Tongue Cancer

Etiology

The two most important independent risk factors for the development of tongue SCCA are heavy smoking and alcohol use.[3] Cigarette smoke contains known carcinogens, mainly nitrosamines, and polycyclic hydrocarbons. Alcohol metabolizes into acetaldehyde, which affects DNA repair.[4][5] Although less known, other important risk factors for the development of tongue cancer are betel use, radiation exposure, immunocompromised states, poor oral hygiene, and genetic factors. Human papillomavirus (HPV) infection is also known to play a role in tongue cancer. More recently, HPV-related carcinoma of the base of the tongue has been linked to an improved response to therapy and improved survival when compared to its HPV-negative counterpart.[6]

HPV-positive tumors of the base of tongue and oropharynx demonstrate such a great response to chemoradiation that experts in the field are exploring treatment de-intensification protocols to achieve cure while minimizing radiation side effects in these patients.[7] This association of HPV-positive oropharyngeal malignancy with an improved overall response has been studied in other sites of the head and neck, including the oral cavity. However, at this moment, a clear, robust correlation has not been found. Thus, contrary to carcinoma of the base of the tongue, the presence or absence of HPV does not appear to have treatment or prognostic implications in cancer of the oral (anterior two thirds) tongue. Although this is the case for the moment, the role of HPV infection in head and neck cancer is still a relatively new topic, and there is extensive ongoing research on the matter.

Of note, even before the risk factors for oral cavity malignancy were known, the concept of field cancerization was introduced by Danely P. Slaughter in 1953. Briefly, he observed that the “benign” epithelium surrounding the oral cavity malignant tumor specimens was abnormal. Microscopic examination of these apparently healthy margins revealed the presence of pre-cancerous or cancerous epithelial cellular changes. This introduced the now popularized idea of a multicentric origin of oral cancer rather than a single anomalous cell as the origin of the disease.[8] Although old and still relatively poorly understood, this concept of field cancerization is fundamental in understanding the aggressive and recurrent nature of oral tongue SCCA.

Epidemiology

Classically, tongue carcinoma is a condition of older males with a history of smoking and/or drinking alcohol. It has a slight male predominance, and the estimated frequency of disease varies widely with geographic location. In the past, there had been a steady decrease in the incidence of the disease, perhaps attributable to a worldwide overall decrease in smoking.[9] 

However, studies suggest an alarming increasing incidence of both oral and base of the tongue squamous cell carcinoma during the last decades, specifically in women and younger patients without the traditional risk factors of alcohol or tobacco use.[10] This is, in part, believed to be related to the dramatic spike in HPV-associated oropharyngeal squamous cell carcinoma.[11] Additional genetic etiologic factors that may help explain this changing demographic profile of the disease are under investigation.

Pathophysiology

A fundamental, albeit simplified concept in oncogenesis, is the overexpression of oncogenes and silencing of tumor suppressor genes. Environmental lifetime exposure of the oral cavity to known carcinogenic agents leads to DNA damage, and the accumulation of genetic events ultimately leads to the development of carcinoma. Despite numerous genetic alterations that have been linked with the development of cancer, we have only begun to scratch the surface in terms of understanding the relationship between these genetic changes and their relative importance in carcinogenesis. Two of the most well-established genetic alterations that lead to tongue cancer, and head and neck squamous cell carcinoma in general, are mutations in the tumor suppressor gene p53 and overexpression of epidermal growth factor receptor (EGFR) oncogene.[1]

Histopathology

The normal tongue epithelium is keratinized stratified squamous epithelium. Several epithelial changes are known to precede the development of invasive tongue carcinoma. These changes include increased mitosis, cellular pleomorphism, abnormal organization, and nuclear enlargement. Depending on the extent of these changes, these are classified from mild dysplasia to severe dysplasia/carcinoma in situ. Important pre-malignant lesions of the tongue that may harbor dysplastic changes are leukoplakia and erythroplakia. Leukoplakia manifests as whitish superficial plaques on the tongue surface that do not scrape off. It carries a low risk of malignant transformation, and simple excision by a variety of different methods is recommended. Erythroplakia, on the other hand, presents as red, erythematous plaques and has a high risk of malignancy, as it almost always harbors significant dysplastic changes and even carcinoma in situ. Wide local excision of these lesions is recommended.[12]

