Malignant Tumors of the Base of Tongue


Background

The location of the base-of-tongue malignancy is critical in the diagnosis, management, and prognosis. The base of tongue is the site for the posterior opening of the oral cavity, the entrance of the pharynx and esophagus, and the inferior aspect of the nasopharynx. The surgical management of malignant neoplasms of the tongue base remains difficult despite recent advances in diagnostic techniques. Many patients present at an older age with advanced disease because of the occult nature of associated symptoms. The disease process and treatment often affect adjacent structures, such as the posterior floor of the mouth, larynx, and esophagus.

Careful multidisciplinary assessment and treatment selection based on the probability of cure and preservation of function are of paramount importance in the treatment of these patients. High recurrence rates, poor survival, and significant alterations in speech and swallowing function are common experiences for patients with malignancies in these anatomic sites. Despite these frustrations, patients are potentially curable and should be offered regimens that carefully consider morbidity and outcome within the context of the patient's overall medical condition.

Etiology

Chronic alcohol and prolonged tobacco use, older age, geographic location, and family history are important risk factors for development of base of the tongue carcinoma. Environmental exposure to polycyclic aromatic hydrocarbons, asbestos, and welding fumes may increase the risk of pharyngeal cancer. Nutritional deficiencies and infectious agents (especially papillomavirus [1and fungi) may also play a significant role. For example, a Danish study, by Garnaes et al, attributed a rise in eastern Denmark in the incidence of squamous cell carcinomas of the base of the tongue between 2000 and 2010 (by 5.4% per year) to an increase in the number of such tumors (by 8.1% per year) that were positive for human papillomavirus (HPV). [2]

A study by Ramqvist et al found that in patients with tonsillar squamous cell carcinoma (TSCC) or base-of-tongue squamous cell carcinoma (BOTSCC), those who were HPV-positive showed different expression of 34 proteins (primarily immunoregulatory proteins and cytokines) than did HPV-negative patients. The investigators reported that several of the proteins had a potential association with clinical outcomes, including, for HPV-positive tumors, those affecting angiogenesis and hypoxia. The fact that expression of the immune-related proteins varied between HPV-positive and HPV-negative cases was considered to be linked to the stronger immune defense activity found in cases of HPV-positive TSCC/BOTSCC. [3]

Pathophysiology

The tongue is vital organ that plays a critical role in speech and swallowing. During the pharyngeal phase of swallowing, food and liquid are propelled toward the oropharynx from the oral cavity by the tongue and muscles of mastication. The larynx is elevated, effectively compressing the epiglottis and supraglottic larynx against the base of the tongue and forcing food, liquid, and saliva into the hypopharynx and cervical esophagus. The anatomic location of the hypoglossal nerve within the base of the tongue puts it at risk from invasion or compression from malignant neoplasms at the primary site or metastatic disease in the neck.

The tongue plays another important function in speech along with larynx and pharynx, which are the primary organs that shape sound into intelligible speech. Any alteration in tongue and pharynx mobility is immediately recognized as altered speech. Any loss of tissue from the base of tongue area prevents a watertight closure with the larynx during the act of swallowing. This mismatch allows food and liquid to escape into the pharynx and larynx, altering the carefully choreographed swallowing reflex and often resulting in aspiration. Both neurologic impairment and alteration in the coordinated act of swallowing from malignancies in this area can have devastating affects on speech and swallowing ability.

Presentation

Dysphagia, odynophagia, sensation of a mass in the throat, or the presence of a mass in the neck are the most common clinical manifestations of the base of the tongue carcinoma. Patients also may complain of referred ear pain or hemoptysis. Delay in diagnosis is not uncommon because of the common and sometimes vague nature of symptoms and the relative inaccessibility of the base of the tongue to examination. Upon physical examination, a mass is usually palpable in this area. Extensive submucosal disease or a strong gag reflex may make palpation more difficult. Patients may have bilateral palpable adenopathy because of the midline location and the high propensity for regional lymph node metastases. Indirect or flexible fiberoptic laryngoscopy in the office is a useful adjunct to the physical examination.

Cutaneous metastases in base-of-tongue malignancies are uncommon, with the incidence of such metastases from head and neck cancers in general being less than 1%. Rahman et al reported on a male aged 55 years with treated squamous cell carcinoma of the tongue who presented with cutaneous metastatic nodules on the face and thigh. [4]

Relevant Anatomy

The base of the tongue is a subsite within the oropharynx and is bounded anterosuperiorly by the circumvallate papilla and the posterior aspect of the oral cavity, inferoposteriorly by the vallecula and lingual surface of epiglottis, and laterally by the glossoepiglottic folds.

