if that is the technique selected to boost the tumor. If intraoral cone radiation therapy is selected to boost the tumor, it precedes the EBRT so the extent of the tumor can be optimally defined and because it may be difficult to place the cone after EBRT because of patient discomfort. The total dose ranges from 65 to 70 Gy.

Figure 30-9 A, Portal for treatment of carcinoma of the floor of the mouth with tongue invasion; the tongue is depressed into the floor of the mouth with a tongue blade and cork. B, Portal for irradiation of limited anterior floor of mouth carcinoma without tongue invasion. Two notches are cut on a cork so it can be held in the same position between the patient’s upper and lower incisors during every treatment session; the tip of the tongue is displaced from the treatment field. The anterior border of the field covers the full thickness of the mandibular arch. The lower field edge is at the thyroid cartilage, ensuring adequate coverage of the submandibular lymph nodes. The superior border is shaped so that much of the oral cavity, oropharynx, and parotid glands are out of the portal. The minimum tumor dose is specified at the primary site (i.e., not along the central axis of the portal) with the aid of computer dosimetry.

From Parsons JT, Mendenhall WM, Moore GJ, Million RR: Radiotherapy of tumors of the oral cavity. In Thawley SE, Panje WR, Batsakis JG, Lindberg RD, editors: Comprehensive management of head and neck tumors, ed 2. Philadelphia, 1999, Saunders, pp 695-719; Figures 35-8 and 35-9, p 704.

The low neck is irradiated with an anterior field, using 4-MV or 6-MV x-rays to 50 Gy in 25 fractions or 40.5 Gy in 15 fractions. The latter schedule is preferred if treatment to the upper neck will be completed in less than 25 fractions. A tapered midline block is used to shield the larynx. The junction between the parallel opposed fields and the low neck field is at the thyroid notch⁹⁰ (Fig. 30-10).

Figure 30-10 A, Portal used to irradiate the ipsilateral neck. In patients with N0 disease, the nodes in the lateral supraclavicular fossa are at very low risk and are not irradiated electively. B, Fields for bilateral lower neck radiation therapy of the N0 neck. The larynx shield should be carefully designed. Because the internal jugular vein lymph nodes lie adjacent to the posterolateral margin of the thyroid cartilage, the shield cannot cover the entire cartilage without producing a low-dose area in these nodes. A common error in the treatment of the lower neck is to extend the low neck portal laterally out to the shoulders, encompassing lateral supraclavicular lymph nodes that are at negligible risk while partially shielding the high-risk midjugular lymph nodes with a large rectangular laryngeal block. The inferior extent of the shield is at the cricoid cartilage or first or second tracheal ring; the shield must be tapered because the nodes tend to lie closer to the midline as the lower neck is approached.

From Parsons JT, Mendenhall WM, Million RR: Radiotherapy of tumors of the oropharynx. In Thawley SE, Panje WR, Batsakis JG, Lindberg RD: Comprehensive management of head and neck tumors, ed 2. Philadelphia, 1999, Saunders, pp 861-875; Part A is Figure 42-2B, p 867; Part B is Figure 42-7A, p 872.

Anatomy

The tongue is located in the floor of the mouth, and, at rest, it fills most of the oral cavity. It is involved with mastication, taste, and oral cleansing, but its main functions are propelling food into the pharynx when swallowing and forming words when speaking.

The sulcus terminalis divides the tongue into the oral and pharyngeal portions; the oral portion consists of the anterior two thirds of the tongue. The tongue is attached to the floor of the mouth by the frenulum. The circumvallate papillae are the largest taste buds; they are 1 to 2 mm in diameter and lie anterior to the sulcus terminalis.

The oral tongue consists of four muscles: the genioglossus, hyoglossus, styloglossus, and palatoglossus muscles. They all originate outside the tongue and insert into it and their function is to move the tongue. There are four intrinsic muscles of the tongue that alter the shape of the tongue.

The muscles and mucous membranes of the tongue have separate nerve supplies. The hypoglossal nerve (cranial nerve XII) is the motor nerve of the tongue. It descends from the medulla and exits through the hypoglossal canal, from whence it passes laterally between the internal jugular vein and internal and external carotid arteries to curve anteriorly and enter the tongue. It passes anteriorly on the inferior aspect of the hyoglossus muscle and then to the lateral aspect of the genioglossus muscle. Injury of the hypoglossal nerve results in paralysis and eventual atrophy of the ipsilateral tongue.

The lingual nerve, which is a branch of the mandibular division of cranial nerve V, is the sensory nerve for the oral tongue. For special sensation such as taste, the anterior two-thirds of the tongue is supplied by the chorda tympani branch of the facial nerve (cranial nerve VII). The chorda tympani joins the lingual nerve and runs anteriorly in its sheath. The blood supply to the tongue is from the lingual artery; two lingual veins accompany the lingual artery. The deep lingual vein begins at the tip of the tongue and runs posteriorly in the median plane.

The tongue has a submucosal plexus of lymph vessels. There are three routes of lymphatic drainage from the oral tongue: the tip of the tongue drains to the submental lymph nodes; lymph from the lateral aspects of the tongue drains to the submandibular lymph nodes and from there into the deep cervical lymph nodes; lymph from the medial tongue drains directly to the inferior deep cervical lymph nodes. Approximately 15% of patients have lymphatic metastases that bypass level II and present in levels III and IV.⁹⁶ Lymphatic drainage is unilateral; drainage to the contralateral lymphatics is unlikely.

Pathology and Patterns of Spread

Ninety-five percent of oral tongue cancers are squamous cell carcinomas. Leukoplakia is also common.⁹⁷ Verrucous carcinoma and minor salivary gland tumors occur infrequently.

Nearly all squamous cell carcinomas occur on the lateral and ventral surfaces of the tongue. Anterior-third (tip) lesions are usually diagnosed early. Middle-third lesions often invade the musculature of the tongue and subsequently extend into the lateral floor of mouth. Posterior-third lesions grow into the musculature of tongue, floor of the mouth, anterior tonsillar pillar, base of the tongue, glossotonsillar sulcus, and mandible.

The distribution of clinically positive neck node metastases on presentation is shown in Figure 30-11.⁶³ Forty-five percent of patients with cancers of the oral tongue have clinically positive nodes at diagnosis; 5% are bilateral. Byers and associates⁶⁴ reported a 19% incidence of subclinical disease for T1N0 and T2N0 lesions, and 32% for T3N0 to T4N0 cancers after elective neck dissection. Ozeki and colleagues⁹⁸ have reported three cases with metastases to the lingual lymph nodes.

Figure 30-11 Carcinoma of the oral tongue: nodal distribution on admission, M.D. Anderson Hospital, 1948 to 1965.