The invasion of the basement membrane is the hallmark of invasive carcinoma. The classic histopathologic features of invasive SCCA of the tongue are keratin deposits and nests of squamous cells with stromal fibrosis. Basaloid, papillary, spindle-cell, and verrucous are some of the histologic subtypes. However, except in the case of very poorly differentiated tumors, the above described prototypic histologic characteristics are fairly constant. Perineural invasion, lymphovascular invasion, and loss of differentiation are important histologic features, and their presence negatively impacts prognosis. In addition, the depth of invasion is the most important histologic finding in tongue SCCA, as it is the major determinant of prognosis and influences treatment selection, and risk of locoregional metastasis. Patients with malignant tongue tumors with more than 5-8 mm of depth of invasion have a relatively high risk of occult nodal micrometastatic disease despite a clinically and radiologically negative neck.[13][14]

Importantly, immunohistochemical staining for p16 protein is traditionally used as a surrogate marker for HPV-associated neoplasia.[15]

History and Physical

The evaluation should include a complete medical history with an emphasis on the head and neck region. Although the typical patient profile is changing, the patient is usually an older male with a history of smoking and/or alcohol use with a non-resolving oral cavity/tongue lesion. A history of accidental trauma to the region is often reported by patients. The most commonly reported symptom is localized pain. Dysphagia, weight loss, dysarthria, and odynophagia are also common. The patient’s ability to tolerate his usual diet should be addressed. Any history of recently noticed neck masses or nodules is also fundamental, as this may represent locoregional metastatic disease. Recent onset of unilateral nasal obstruction, unilateral hearing loss, or unilateral otalgia is worrisome for disease extension beyond the oral cavity to the pharyngeal region.

The examination should include a complete physical exam with an emphasis on the head and neck region. The neck should be thoroughly examined for palpable lymphadenopathy, especially the submental, submandibular, and jugulodigastric regions. An invasive examination of the patient’s oral cavity should be performed. This includes a detailed description of the lesion or mass in question, including but not limited to location, general appearance, color, shape, margins, and the presence or absence of ulceration. Thorough palpation should also be performed with the intention of assessing the regions of the tongue that are involved or spared by the tumor. Palpation of the base of the tongue/vallecula region is also encouraged, as it may reveal asymmetrically indurated or protruding areas. Several specific clinical signs and symptoms may offer insight into the extent of tumor extension.

Hypoglossal nerve or tongue muscle involvement may manifest as ipsilateral tongue deviation. Lingual nerve involvement may manifest as an altered sensation in the tongue. Inferior alveolar nerve involvement manifests as numbness in the chin, lower lip, and/or mandibular teeth and indicates more advanced disease. Lastly, an awake fiberoptic examination of the patient’s upper airway is also recommended, as the usual risk factors for oral cavity carcinoma are common to other head and neck sites. A flexible nasolaryngoscopy under local anesthesia excludes grossly suspicious pathology in the nasal cavity, nasopharynx, oropharynx, hypopharynx, and larynx.

Evaluation

In addition to the clinical examination, other studies are necessary to diagnose, characterize, and appropriately stage the disease. In the case of the tongue, lesions are usually readily accessible and, therefore, amenable to incisional biopsy or punch biopsy under local anesthesia in a clinic setting. In the case of the base of the tongue lesions, if not accessible trans-orally, tissue diagnosis may be obtained during flexible laryngoscopy or under direct visualization with general anesthesia. In the case of patients with gross neck lymphadenopathy, ultrasound-guided fine-needle aspiration (FNA) biopsy is also an option.

Computed tomography (CT) scan of the neck with intravenous contrast is also part of the diagnostic workup. This will provide information regarding tumor size, location, extension, and radiologic appearance of the draining neck lymph nodes. In the case of advanced disease at presentation, further imaging of the chest with a CT scan or whole-body positron emission tomography (PET)/CT is usually done to rule out distant metastatic spread of disease.

Treatment / Management

The management of tongue carcinoma is primarily surgical, with radiation also having an important role mainly in advanced disease, poor surgical candidates, unresectable disease, and importantly, as an adjuvant to surgery in some cases. Unless there is a clear contraindication for surgery or the tumor is unresectable, surgery should be offered as primary treatment for tongue squamous cell carcinoma. The ultimate goal of treatment is complete cure while minimizing therapy sequela and preserving functionality.  

In general, early-stage tongue carcinoma (T1 or T2) can be treated successfully with single-modality therapy, namely surgery or radiation. However, when long-term morbidity of treatment, cost, and other factors are considered, surgery is recommended upfront.