Tongue development begins in the floor of the primitive oral cavity along with thyroid gland during the fourth embryonic week and develops from the region of the first 3-4 branchial arches. If the thyroid gland fails to migrate to the neck, it will result as a lingual thyroid. The tongue is eventually supplied by the lingual arteries and has complex capillary and venous systems.

Innervation of the tongue includes the lingual and hypoglossal nerves for sensation and movement and the sympathetic, parasympathetic, and special sensory fibers for salivation and taste ability. Tongue musculature includes both intrinsic and extrinsic muscles that contribute to the varied and subtle movements involved in speech and swallowing. Because the mucosa of the base of the tongue contains squamous epithelium, minor salivary glands, and lymphoid tissue, malignant neoplasms may arise from these tissues.

Contraindications

Surgical excision and other modalities of treatment for the malignant base of the tongue tumors are based on the patient's comorbidities and his or her ability to tolerate surgery, radiation, and chemotherapy. An obvious contraindication is patient refusal. Of primary consideration is the patient's ability to tolerate some degree of aspiration as a consequence of treatment. Underlying lung disease must be carefully assessed prior to surgery. Informed consent must be obtained prior to surgical intervention. Additionally, tumors may be considered inoperable because of their size (ie, extent) or location.

As is true with other sites of the head and neck, early-stage mucosal squamous cell carcinomas of the base of tongue can be treated adequately with radiotherapy or surgical resection. Chemoradiation has been advocated because of the morbidity associated with extensive surgical resection. Recent advances in surgical techniques, including endoscopic/video-assisted resection and vascular tissue grafts, have decreased the morbidity historically associated with tongue base surgery.


TREATMENT & MANAGEMENT


Medical Therapy

Treatment for patients with malignant neoplasms of the base of tongue depends on various factors. These factors include the clinical stage, histology, age, associated medical conditions, patient compliance, and potential adverse effects, complications, and outcomes. In order to allow the patient to make a reasonable and informed decision regarding treatment options, discuss these factors in detail before treatment.

Nonsurgical therapy for malignant neoplasms of the base of tongue has garnered long-standing interest because of the significant potential morbidity associated with surgical resection. Historically, chemotherapy for squamous cell carcinoma of the head and neck has had limited success. Increased efficacy with platinum-based drugs and newer drug regimens has been demonstrated in the last 20 years. Typically, these clinical protocols include radiotherapy as a major component of the treatment plan. Curative chemotherapy given as single-modality treatment for squamous cell carcinoma of the base of tongue, regardless of clinical stage, is uncommon and is not recommended at present.

As is true with other sites of the head and neck, early-stage mucosal squamous cell carcinomas can be treated adequately with radiotherapy or surgical resection. With increasing tumor stage, cure rates decrease significantly regardless of treatment. Chemoradiation protocols are generally associated with significant morbidity in terms of speech and swallowing which tend to improve over time. Tumor stage, overall treatment time, overall stage, and the addition of a neck dissection significantly influence locoregional control.

Base of tongue carcinomas can be managed with primary chemoradiotherapy, with elective planned neck dissection for patients with palpable lymph node metastases. Brachytherapy boost (20-30 Gy) to the base of the tongue has been used in the past but has largely been replaced by three dimensional radiotherapy treatment planning. Patients usually require gastrostomy and occasional tracheostomy. The addition of epidermal growth factor receptor (EGFR) inhibitors, including the monoclonal antibody (MAb) cetuximab, has show efficacy in the treatment of primary and recurrent squamous cell carcinomas of the head and neck. They may be promising modes of therapy for base of the tongue carcinoma in the future.

Surgical Therapy

Cancer of the base of tongue has traditionally been removed by resecting the mandible or by using a translabial transmandibular approach. These procedures involve significant morbidity, including lip and chin scars, malocclusion, compromised deglutition, chronic aspiration, and altered speech articulation. Therefore, alternative techniques have been described to minimize the morbidity associated with transmandibular tongue resection. [7]

As compared with transmandibular resection of tumors, transpharyngeal approaches show no measurable difference in terms of survival, tumor-free margins, speech, or swallowing; furthermore, transpharyngeal approaches result in less aspiration than transmandibular resection.

Many clinicians treat cancer of the base of tongue with combined partial glossectomy (avoiding laryngectomy if possible) and postoperative radiotherapy. [8The risk of aspiration is higher for older patients with large primary tumors, and total laryngectomy is sometimes required. Advances in the application of minimally invasive technologies to cancers of the base of tongue have resulted in similar locoregional control rates with the decreased morbidity of larger, open procedures.