From Lindberg RD: Distribution of cervical lymph node metastases from squamous cell carcinoma of the upper respiratory and digestive tracts, Cancer 29:1448, 1972.

Clinical Manifestations, Patient Evaluation, and Staging

Patients with oral tongue carcinomas usually present with a sense of tongue irritation or of a mass in the tongue. Deep infiltration may affect speech and swallowing. Advanced ulcerative lesions are often associated with a foul odor and pain.

Palpation of the tongue and floor of the mouth, visual examination, and assessment of tongue mobility will help define the extent of the primary tumor. CT and, to a lesser extent MRI, is useful for defining the deep extent of larger primary tumors and to assess the neck. The staging system is depicted in Table 30-2.³¹

Treatment

A treatment algorithm is shown in Figure 30-12.

Figure 30-12 Treatment algorithm for de novo oral tongue cancer. *Concomitant chemotherapy may be used.¹⁵⁴

Results

Wang¹⁰⁴ evaluated results of various boost techniques combined with EBRT for patients with T1 and T2 oral tongue lesions and observed a 5-year actuarial local control rate of 54% after an interstitial implant, 50% after intraoral cone orthovoltage irradiation, and 86% after intraoral cone electron beam therapy. The reason that local control was better after the electron beam intraoral cone boost compared with the orthovoltage intraoral cone treatment is unclear. Compared with interstitial implantation, intraoral cone irradiation is associated with a lower dose to the mandible and does not require anesthesia or hospitalization. It may also be associated with fewer complications. Currently, physicians at Massachusetts General Hospital give 3 Gy per fraction for eight or nine daily fractions with intraoral electron beam RT (five fractions per week) followed immediately by EBRT with 1.6 Gy twice daily for 12 days.¹⁰⁴ The patient is given a 1.5- to 2-week split and resumes radiotherapy to an EBRT dose of 51.4 Gy; the total dose is approximately 75 Gy.

Intraoral cone irradiation with orthovoltage x-rays is preferred at the University of Florida.⁸⁹ Patients usually receive 3 Gy per fraction with intraoral cone treatment for 7 to 9 days for a total of 21 to 27 Gy followed by EBRT to 30 Gy in 10 once-daily fractions or 32 Gy at 1.6 Gy per fraction twice daily over 2 weeks to the primary site and neck.

Brachytherapy may also be combined with EBRT to treat oral tongue cancer.100,103,105 Patients treated at the University of Florida with EBRT followed by an interstitial implant had a local control rate of 83%.¹⁰² Wendt and colleagues¹⁰⁵ reported on the M.D. Anderson Cancer Center experience with T1N0 and T2N0 oral tongue carcinomas in which patients underwent either brachytherapy alone or combined with EBRT. Of eight patients who were treated with EBRT alone, five (63%) developed a local recurrence. Six of 18 patients (33%) treated with interstitial therapy failed at the primary site. In those patients treated with a combination of EBRT and brachytherapy, the 2-year local control rate was 92% for those treated with EBRT doses less than 40 Gy combined with a moderately high brachytherapy dose, compared with 65% for patients who received EBRT doses of 40 Gy or more with a lower brachytherapy dose.¹⁰⁵ A review of the pertinent literature supports the efficacy of brachytherapy⁸³ (Table 30-11).

Subclinical disease in the neck nodes is common in patients with oral tongue cancer. Matsuura and colleagues stressed the importance of elective treatment to the neck, especially as tumor thickness increases.¹⁰⁶ In their experience, patients with tumor thickness of 8 mm or more were at an increased risk of nodal failure in the clinically negative neck. Wendt and associates¹⁰⁵ also showed the importance of elective therapy to the clinically negative neck. Failure in the neck occurred in 44% of patients receiving no elective neck irradiation; 27% of the failures were in patients receiving less than 40 Gy compared with an 11% failure rate for those who received 40 Gy or more. Byers and associates¹⁰⁷ recommended elective treatment to the clinically negative neck in patients with T2 to T4 primary tumors. Haddadin and colleagues¹⁰⁸ observed that patients with T2 tongue carcinomas had a significantly better outcome after an elective neck dissection compared with those who were followed with salvage reserved until development of a regional failure (75% vs. 39% 5-year OS, respectively). Based on a review of the Memorial Sloan-Kettering Cancer Center experience, Spiro and colleagues⁹⁹ recommended that elective neck therapy be given for primary tumors exceeding 2 mm in thickness because the risk of cervical metastasis approached 40% in this cohort of patients. O-Charoenrat and associates¹⁰⁹ found that increasing tumor thickness predicted for occult cervical node metastasis and poor outcomes in patients with stage I and II oral tongue squamous cell carcinoma treated at the Royal Marsden Hospital. Univariate analysis of DFS showed poorer outcomes for patients older than 60 years (p = .0423) and with tumors thicker than 5 mm (p = .0067). The impact of tumor thickness on outcome (p = .005) was also appreciated in a multivariate analysis. They recommended elective neck treatment for tumors more than 5 mm thick.

The use of sentinel lymph node biopsy and PET scanning may alter the treatment paradigm as more experience is gained in their use for oral cavity cancers.¹¹⁰

Bourgier and colleagues reported on 279 patients treated with exclusive low-dose-rate brachytherapy with or without an elective neck dissection for T2N0 squamous cell carcinoma of the oral tongue.¹¹¹ The incidence of subclinical cervical node metastases was 45%. The 2-year local and regional control rates were 79% and 76%, respectively. The incidence of grade 3 complications was 3%.

Fein and colleagues¹⁰² compared the results and complications of treatment with irradiation and/or surgery for squamous cell carcinoma of the oral tongue. The control rates for RT alone or surgery alone or in combination with RT were the same for stage T1 and T2 lesions; combined-modality treatment resulted in higher cure rates for T3 and T4 tumors (Table 30-12). In an analysis of patients with T1 and T2 lesions, those receiving less than 30 Gy of EBRT plus an interstitial implant had a better outcome than those receiving surgery plus or minus postoperative RT.¹⁰² Currently, for patients receiving radiation therapy alone, a dose of 1.6 Gy per fraction is given twice daily to 32 Gy followed immediately by an interstitial implant for an additional 35 to 40 Gy. This technique decreases the overall treatment time and avoids the large dose per fraction associated with 30 Gy in 10 fractions over 2 weeks.¹⁰²

Chao and associates¹⁰¹ reported on 55 patients with stage T1 and T2 lesions treated with surgery and postoperative RT. Thirty-nine patients received EBRT alone, and 16 patients had an interstitial implant as part of the treatment. By adding an interstitial implant for patients with positive margins, the local control rate was equivalent to that observed for patients with negative margins treated with EBRT alone.

