Malignant Neoplasms of the Oral Cavity

Molecular Biology

Tumor development represents the loss of multiple signaling mechanisms that regulate the control of cell growth. Advances in molecular biology have allowed for the identification of many of the mutations associated with this transformation. Contemporary molecular analysis of tumors is providing insight into the processes of malignant transformation and tumor progression.

Human papilloma virus (HPV) is an epitheliotropic virus detected to varying degrees within samples of oral cavity SCC. The overall incidence of oral HPV infection in the United States, based on 2009/2010 survey data, was 6.9% in men and women aged 14 to 69 years. Oral HPV subtype 16 infection was 1.0%. The prevalence of oral HPV was significantly higher in men and was linked to the number of sexual partners in the patient history and the number of cigarettes smoked per day. For nonoropharyngeal carcinomas, no significant data are available to suggest that a survival advantage or improved prognosis can be experienced at other head and neck primary sites found to be HPV positive.

The neutrophil-to-lymphocyte ratio (NLR), considered a marker reflecting of host inflammation status, was examined in over 1200 patients with oral squamous carcinoma. Researchers found that patients with a high NLR had a worse OS but were potentially better responders to systemic chemotherapy.

Chen et al. demonstrated a negative correlation between strong Rap-1A, a subgroup of the Ras family of G-proteins, expression and overall and 5-year disease-specific survival (DSS) for patients with oral cavity carcinoma. Rap-1A expression, modulated by Aurora-A, may be one of the mechanisms responsible for metastasis and was advocated by the authors as a potential marker for identifying patients with aggressive presentations of oral cavity carcinoma.

In 57 patients with oral squamous carcinoma, Metin et al. noted statistically significant lower mean serum levels of paraoxonase 1 than in healthy controls. Paraoxonase 1 is an enzyme with activity against carcinogenic liposoluble radicals and levels are noted to be decreased in patients who smoke.

MTBP is an MDM2-binding protein that can alter p53/MDM2 homeostasis, and it correlates with Ki-67 expression; it likely has both oncogenic and tumor-suppressing properties. Vlatkovic and colleagues generated and validated an antibody to MTBP and utilized it in evaluating 198 head and neck SCC samples. They revealed that the biomarker combination of p53 positivity and low MDM2 levels were significantly associated with reduced OS. In patients with this phenotype, the authors also found that loss of MTBP expression was associated with markedly reduced OS.

MicroRNA-137 plays an essential role in cell cycle control at the G1/S phase checkpoint. Langevin and colleagues detected aberrant microRNA-137 promoter methylation in 16.4% (11/67) of head and neck SCC specimens (oral cavity, 4; oropharynx, 5; larynx, 2). This finding was seen more frequently in individuals who ate fewer daily servings of fruit and vegetables and was significantly associated with a lower OS rate.

In a unique study examining the contents of patients’ postoperative drain fluid, Lassig et al. found that the matrix metalloproteinase 1 (MMP-1), MMP-3, and soluble FMS-like tyrosine kinase-1 (sFlt-1) levels in the drains of 20 patients, sampled during their postoperative hospitalization, correlated with patient's subsequent clinical course and was predictive of future recurrence. In the six patients who developed recurrence the MMP-1, MMP-3, and sFlt-1 drain fluid levels were significantly lower than in those patients who were recurrence-free at 1 year.

High perinodal monocarboxylate transporter (MCT) 4, normally a transporter of pyruvate and lactate out of cells, has been associated with worse survival in patients within regionally metastatic oral cavity carcinoma and may be a future marker for identifying patients with aggressive disease compromising DFS. MCT 4 is upregulated in the setting of hypoxia and inflammation and is found with cancer-associated fibroblasts.

A new approach in cancer therapy includes the development of the DNA damage response (DDR) kinase inhibitors. This class of drugs has the capacity to increase the efficacy of conventional DNA-damaging therapies by inactivating a cell's DNA repair pathway activation. DDR inhibitor-9, an example of this class of drugs, has demonstrated the ability to enhance the toxicity of etoposide and ionizing radiation in preclinical trials. Additional investigation into the role of this line of therapy is ongoing in clinical trials.

In a study of whole-exome sequencing, Agrawal and associates identified six gene mutations— TP53, CDKN2A, PIK3CA, HRAS, FBXW7, and NOTCH1 —in multiple specimens that were associated with the development of head and neck SCC. Findings from this study suggested that NOTCH1 functions as an important tumor suppressor gene in head and neck SCC. Overexpression of mutant TP53 has been associated with carcinogenesis at multiple sites. Point mutations in TP53 have been reported in up to 45% of head and neck squamous carcinomas. Koch et al. noted that TP53 mutation is a key event in the malignant transformation of more than 50% of head and neck SCCs in smokers.

The Akt receptor has been correlated with the histologic progression of oral premalignant lesions to carcinoma. Massarelli and colleagues demonstrated that phosphorylated Akt, when highly expressed, is associated with recurrence and shorter DFS independent of a patient's overall staging.

Apolipoprotein E (APOE), which is normally involved in cellular cholesterol efflux, is believed to have a significant role in tumor invasion with oral cavity squamous carcinoma. Jayakar et al. demonstrated with siRNA knockdown of specific genes in an oral carcinoma cell line that the reduction of APOE was associated with a reduction in tumor invasion. Additionally, levels of activator protein-1 were also reduced, as APOE was negatively affected, which resulted in a downstream impact on MMP-7 expression. The authors concluded that high levels of APOE expression are associated with a more aggressive and invasive phenotype of oral carcinoma.