On the other hand, patients with advanced disease (T3 or T4) have a poor response to single-modality treatment. Two independent clinical trials found that postoperative adjuvant chemoradiation offered improved survival when compared to single-modality therapy in these patients.[16] Therefore, if feasible, surgery and postoperative chemoradiation would be the optimal treatment plan for a patient with advanced disease. Chemoradiation up-front typically offers poor locoregional control, negatively impacting prognosis, and frequently leads to more destructive salvage surgery without the possibility of adjuvant radiation. When indicated, the standard of care for radiation therapy doses in patients with oral cavity cancer range from 60-65Gy in 30-35 treatment fractions.

Surgical interventions range from simple wide local excision and primary closure in small tumors to composite resections of the tongue/floor of mouth/mandible in advanced tumors with the need for locoregional flaps or microvascular free flap reconstruction. Regardless of the extent of surgery required, several fundamental cancer surgery principles should be followed for the best oncologic outcomes. The primary tumor resection should include at least a 1cm margin of resection when possible. Intraoperative frozen sections should be sent to pathologically confirm disease-free margins. If a significant functional deficit is anticipated, reconstruction with free vascularized tissue (free flap) should be offered when available, as this offers optimal functional outcomes after surgery in terms of swallow and speech function. The radial forearm free flap and the anterolateral thigh free flap are the two most commonly used free flaps for tongue reconstruction. The fibula free flap is also commonly used when large resections are needed, and mandibular reconstruction is necessary. Although free flaps are the mainstay of reconstructive options, locoregional pedicled flaps are a viable alternative when free flap reconstruction is contraindicated, not available, or has failed. These include the submental island flap, latissimus dorsi pedicled flap, and the pectoralis major myocutaneous flap. When compared to free flaps, these have the advantage of shorter operative times, decreased donor site morbidity, and good reliability.

Regarding the base of tongue HPV-related squamous cell carcinoma, the treatment algorithm has completely shifted during the last decades. Trans-oral robotic surgery has a role mainly in early-stage disease, while advanced tumors in this region are usually treated with primary radiation and chemotherapy, given its excellent response.[6][15] This observation, while opposite to its HPV-negative counterpart, is well documented and supported in the literature and has led to research looking at de-intensifying treatment for this specific HPV-positive patient sub-group.[7](B2)

Management of the neck is essential, as recurrence or persistence of disease in the neck after primary therapy confers a poor prognosis. The tongue has a rich network of lymphatics that drain to neck levels I-III, which is the usual pattern of spread when these tumors metastasize. As stated before, the depth of invasion is a major prognostic indicator. Studies show that tongue tumors with anywhere between three and eight millimeters of the depth of invasion have up to a 40%-50% risk of occult nodal metastasis and up to 65% overall incidence of nodal metastasis.[17] Because without a complete histopathological analysis, the true depth of invasion of a tongue tumor cannot be determined, many head and neck oncologic surgeons argue that any malignant tongue lesion with grossly palpable depth to it will likely exceed this depth mark. With this in mind, the majority of patients that present with a primary tongue squamous cell carcinoma must be offered a neck dissection to pathologically rule out occult nodal metastasis (termed an elective neck dissection) or to surgically remove the clinically evident nodal disease. When there is no clinical or radiologic evidence of neck disease but an ipsilateral elective neck dissection is warranted, a selective dissection of levels I-III, also called a supraomohyoid neck dissection, is usually employed.[14] On the other hand, when there is gross evidence of neck disease either preoperatively or intraoperatively, an ipsilateral modified radical neck dissection is recommended.(A1)

Patients with pathologic confirmation of disease presence in the locoregional lymph nodes, most of the time, require additional treatment after surgery to achieve a cure. Usually, this consists of a combination of cisplatin-based chemotherapy and radiation. Positive surgical margins and pathologically confirmed extranodal extension of the disease are two absolute indications for adjuvant chemoradiation. Other indications for radiation therapy include advanced stage (T3 or T4) disease, close surgical margin, lymphovascular invasion, perineural invasion, and two or more positive neck lymph nodes. 

Immunotherapeutic agents, specifically tyrosine kinase inhibitors and PD-1 inhibitors, are now being used more frequently in combination with cisplatin-based chemotherapy or alone, and there is ongoing clinical research regarding their potential benefits in head and neck squamous cell carcinoma.

Patients with known distant metastatic spread of disease are not surgical candidates and are offered primary chemoradiation, chemotherapy, or immunotherapy.