Sessions and colleagues¹⁰⁰ reported on 332 patients with oral tongue cancer treated with surgery and/or RT at Washington University. Tumor stages at presentation were T1, 116 patients; T2, 128 patients; T3, 71 patients; and T4, 17 patients. Local recurrences occurred in 34%, and 31% suffered a neck recurrence. The 5-year CSS by treatment group for 279 of the 332 patients are shown in Table 30-13.

Irradiation Techniques

T1 and T2 Cancers

Reduction of overall treatment time is key to the successful treatment of oral tongue carcinomas with RT alone. Patients with well-differentiated carcinomas that are 4 mm or less are optimally treated with brachytherapy alone (Fig. 30-13). Interstitial implantation may be accomplished using rigid cesium needles mounted in a bar or with iridium using the plastic tube technique. Rigid cesium needles mounted in a bar are difficult to position because of the length of the needles, unless the lesion is relatively superficial. Therefore the plastic tube technique is preferred. The total dose varies from 65 to 70 Gy over 5 to 7 days.

Figure 30-13 A 51-year-old man presented with a 3-month history of a painful sore on the right dorsum of the tongue. The lesion measured 3 × 2 cm and extended near the midline. Biopsy revealed squamous cell carcinoma (T2N0). The treatment plan involved using opposed lateral portals and a dose of ⁶⁰Co at 30 Gy over 2 weeks plus a radium needle implant for 45 Gy. A, Squamous cell carcinoma on dorsum of oral tongue. B, Radiograph of radium needles in a patient. The needles were mounted in a nylon bar. There were two crossing needles in the lateral bar and one crossing needle in the medial bar. The nylon holder assisted in maintaining the active portion of the needles above the lesion to give an adequate dose to the dorsum of the tongue. C, Radium implant in place. D, Complete healing at 3 months. There was no evidence of disease at 8 years.

CREDIT LINE: Figure 3 from Hinerman RW, Mendenhall WM, Morris CG, et al: Radiation therapy in the management of the oral cavity cancer. In Werning JW, editor: Oral cancer, New York, 2005, Thieme.

Although intraoral cone irradiation has been used successfully to treat oral tongue cancers, it is often difficult to immobilize the lesion, so that setup reproducibility may be problematic. If treatment with an intraoral cone is chosen, then the cone is positioned so that the tumor is treated with a 1-cm margin. The intraoral cone therapy should be done before EBRT because of better tolerance and because the lesion can be clearly defined. Orthovoltage x-rays or electron beam therapy may be used. If electrons are used, a beam spoiler or bolus is necessary to ensure an adequate surface dose. Additionally, a larger margin is necessary due to beam constriction compared with orthovoltage irradiation.

Patients who have poorly differentiated carcinomas, as well as those with 5 mm or more depth of invasion, should be treated with a combination of EBRT and brachytherapy. Parallel opposed fields include the primary tumor as well as the level I and II lymph nodes. A cork and tongue block displaces the tongue inferiorly and the maxilla superiorly to minimize the amount of normal tissue included in the portals (Fig. 30-14). The fields are weighted 3 : 2 to the side of the tumor and either 30 Gy in 10 fractions once daily or 32 to 38.4 Gy at 1.6 Gy per fraction twice daily is delivered over 2 to 2.5 weeks with 4-MV or 6-MV x-rays. Although ⁶⁰Co is an ideal beam for treatment of patients with oral cavity cancers, it is not available in most clinics. The level III and IV nodes are included in an anterior field as previously described. After EBRT, 35 to 40 Gy is added with an interstitial implant.

Figure 30-14 Well-lateralized squamous cell carcinoma of the oral tongue (neck category N0). A single ipsilateral field is used. The field encompasses the submaxillary and subdigastric lymph nodes; the entire width of the vertebral body is included to ensure adequate posterior coverage of the subdigastric lymph nodes. Stainless steel pins are usually inserted into the anterior-most and posterior-most aspects of the lesion to aid in localizing the cancer on the treatment planning (simulation) roentgenogram and to confirm coverage by the interstitial implant. For lesions smaller than 2 cm in diameter, the low neck is not irradiated (unless the histologic type is poorly differentiated squamous cell carcinoma). The larynx is excluded from the radiation field. The anterior submental skin and subcutaneous tissues are shielded, when possible, to reduce submental edema and late development of fibrosis. The upper border is shaped to exclude most of the parotid gland. An intraoral lead block (stippled area) shields the contralateral mucosa. The block is coated with beeswax to prevent a high-dose effect on the adjacent mucosa resulting from scattered low-energy electrons from the metal surface. The usual preinterstitial tumor dose is 32 Gy using 1.6 Gy per fraction at twice-a-day fractionation. For larger lesions, which extend near the midline, treatment is applied by means of parallel opposed portals with no intraoral lead block.

From Parsons JT, Mendenhall WM. Million RR: Radiotherapy of tumors of the oral cavity. In Thawley SE, Panje WR, Batsakis JG, Lindberg RD: Comprehensive management of head and neck tumors, ed 2. Vol 1. Philadelphia, 1999, Saunders, pp 695-719; Figure 35-17A and B, p 714. Copyright 1999, with permission from Elsevier.

Complications

After RT, patients may complain of a sensitive tongue, even after the mucosa appears to have healed. Taste tends to reappear from 1 to 3 months after treatment; however, because of xerostomia, post-RT taste perception is less sensitive.

Small, self-limited soft tissue necroses are fairly common. If these occur, recurrent cancer must be ruled out. If the lesion is thought to be necrotic, conservative treatment is instituted. The patient is examined frequently and broad-spectrum antibiotics such as tetracycline are initiated as well as pentoxifylline.⁹³ Viscous lidocaine can be applied to the ulcer for local analgesia. Hyperbaric oxygen treatment is indicated for larger progressive necroses that do not respond to conservative management. Surgery is employed as a last resort for large persistent necroses that are often associated with bone necrosis.

Osteoradionecrosis occurs infrequently; the onset varies from 1 month to many years after radiation therapy.¹¹² It is more common in patients receiving higher doses per fraction and/or with tumor invading the bone.¹¹³ If a patient has dentures, the dentures must be removed or altered by the dentist to avoid trauma to areas of exposed bone; healing may require many months. Management is similar to that for soft tissue necroses.

Irradiation-induced xerostomia is common and is related to the volume of salivary tissue irradiated and the radiation dose. Patients who are treated with brachytherapy or intraoral cone irradiation without EBRT usually retain salivary function.