Good locoregional control rates have been reported at the expense of functional outcome. In general, surgery with radiotherapy is associated with better survival and less locoregional failure but more systemic failure than nonoperative methods of treatment. Positive margins are associated with a higher local failure rate. The placement of permanent gastrostomy tubes and/or the performance of tracheostomy to prevent aspiration are not uncommon. Planned postoperative chemoradiotherapy is indicated for advanced disease.

Follow-up

Postoperative patients are monitored monthly for the first 12-18 months following therapy. Follow-up diagnostic imaging studies are recommended in the first 6 months, particularly in patients who undergo nonsurgical treatment.

For excellent patient education resources, visit eMedicineHealth's Cancer Center. Also, see eMedicineHealth's patient education article Cancer of the Mouth and Throat.

Complications

Treatment complications include chronic dysphagia, sepsis, anemia, fistula, osteoradionecrosis, aspiration, and even death.

Outcome and Prognosis

Historically, patients with advanced-stage disease have been treated with surgical resection and postoperative radiotherapy.

Considering all stages, locoregional control rates approach 70-85% versus 50-75% with stage 4 disease following partial glossectomy, neck dissection, and postoperative radiotherapy. Overall survival rates range from 50-65%, with improved survival with early-stage disease. Even in the presence of advanced-stage disease, the mandible and larynx can be preserved in 80% of patients.

Patients with positive surgical margins are at high risk of locoregional failure and death from disease. Among patients with positive or close margins, postoperative radiotherapy doses of 60 Gy or more achieve excellent long-term local control rates. Complications for this approach include pharyngocutaneous fistula and chronic aspiration. Long-term functional outcome data demonstrate decreasing function with increasing T stage following surgical resection. The prevalence rates of regional and distant failure are approximately 20% and 30%, respectively. The actuarial incidence rate of a second primary malignancy of the upper aerodigestive tract is approximately 35% at 5 years.

In an effort to decrease the alteration in speech and swallowing function associated with extensive surgical resection of the base of the tongue, external radiotherapy alone or in combination with brachytherapy and/or neck dissection has been used as a treatment strategy. The best local control rates at 5 years with external radiotherapy alone are, for T1, 96%; for T2, 91%; for T3, 81%; and for T4, 38%.

A study by Kawaguchi et al indicated that external-beam radiotherapy can effectively treat stage T1-T3 squamous cell carcinoma of the base of the tongue. The study involved 26 patients who underwent the treatment, with the 3-year overall survival rate found to be 69% and 3-year local control for T1,  T2, T3, and T4 tumors reported to be 100%, 86%, 100%, and 20%, respectively. Three-year regional control for patients with N0, N1, N2a, N2b, N2c, and N3 lymph node involvement was 100%, 100%, 100%, 83%, 75%, and 0%, respectively. Treatment also included concurrent or neoadjuvant chemotherapy for 11 patients with advanced loco-regional disease and two or three cycles of concurrent intra-arterial cisplatin for four T3 patients and one T2 patient. [9]

Brachytherapy alone is effective for lesions smaller than 4 cm, but extensive lesions have reported local recurrence rates of as high as 50-60%. Improved local control rates approaching 80% can be achieved with the combination of external and implant radiation for T1-3 lesions.

The addition of a planned neck dissection for patients with clinically evident regional lymph node metastases offers statistically significant improved regional control (80-90%) and disease-specific survival. A brachytherapy boost (20-30 Gy) to the base of the tongue can be performed at the same anesthesia level used for the neck dissection with temporary tracheostomy.

The addition of chemotherapy to the management of advanced base of tongue carcinoma is ongoing, and the results from this treatment option are not widely reported in the literature. The 5-year disease-specific and absolute survival rates of 50-65% are comparable with surgical resection. Most recurrences are evident within the first 2 years following treatment. Complications of radiotherapy include lost of taste/saliva, tissue necrosis, and osteoradionecrosis of the mandible.

Improved quality-of-life data have been reported from selected patients treated with radiotherapy for carcinoma of the tongue base, although no prospective, randomized, or case-matched controlled studies are available in the literature. Advancing T stage is associated with decreased quality-of-life scores regardless of treatment modality. Of all head and neck subsites, treatment of base of tongue cancer has the greatest impact on speech and swallowing function and on quality of life. [10The addition of neck dissection to primary radiotherapy for tongue base cancer has no impact on posttreatment quality of life.

A study by Bersani et al indicated that patients with HPV-positive tonsillar or base-of-tongue squamous cell carcinoma tend to have a worse prognosis when FGFR3 mutations are present. [11]

Future and Controversies

Management of base of tongue cancer remains difficult because of the complex anatomic structure. A variety of new techniques have become available for treatment, including gene therapy and new chemotherapeutic agents. These advances in treatment have garnered great interest in an effort to control this complex anatomic site and thus reduce morbidity and mortality.

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