Differential Diagnosis

• Squamous cell carcinoma
• Leukoplakia
• Carcinoma in situ
• Sarcoma
• Rhabdomyosarcoma
• Lymphoma
• Rhabdomyoma
• Neurofibroma
• Pyogenic granuloma
• Papilloma
• Vascular or lymphatic malformation
• Lingual thyroid
• Dermoid cyst
• Epidermoid cyst

Staging

Staging

The American Joint Committee on Cancer uses the TNM system for staging tumors of the head and neck region by the site. It was recently updated to incorporate the prognostic impact of the presence of extranodal extension. Accordingly, clinically evident extranodal extension upstages the N-stage of a tumor to N3b.[10][18]

T-stage is classified as follows:

• T0: No evidence of primary tumor
• Tis: Carcinoma in situ
• T1: Tumor 2cm or less with a depth of invasion (DOI) less than or equal to 5mm
• T2: Tumor 2cm or less with DOI more than 5mm OR tumor more than 2cm but less than or equal to 4cm
• T3: Tumor more than 2cm but less than or equal to 4cm with DOI more than 10mm OR tumor more than 4cm with DOI less than or equal to 10mm
• T4a: Tumor more than 4cm with DOI more than 10mm OR invades adjacent structures only (skin of the face, maxillary sinus, cortical bone of maxilla or mandible)
• T4b: Tumor invades masticator space, pterygoid plates, skull base, and/or encases the internal carotid artery. 

N-stage or clinical nodal stage is classified as follows:

• N0: No regional nodes metastasis.
• N1: Metastasis in a single ipsilateral lymph node 3cm or less in the greatest dimension - negative extranodal extension (ENE)
• N2a: Metastasis in a single ipsilateral lymph node more than 3cm but not larger than 6cm in the greatest dimension, negative ENE
• N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6cm in greatest dimension, negative ENE
• N2c: Metastasis in bilateral or contralateral lymph node(s), none more than 6cm in greatest dimension, negative ENE
• N3a: Metastasis in any lymph node more than 6cm in the greatest dimension, negative ENE
• N3b: Metastasis in a lymph node with clinically overt positive ENE

M-stage is classified as follows:

• MX: Distant metastasis cannot be assessed
• M0: No distant metastasis
• M1: Distant metastasis

Prognosis

A recent study using the Surveillance, Epidemiology, and End Results (SEER) database looked at the incidence and survival of oral tongue squamous cell carcinoma. They report that although the incidence is increasing for both oral tongue SCCA and oropharyngeal squamous cell carcinoma, survival has also significantly improved.[19] 

The study shows that from 1976 to 2015, oral tongue SCCA and oropharyngeal squamous cell carcinoma both showed the highest absolute increase in survival, with conditional survival of over 90% for both diseases independent of the treatment.

Complications

Complications of surgery are multiple and include bleeding, infection, and orocutaneous fistula. When a free or pedicled flap is employed, complications include donor site infection, bleeding, and partial or complete flap loss or infection. Depending on the extent of resection and adequacy of reconstruction, there may be function-related complications such as impaired speech, dysphagia, and odynophagia. A gastrostomy is frequently needed at the time of surgery if speech and swallow rehabilitation are anticipated to be problematic or prolonged. A tracheostomy is also frequently employed if significant oral cavity and pharyngeal airway edema are anticipated in the immediate postoperative period.

Radiation therapy complications include oral/pharyngeal mucositis, skin damage, cellulitis, dysgeusia, xerostomia, fibrosis, and oral mucosal neuropathy. One of the most troublesome complications of radiation therapy in this region is mandibular osteoradionecrosis (ORN). This may require surgical intervention for curettage, and in severe cases, segmental mandibulectomy of the affected region and reconstruction. Although hyperbaric oxygen therapy is sometimes given to treat mandibular ORN, some surgeons argue this may increase the probability of malignancy recurrence or may catalyze the growth of microscopic persistent disease. No high-level evidence studies to date have conclusively demonstrated this correlation, but anecdotal evidence exists, and the decision remains clinician-dependent.

Common radiation side effects in the neck region include post-radiation fibrosis, frozen neck, neuropathy, and hypothyroidism, among others. Symptomatic esophageal stenosis due to post-radiation fibrosis is not uncommon and may manifest even years after radiation therapy.

One of the most feared complications of advanced-stage head and neck cancer is carotid blowout. This usually presents with life-threatening hemorrhage and used to be almost uniformly fatal. However, mortality today is close to 60% due to major surgical and endovascular advances. Nonetheless, periprocedural morbidity is high and may include re-bleeding and stroke.