Oral pilocarpine has been advocated by some for xerostomia. Pilocarpine exercises a broad spectrum of pharmacologic effects, including increasing the secretions of exocrine glands, most notably the salivary glands. In a multicenter, randomized, double-blind, placebo-controlled trial published in 1993, pilocarpine produced a clinically significant benefit.¹¹⁴ However, its efficacy has been questioned by the outcomes of recent randomized trials.^115,116 The recommended dosage is 5 mg, three or four times a day. The time interval necessary to achieve optimal results is 8 to 12 weeks.

Amifostine has been used more recently in an effort to lessen the untoward effects of RT. It can be administered either intravenously or subcutaneously.^117,118 The latter is generally felt to be more convenient and associated with less toxicity.¹¹⁹ A full course of treatment with amifostine is quite expensive. This fact, coupled with its potential to cause nausea and skin reactions, has limited its acceptance in some centers.

At the University of Florida, the severe complication rate for 170 patients treated with surgery alone or in combination with RT for oral tongue cancer has been compared with the severe complication rate for patients treated with RT alone; the findings are presented in Table 30-14.¹⁰²

Sessions and colleagues¹⁰⁰ reported major treatment complications in 21 of 270 patients (12.8%), most of which occurred in those receiving composite resection and RT. Complications associated with RT included orocutaneous fistula (6/224 [2.7%]), flap necrosis (1/224 [0.4%]), carotid hemorrhage (1/224 [0.4%]), xerostomia (7/224 [3.1%]), trismus (5/224 [2.2%]), radiation caries (3.1%), soft tissue ulcer (22/224 [9.8%]), bone necrosis (14/224 [6.2%]), and dysphagia (3/224 [1.3%]).¹⁰⁰

Anatomy

The lateral walls of the oral cavity are formed by the cheeks. The buccal mucosa is composed of the inner lining of the cheeks. It is contiguous with the lips and has the same structure.

The muscle of the cheek is the buccinator muscle. The buccal fat pad is superficial to the fascia covering the buccinator muscle and gives the cheeks a rounded contour.

Branches of the maxillary and mandibular nerves (cranial nerves V2 and V3) provide sensory innervation to the skin, the cheek, and the mucous membranes lining the cheeks. The facial nerve (cranial nerve VII) provides motor innervation to the muscles of the cheeks and lips. The lips and cheeks function together as an oral sphincter propelling food into the oral cavity. If the facial nerve is paralyzed, food tends to accumulate within the cheek along the affected side so that saliva and food dribble out of the corner of the mouth.

Pathology and Patterns of Spread

The majority of tumors originating from the buccal mucosa are low-grade squamous cell carcinomas that are frequently associated with leukoplakia. Verrucous carcinomas are observed more frequently in the buccal mucosa than in other parts of the oral cavity.¹²⁰

Early lesions tend to be discrete, exophytic, mucosal growths. Advanced tumors tend to be ulcerated and are often associated with muscle invasion. Lesions that involve the lower gum may invade the mandible. Advanced lesions may extend to the soft tissues of the cheek.

The first-echelon lymphatics are the submandibular and subdigastric lymph nodes. The incidence of positive nodes at diagnosis ranges from 9% to 31%; the risk of subclinical disease is 16%.¹²¹ Bilateral cervical node metastases are very unusual. Advanced cancers have a higher propensity (60%) for lymph node metastases.¹²⁰

Clinical Manifestations and Staging

Although pain tends to be minimal, even when the lesion is large, posterior extension may result in involvement of the lingual or dental nerves, which may cause ear pain. Extension behind the pterygomandibular raphe into the pterygoid muscles or into the buccinator and masseter muscles may cause trismus. Intermittent bleeding may occur when the lesions are irritated by chewing.

CT imaging can be used to evaluate the deep extension of the lesion, to detect bone invasion, and to assess the parotid and facial nodes.⁶⁶ The AJCC staging system is depicted in Table 30-2.³¹

Treatment

Early Lesions (T1 and Superficial T2)

The preferred treatment for patients with carcinoma of the buccal mucosa is surgery. Radiotherapy alone is used to treat patients by default in the uncommon situation where surgery is not feasible. Patients with T1 and T2 cancers may be treated with a combination of EBRT and an interstitial implant.¹²⁰ A treatment algorithm is shown in Figure 30-15.

Figure 30-15 Treatment algorithm for de novo buccal mucosa cancer. *Treat neck (radiotherapy or neck dissection) for T2 to T4 tumors.120,121,154.

Results

Five-year DFS after RT range from 50% to 60%, depending on the stage of the primary lesion and the presence or absence of lymph node metastases.^61,126 Ash⁶¹ reviewed the outcomes of 374 patients; 97% were initially treated with RT. The primary lesion was controlled in 52% of the patients; however, only 25% of advanced lesions were controlled. Nair and colleagues¹²⁷ evaluated the role of RT in the management of carcinomas of the buccal mucosa; irradiation was either administered with an interstitial implant consisting of 65 Gy over 6 days (45 patients), continuous course EBRT consisting of 52.5 Gy in 15 fractions over 19 days or 60 Gy in 25 fractions over 33 days (139 patients), or as planned split-course EBRT consisting of 35 Gy in 15 fractions over 19 days—3-week split—25 Gy in 10 fractions over 12 days (46 patients). The split-course technique tended to be used in elderly patients or for those with massive tumors. The results are shown in Table 30-15. Relapse at the primary site increased with T stage.

Urist and associates¹²⁸ reviewed results of 105 patients with squamous cell carcinomas of the buccal mucosa treated by resection of the primary tumor and neck dissection (Table 30-16). In a multivariate analysis, tumor thickness greater than 6 mm was the only significant prognostic factor. Depth of invasion greater than 3 mm was also highly significant but only in the univariate analysis.

TABLE 30-16 Carcinoma of the Buccal Mucosa Treated Surgically: Primary Tumor Parameters versus Outcome

Reprinted from Urist MM, O’Brien CJ, Soong SJ, et al: Squamous cell carcinoma of the buccal mucosa. Analysis of prognostic factors, Am J Surg 154:411-414, 1987.

Diaz and colleagues¹²³ reported on 119 patients with buccal mucosal carcinomas treated at the M.D. Anderson Cancer Center. Eighty-four were treated with surgery alone (71%), whereas 22 received postoperative RT and 13 received preoperative RT. None were treated with irradiation alone. Thirty-eight patients (32%) experienced local recurrences. Five-year OS by T category were T1, 79%; T2, 65%; T3, 56%; and T4, 69%. Muscle invasion, Stensen’s duct involvement, and extracapsular spread of involved nodes were significantly associated with decreased survival.¹²³

Irradiation Techniques

T1 and T2 Lesions

The patient is immobilized in the supine position with an Aquaplast face mask. EBRT is administered with an ipsilateral field arrangement that includes the primary lesion and the level I and II lymph nodes. The anterior and superior borders of the field should be at least 2 cm from the borders of the primary tumor. The posterior border should be at the posterior aspect of the spinous processes if the nodes are to be irradiated; the inferior border is at the thyroid notch. The oral commissures and lips are shielded if possible to reduce the acute effects. Patients may be treated with either a “wedge pair” of 6-MV x-ray beams or an en face “mixed beam” of 6-MV x-rays and electrons (Fig. 30-16). The electron energy used in the mixed beam technique varies depending on the depth of the tumor. Because of the steep fall-off of the electron beam at depth, it is preferable to risk overshooting rather than underdosing the deep extent of the tumor, and to use higher electron beam energies such as 15-MeV or 20-MeV beams. The EBRT dose fractionation schedule is 38.4 Gy at 1.6 Gy per fraction, twice daily. The ipsilateral low neck is treated with an en face 6-MV x-ray field matched at the level of the thyroid notch.

Figure 30-16 Buccal mucosa. Mixed ipsilateral en face 6-MV x-rays (solid line) and electrons (dotted line). The electron field is 1 cm larger in all dimensions due to beam constriction, except where it matches the anterior low neck field at the thyroid notch.

From Mendenhall WM: Radiotherapy treatment technique. Cancer of the buccal mucosa. In Werning JW, editor: Oral cancer, New York, 2005, Thieme, Figure 1.

If possible, a portion of the treatment should be given with intraoral cone irradiation or an interstitial implant to minimize the high dose volume and reduce the overall treatment time. Interstitial implantation is accomplished using ¹⁹²Ir via the plastic tube technique. The implant consists of a single plane of three to five horizontal tubes spaced 10 to 12 mm apart with crossing tubes at either end of the horizontal tubes. Ribbons containing ¹⁹²Ir seeds are afterloaded into the tubes to deliver approximately 30 to 35 Gy at 10 to 12 Gy per day specified at 5 mm from the plane of the sources.

Complications

The buccal mucosa tolerates high-dose RT with a low risk of late complications. Trismus may develop if the muscles of mastication receive high doses of irradiation.

Anatomy

The gingiva is composed of fibrous tissue covered by mucous membrane that is firmly attached to the periosteum of the alveolar processes of the mandible and maxilla. The lower gingiva includes the mucosa covering the mandible from the gingival-buccal gutter to the origins of the mobile mucosa on the floor of the mouth. There are no minor salivary glands in the mucous membranes of the alveolar ridges.

The gingiva receives sensory innervation from the nerves supplying the teeth that are branches of cranial nerves V2 and V3 (buccal, infraorbital, greater palatine, and mental nerves).

Pathology and Patterns of Spread

Squamous cell carcinomas are most common, usually arise from the posterior portion of the mandibular gingiva, and are often associated with leukoplakia. Verrucous carcinomas may also occur, usually on the lower gingiva.

Squamous cell carcinomas of the mandibular gingiva may invade the underlying bone, retromolar trigone, adjacent buccal mucosa, and floor of the mouth. Byers and colleagues¹²⁹ reported that 22% had associated leukoplakia, 36% had mandibular invasion, and 5% had perineural involvement. Bone invasion usually starts because there is no complete bony barrier in the edentulous portion of the mandible. The lingual and buccal plates are relatively resistant to tumor penetration. Tumor entry through the mental, mandibular, and other small foramina tends to occur in less than 10% of patients.¹³⁰

Metastatic spread occurs first to the submandibular (level I) and upper internal jugular (level II) lymph nodes. Byers and associates¹²⁹ reported 16% clinically positive nodes at diagnosis; contralateral lymph node involvement was found in only 3% of cases. Subclinical lymph node disease has been reported in 17% to 19% of cases.¹²⁹ The incidence of involved lymph nodes was 12% for T1 and T2 lesions and 13% for T3 and T4 stage cancers.⁶⁴ Figure 30-17 shows the distribution of positive lymph nodes after elective neck dissection.⁶⁴

Figure 30-17 Carcinoma of the gingiva. The distribution of involved lymph nodes after elective modified neck dissection for patients with a clinically negative neck.

Clinical Manifestations and Staging

The patient with squamous cell carcinoma of the gingiva may first present to the dentist with ill-fitting dentures, pain, loose teeth, or a sore that will not heal. Intermittent bleeding and pain may occur when the lesion is traumatized. Invasion of the inferior dental nerve may produce paresthesia or anesthesia of the lower lip.

Because bone invasion compromises the results of RT, careful radiographic examination of the mandible with panoramic x-ray films, dental radiographs, and CT scanning is essential. The AJCC staging system is shown in Table 30-2.

Treatment

Early Lesions (T1 and Superficial T2)

The majority of these lesions are managed by surgery. Small lesions may be removed by transoral resection; however, rim resection is necessary in most cases. When direct bone invasion is present, removal of a segment of the mandible (segmental mandibulectomy) or maxilla is required. A treatment algorithm is shown in Figure 30-18.

Figure 30-18 Treatment algorithm for de novo gingival cancer. *Treat neck (neck dissection).

^64,129

Results

Cady and Catlin¹³¹ reviewed 606 patients with squamous cell carcinoma of the gingiva treated by surgery. The survival rate was 43% for patients with mandibular gingival lesions and 40% for those with maxillary alveolar ridge cancers. Soo and colleagues¹³² reviewed a 20-year experience with squamous carcinoma of the gums in 347 patients treated at the Memorial Sloan-Kettering Cancer Center. Sixty-four percent of patients presented with a clinically negative neck (N0). Ninety-seven percent of patients were treated surgically. The 5-year CSS was 54%. Advanced clinical stage (stages III and IV), prior dental extractions, bone invasion, and involvement of surgical margins were predictive of a lower survival rate on univariate analysis. Clinical stage was the only significant predictor of survival on multivariate analysis.

Byers and associates¹²⁹ reported a 5-year OS of 43% for patients with squamous cell carcinoma of the mandibular gingiva. Fifty-one of these patients were treated with surgery that included resection of bone in 28 patients with early lesions. Only 1 of 28 patients developed a recurrence. Segmental mandibulectomy and neck dissection were used for 23 patients with advanced disease; there were no local failures. Postoperative irradiation was given for close margins, nerve invasion, or extensive nodal metastases. For those treated with surgery and postoperative RT, control above the clavicles was achieved in 95% of patients.

Overholt and colleagues¹³³ retrospectively reviewed results of 155 patients treated surgically for carcinoma of the mandibular gingiva. Decreased local control was observed for primary lesions larger than 3 cm (p = .021) and persistently positive surgical margins (p = .027). Survival was adversely affected by advanced T category (p = .001), positive initial and final surgical margins (p = .004), mandibular invasion (p = .014), and cervical metastases (p < .001). Local control and survival were not affected by extent of mandibular resection, tumor extension beyond the mandibular gingiva, recent dental extractions in the region of the primary tumor, perineural invasion, or histologic grade.

Patients treated with RT alone for T3 and T4 lesions have 5-year OS ranging from 30% to 40%.121,129 Wang¹²⁶ reported a 78% control rate for patients with T1 lesions and 27% for those with T2 cancers after treatment with RT alone. Fayos¹³⁴ reported a 50% local control rate after irradiation alone for lesions with early bone invasion and a 25% local control rate after irradiation alone for those with extensive invasion.

Irradiation Techniques

T1 and T2 Lesions

Patients who are not deemed to be surgical candidates are treated with RT. Small lesions may be treated by intraoral cone irradiation combined with EBRT. Interstitial implant has no place in the management of this disease because of the proximity of the bone and the high risk of osteoradionecrosis.

EBRT may be administered with either an ipsilateral en face combination of 4-MV or 6-MV x-rays and electrons, or with two 4-MV or 6-MV x-ray beams arranged in a “wedge pair” (Fig. 30-19). The latter technique is preferred because it is possible to vary the depth of the target volume more precisely and underdosing of the medial extent of the tumor is less likely. Lesions that exhibit significant extension onto the soft palate or into the tongue (unusual for a T1 or T2 tumor) would be treated with parallel opposed fields weighted 3 : 2 to the side of the tumor. Alternatively, IMRT may be employed to spare the contralateral parotid gland. The doses used are from 60 to 65 Gy over 6 to 6.5 weeks for T1 tumors, and 70 Gy over 7 weeks or 74.4 Gy in 62 fractions twice daily for T2 tumors. The low neck is treated with an anterior 4-MV or 6-MV x-ray field matched at the thyroid notch and receives 50 Gy in 25 fractions.

Figure 30-19 Patient with an early-stage carcinoma of the retromolar trigone. Radiotherapy is delivered with two 6-MV x-ray beams via a “wedge-pair” arrangement.

From Mendenhall WM: Radiotherapy treatment technique. Cancer of the maxillary alveolar ridge and retromolar trigone. In Werning JW, editor: Oral cancer, New York, 2005, Thieme, Figure 1.

T3 and T4 Lesions

Patients with T3 and T4 carcinomas have a relatively low chance of cure with RT alone and are optimally treated with surgery and postoperative RT. The postoperative dose varies with the margins. Patients with negative margins generally receive 60 Gy at 2 Gy per fraction. Altered fractionation is considered for patients with positive margins and for those with multiple risk factors and/or a prolonged interval between surgery and RT. At our institution, the preferred schedule is 74.4 Gy at 1.2 Gy per fraction administered twice daily in a continuous course over 6.5 weeks. As with other sites, concomitant cisplatin is also recommended for high-risk situations.

Patients are treated with parallel opposed portals that include the primary tumor and upper neck nodes (Fig. 30-20). The fields are weighted 3 : 2 toward the side of the tumor. The anterior low neck is treated with an en face 6-MV x-ray field matched at the level of the thyroid notch. A petroleum jelly gauze bolus is placed on the incisions to ensure an adequate surface dose. Fields are reduced off of the spinal cord at approximately 45 Gy. An electron beam may be used to irradiate the posterior strips if additional RT to these sites is indicated after off-cord reduction.

Figure 30-20 Typical portal for irradiation after hemimandibulectomy, partial maxillectomy, and radical neck dissection for pathologic T4N0 retromolar trigone lesion. Field reductions made at 45 Gy (dashed line) and 60 Gy (dotted line).

From Mendenhall WM: Radiotherapy treatment technique. Cancer of the maxillary alveolar ridge and retromolar trigone. In Werning JW, editor: Oral cancer, New York, 2005, Thieme, Figure 2.

Patients who are not suitable for surgery are treated with twice-daily EBRT to 76.8 Gy in 64 fractions over 6.5 weeks combined with concomitant chemotherapy. The field arrangements are similar to those previously described. We routinely exclude the spinal cord at 40 Gy if chemotherapy is used concomitantly. IMRT may be used to reduce the dose to the contralateral parotid gland, unless bilateral positive nodes are present. Patients who are unsuitable for aggressive treatment receive moderate-dose, palliative RT at 30 Gy in 10 fractions over 2 weeks or 20 Gy in 2 fractions with a 1-week interfraction interval.

For postoperative cases, radiation portals include the adjacent segment of the mandible or maxilla. The entire hemimandible or hemimaxilla from the distal neural foramen to the pterygopalatine ganglion must be treated when perineural invasion is present. The low neck must be irradiated if involved nodes are present or if the primary tumor is advanced. Postoperative EBRT doses range from 60 to 75 Gy at 1.8 to 2.0 Gy per day. If the resection margins are positive, 74.4 Gy at 1.2 Gy per fraction, twice daily with a minimum 6-hour interfraction interval, is currently used at our institution. Cisplatin is administered concomitantly, based on the results of recently published randomized data from the RTOG and EORTC.^49,51

Complications

Surgical complications include orocutaneous fistulae and bone exposure. The complications of radiation therapy include dental caries, soft tissue necrosis, and osteoradionecrosis. The risk is greatest for more advanced lesions.

Anatomy

The small triangular surface posterior to the third mandibular molar, overlying the ascending ramus, is called the retromolar trigone. Beneath the mucosa of the retromolar trigone is the pterygomandibular raphe, which is attached to the pterygoid hamulus on the posterior mylohyoid ridge of the mandible. It serves as the insertion of the buccinator and superior constrictor muscles. Behind the pterygomandibular raphe (between the medial pterygoid muscle and the ascending ramus of the mandible) is the pterygomandibular space, which contains the lingual and dental nerves. There is a small fat pad between the pterygoid muscle group and the mandibular foramen through which the mandibular nerve passes before it enters the alveolar canal. The subdigastric lymph nodes are the first-echelon nodes for the retromolar trigone.

Pathology and Patterns of Spread

The vast majority of these tumors are squamous cell carcinomas. The primary tumor may spread to the adjacent buccal mucosa, anterior tonsillar pillar, mandibular gingiva, and mandible. Posterior spread to the pterygomandibular space and medial pterygoid muscle may occur. Invasion of the periosteum may occur early. Byers and colleagues¹³⁵ reported a 25% incidence of bone invasion at diagnosis.

The incidence of clinically positive ipsilateral nodes on presentation is 39%, and the risk of subclinical disease in the cervical lymph nodes is approximately 25%.¹³⁵ The distribution of positive nodes after an elective neck dissection⁶⁴ is shown in Figure 30-21.

Figure 30-21 Carcinoma of the retromolar trigone. The distribution of involved lymph nodes after elective modified neck dissection for patients with a clinically negative neck.

From Byers RM, Wolf PF, Ballantyne AJ: Rationale for elective modified neck dissection, Head Neck Surg 10:163, 1988.

Clinical Manifestations and Staging

Retromolar trigone cancers tend to produce pain that may be referred to the external auditory canal and preauricular area. Invasion of the pterygoid muscles can produce trismus and is better demonstrated by MRI than by CT.⁶⁶ CT scan of the head and neck (and MRI in selected cases) is useful for determining the deep extent of the primary tumor, bone invasion, and presence of positive neck nodes. The staging system is depicted in Table 30-2.

Treatment

Early Lesions (T1 and T2)

Local control rates for T1 and T2 lesions are similar following surgery or RT.¹³⁵ If the tumor extends to the tonsillar pillar, soft palate, or buccal mucosa and an extensive resection is required, RT is selected. If possible, intraoral cone irradiation should be used for a portion of the treatment. Small lesions without detectable bone invasion can be resected with removal of the periosteum or a rim resection of the mandible. A treatment algorithm is shown in Figure 30-22.

Figure 30-22 Treatment algorithm for de novo retromolar trigone cancer. *Treat neck with radiotherapy or neck dissection.

Results

Lo and associates¹³⁶ reported on a series of patients treated with radiation therapy at the M.D. Anderson Hospital (Table 30-17). Patients with retromolar trigone cancers were grouped with those having anterior tonsillar pillar lesions. Local control varied from 70% to 76% after RT for those with T1, T2, and T3 cancers. Salvage surgery resulted in ultimate local control rates varying from 92% to 100%.

Mendenhall and colleagues¹³⁷ reported on 99 patients treated with RT alone or combined with surgery at the University of Florida. The likelihood of cure was influenced by extent of disease and treatment; those treated with surgery and RT had a better chance of cure than those treated with RT alone (Table 30-18).

Kowalski and associates¹³⁸ reported on 114 patients who underwent an extended “commando” operation between 1960 and 1991 for carcinoma of the retromolar trigone. Sixty-six patients received postoperative RT (median, 50 Gy). Tumor categories were T1, 5 patients; T2, 44 patients; T3, 24 patients; T4, 28 patients; and TX, 13 patients. Forty-one patients (36%) experienced a recurrence at one or more sites: local, 31 (27%); dissected neck, 9 (22%); contralateral neck, 3 (7%); and distant, 7 (17%). The 5-year OS by T category was T1, 80%; T2, 57.8%; T3, 46.5%; T4, 65.2%; and overall, 55.3%.

Byers and colleagues¹³⁵ reported on 110 patients with squamous carcinoma of the retromolar trigone who were treated at the M.D. Anderson Hospital from 1965 to 1977 and followed for 5 years or longer. Seventy patients had T1 and T2 tumors, and 77 patients had a clinically negative neck. Sixty patients received either surgery alone (n = 46) or combined with preoperative or postoperative radiation therapy (n = 14). Fifty patients were treated with irradiation alone. Failure at the primary site occurred in 7 of 60 patients (12%) treated surgically, and in 8 of 50 patients (16%) treated with RT alone.

Irradiation Techniques

Treatment techniques for retromolar trigone cancers are similar to those discussed in the preceding section on gingival cancers.

Complications

Thirty percent of the patients reported by Lo and colleagues¹³⁶ developed some degree of bone exposure, but only nine patients (5.6%) required a segmental mandibulectomy. The probability of bone exposure was not found to be dose related. Huang and associates¹³⁹ reported on 65 patients treated for retromolar trigone cancer and observed complications that included bone necrosis, soft tissue necrosis, and severe trismus, occurring in 12% after surgery and postoperative RT, 11% after RT alone, and none after preoperative RT and surgery.

Kowalski and colleagues¹³⁸ observed complications in 51.8% of 114 patients who underwent an extended “commando” operation between 1960 and 1991; 21 patients (18.4%) had a wound infection.

Anatomy

The palate forms the roof of the oral cavity and the floor of the nasal cavity. The anterior two-thirds, or bony part of the palate, is called the hard palate and is formed by the palatine processes of the maxilla and the horizontal plates of the palatine bones. Anteriorly and laterally, the hard palate is bounded by the maxillary alveolar ridge and gingiva. Posteriorly, the hard palate is contiguous with the soft palate. The hard palate is covered by a mucous membrane overlying the periosteum. Deep to the mucosa are the secreting palatine glands. The incisive foramen is posterior to the maxillary central incisors; the nasopalatine nerves pass through this foramen.

The greater palatine foramina are medial to the third maxillary molars; the greater palatine vessels and nerves emerge from this foramen. The greater palatine nerve innervates the gingiva, mucous membrane, and glands of the hard palate. The nasopalatine nerve innervates the mucous membrane of the anterior part of the hard palate. Because of the rich blood supply from the greater palatine artery, the incidence of osteoradionecrosis and soft tissue necrosis is lower than that reported for the mandible.¹⁴³

Pathology and Patterns of Spread

Malignant tumors of the hard palate are most often adenoid cystic carcinomas and mucoepidermoid carcinomas arising from minor salivary glands. Squamous cell carcinoma is relatively uncommon. Kaposi’s sarcoma and melanomas may also originate on the hard palate.¹⁴²

Most squamous cell carcinomas originate on the gingiva and spread secondarily to the hard palate. Perineural invasion occurs via the greater palatine foramen. The risk of positive lymph nodes is 13% to 24% at diagnosis.^144,145 The incidence of subclinical disease in the cervical lymphatics is 22%.⁶¹

Clinical Manifestations, Patient Evaluation, and Staging

Patients with squamous cell carcinomas of the hard palate may first present to the dentist with ill-fitting dentures, pain, loose teeth, or a sore that will not heal. Intermittent bleeding and paresthesias may also occur.

Imaging of the hard palate is primarily with CT scanning and is occasionally supplemented with MRI. Imaging of the neck nodes must include the facial and retrozygomatic nodes.⁶⁶ Facial nodes are best assessed by bimanual examination, particularly in patients with dental fillings. If the lesion is an adenoid cystic carcinoma, it is essential to search for perineural spread. The AJCC staging system³¹ is shown in Table 30-2.

Treatment

Surgery is the usual initial treatment for most lesions; postoperative RT is indicated for patients with more extensive cancers. The role of primary RT in the management of hard palate carcinomas is ill defined. If the lesion has a large surface area and is superficial, irradiation can be used as initial treatment. However, most patients are treated with surgery because the underlying bone is often involved and, in that scenario, RT is unlikely to be effective.¹⁴⁶ Postoperative radiotherapy is indicated for close or involved margins, perineural or vascular invasion, multiple involved nodes, extracapsular extension, or bone invasion.⁵² Dose and fractionation recommendations are similar to those given for other sites. A treatment algorithm is shown in Figure 30-23.

Figure 30-23 Treatment algorithm for de novo hard palate cancer. *Treat neck with neck dissection.

See references 61, 144, 145.

Malignant salivary gland tumors of the hard palate are often treated by a combination of surgery and postoperative RT, particularly if they are high-grade tumors. Low-grade minor salivary gland carcinomas can be treated by surgery alone if negative margins can be achieved. Some malignant minor salivary gland tumors have been successfully controlled by high-dose RT alone.¹⁴⁷

Results

Shibuya and colleagues¹⁴⁸ reported the radiation therapy results for malignant lesions of the hard palate; the 5-year OS for those with squamous cell carcinomas was approximately 45%. For patients with minimal bone invasion and a clinically negative neck, the 5-year OS was 75%. Data from the University of Virginia are presented in Table 30-19 for 41 patients treated with surgery, RT, or both.¹⁴⁹

Yorozu and colleagues¹⁵⁰ reported on 31 patients treated with EBRT at the Christie Hospital between 1990 and 1997. Twenty-six received RT alone and five were treated postoperatively for positive surgical margins. The 5-year local and ultimate local control rates after salvage surgery were 53% and 69%, respectively. Survival rates were 48% for patients with squamous carcinomas and 63% for those with minor salivary gland carcinomas. T category was the only significant predictor of 5-year local control rates, which were 80% for T1 and T2 lesions and 24% for T3 and T4 lesions, respectively. The only significant predictor for survival was N category.

Tran and associates¹⁵¹ reported on 38 patients treated for salivary gland tumors of the palate at the University of California at Los Angeles. Twenty-three of 38 tumors were on the hard palate; adenoid cystic carcinoma was the most common histologic type. Twenty-five patients received surgery alone; 13 were treated with surgery and postoperative irradiation. The local control rates were comparable for the two groups of patients (88% and 85%, respectively).

Kovalic and colleagues¹⁵² reported on 13 patients with carcinoma of the hard palate treated at Washington University. Histologic types included adenoid cystic carcinoma, nine patients; squamous cell carcinoma, three patients; and mucoepidermoid carcinoma, one patient. T stages were T1, one patient; T2, five patients; T3, three patients; and T4, four patients. All had a clinically negative neck. Ten patients received excision and postoperative RT; three patients were treated with RT alone. The 10-year actuarial DFS and local control rates were 77% and 92%, respectively.

A group of 50 patients was treated surgically at the University of Cincinnati; it included 25 patients with squamous cell carcinomas, 11 with adenoid cystic carcinomas, 6 with adenocarcinomas, and 8 with tumors of miscellaneous histologic types.¹⁵³ The 5-year OS by histologic type were squamous carcinoma, 76%, and adenoid cystic carcinoma, 90%; the overall survival rate was 85%. The 10-year OS for adenoid cystic carcinomas fell to 75%, consistent with their tendency to develop late recurrences.

Most relapses are found at the primary site. Evans and Shah¹⁴² reported a 53% incidence of isolated primary site failure. The incidence of recurrence in the cervical nodes was 30%; failure involving both the primary site as well as the cervical lymph nodes was 10%. No patient treatment failed with results of distant metastases only. Seven percent of the patients experienced treatment failure in both distant and locoregional sites.¹⁴²

The risk of developing metachronous carcinoma is high. In the University of Virginia’s experience,¹⁴⁴ 28% of the patients developed a metachronous primary carcinoma during their lifetime and 13% developed a third, fourth, or fifth carcinoma. The oral cavity was the most common site for metachronous cancers.

Irradiation Techniques: Hard Palate and Maxillary Alveolar Ridge

T1 and T2 Lesions

The preferred initial treatment for patients with T1 and T2 carcinomas of the hard palate is surgery. Radiation therapy is used by default to treat the occasional patient who is not a surgical candidate. Most of these lesions are not well lateralized; consequently, irradiation is administered with parallel opposed fields encompassing the primary tumor, with a margin of 2 cm or less. A cork and tongue block are placed in the mouth to displace the tongue, mandible, and lower lip inferiorly and to reduce the amount of normal tissue included in the fields (Fig. 30-24A). These lesions are not amenable to brachytherapy and so patients are treated with EBRT alone. The likelihood of cure with RT alone, even for early-stage lesions, is relatively low, so that an altered fractionation technique should be employed. We prefer hyperfractionated irradiation and use 74.4 to 76.8 Gy at 1.2 Gy per fraction, twice daily, over 6 to 6.5 weeks. The fields are extended to include the regional lymph nodes (levels I and II) for patients with aggressive, poorly differentiated cancers (Fig. 30-24B). The disadvantage of irradiating the regional lymph nodes is that the acute toxicity of the treatment is significantly increased. Fields are reduced at 45.6 Gy in 38 fractions to limited portals that adequately encompass the primary cancer. The low neck is irradiated with an anterior field that abuts the primary fields at the level of the thyroid notch and receives 50 Gy in 25 fractions over 5 weeks.

Figure 30-24 Early-stage hard palate carcinomas. A, Parallel opposed 6-MV x-ray fields include the tumor plus a 2-cm margin. A cork and a tongue block displace the tongue and mandible inferiorly to minimize the amount of normal tissue included in the fields.

B, Advanced hard palate carcinoma. Portals include the primary tumor and upper neck nodes. The superior margin of the portals is extended to include V2 to the skull base.

From Mendenhall WM: Radiotherapy treatment technique. Cancer of the maxillary alveolar and hard palate. In Werning JW, editor: Oral cancer, New York, 2005, Thieme; Part A is Figure 1; Part B is Figure 2.

Complications

No severe complications occurred in the patients who received radiation therapy (60 Gy in 5 to 6 weeks) at the University of Virginia.¹⁴⁹ Most patients developed xerostomia and temporary loss of taste.¹⁴⁴

Yorozu and colleagues¹⁵⁰ reported results for 31 patients treated with EBRT at the Christie Hospital between 1990 and 1997. Twenty-six patients received irradiation alone, and five patients were treated postoperatively for positive surgical margins; necrosis occurred in one patient.