DF3/MUC1 overexpression is associated with regional metastatic spread and is considered an indicator of poor prognosis. DF3/MUC1 protein, which functions as a oncogene, is not expressed in normal squamous epithelium and when expressed in cancer cells is typically at the invasive front of the tumor.

Habitual betel quid use that results in the development of an oral malignancy has been shown to have an association with tissue inhibitor of metalloproteinase-3 (TIMP3) rs9862 polymorphisms. TIMP3 normally binds extracellular matrix and can suppress tumor growth and migration and loss of TIMP3 expression is associated with a poor prognosis in the setting of cancer.

Arteriovenous Anatomy

The arterial supply to the oral cavity includes multiple contributions from the external carotid artery. The lingual artery provides the majority of the vascular supply to the oral tongue and tongue base. Identification of the artery within the neck requires the exposure of the floor of the submandibular region. The artery is found deep to the hyoglossus muscle and requires the division of the muscle for maximal exposure. Superficial to the hyoglossus and deep to the mylohyoid muscle are the hypoglossal nerve and lingual veins ( Fig. 91.2A and B ). An understanding of this relationship can aid in the localization of the artery when necessary for microvascular reconstruction or selective ligation. The ranine vein, which closely approximates the nerve in this region, is prone to injury during dissection and necessitates care if hypoglossal nerve injury is to be avoided.

The hard palate blood supply is derived from the greater palatine and the superior alveolar arteries. After branching off the descending palatine artery at the greater palatine foramen in the region medial to the second maxillary molar, the artery runs anteromedially within the soft tissue of the hard palate ( Fig. 91.3 ). The venous drainage is to the pterygoid plexus and subsequently to the internal jugular venous system. The superior alveolar arteries—anterior, middle, and posterior—arise as terminal branches after the transition of the internal maxillary artery to the sphenopalatine artery at the pterygopalatine fossa. These arteries provide blood supply to the maxillary gingiva, alveolar ridge, and dentition.

The facial artery crosses over the lateral aspect of the mandible approximately 1 cm anterior to the ascending ramus and courses toward the oral commissure, where it gives rise to the labial arteries. These paired vessels are readily apparent during lip-splitting procedures and anastomose in the midline to create a vascular ring.

The primary vascular supply to the mandible and the lower dentition is from the inferior alveolar artery. Blood supply from the mandibular periosteum becomes more important with advancing age. The inferior alveolar artery, vein, and nerve enter the mandibular foramen along the medial aspect of the ramus of the mandible. Before their entry into the foramen, both the nerve and artery send off branches that extend anteriorly to supply the mylohyoid muscle.

The posterior floor of the mouth and retromolar trigone has an arterial supply and venous drainage similar to that of the anterior tonsillar region. The ascending pharyngeal and lesser palatine vessels contribute to the vascularity that may be encountered with surgical procedures at this site.

Subsites of the Oral Cavity

Lips

The lips represent a transition from external skin to internal mucous membrane that occurs at the vermilion border. The underlying musculature of the orbicularis oris, innervated by the facial nerve, creates a circumferential ring that allows the mouth to have a sphincter-like function. The sensation for the upper lip is supplied by the infraorbital nerve (cranial nerve [CN] V2), whereas sensation for the lower lip is provided by the mental nerve (CN V3). Lymphatics from both the upper and lower lips drain primarily to the submandibular lymph nodes, yet midline lower-lip lesions may present with submental lymphatic spread. In addition, the upper lip may drain to preauricular, infraparotid, and perifacial lymph nodes ( Fig. 91.4 ).

Retromolar Trigone

This region is represented by the mucosa that overlies the ascending ramus of the mandible toward the coronoid process. It is continuous with the buccal mucosa laterally and the anterior tonsillar pillar medially. The superior extent is the maxillary tuberosity, and the anterior margin is the posterior aspect of the second mandibular molar. The same considerations that were true for alveolar lesions apply for this anatomic site, given the close approximation of mucosa to the underlying mandible. Lower-lip paresthesia may be an indication of perineural invasion (PNI) at the level of the mandibular foramen with invasive lesions. The sensation to this region is provided by the lesser palatine nerve and branches of the glossopharyngeal nerve. It is the presence of CN IX that causes patients with lesions in this area to present with referred otalgia. The primary lymphatic drainage for this region is to the upper cervical-jugulodigastric nodal group ( Fig. 91.5 ).

Premalignant Lesions

Leukoplakia is a white, mucosal-based keratotic plaque that cannot be wiped free from the underlying tissue. It is a clinical term without a histologic definition. Leukoplakic lesions may demonstrate parakeratosis, hyperkeratosis, and acanthosis on histologic examination. Paradoxically, an increased risk of malignant transformation of leukoplakic lesions is seen more commonly in nonsmokers. If a leukoplakic lesion is associated with an area of dysplasia (in 1% to 3% of all lesions), the risk of progression to malignancy increases sevenfold. Bánóczy followed 670 patients with leukoplakic lesions for 3 years and noted that 31% of lesions disappeared, 30% improved, 25% experienced no change, and 7.5% demonstrated progressive enlargement. Only 6% of lesions in the series underwent subsequent progression to SCC.

Erythroplakia is a red mucosal plaque that does not arise from any obvious mechanical cause and persists after removal of possible etiologic factors. The associated risk for progression to carcinoma is significantly greater than for leukoplakic lesions. Shafer and Waldron resected erythroplakic lesions in 58 patients and found that 91% had evidence of dysplasia (mild, moderate, or severe) or carcinoma in situ within specimens.

Telomere dysfunction is associated with oncogenesis in many cancer types. Short leukocyte telomere length (LTL) in peripheral blood leukocytes has been to found to be associated with the likelihood of progression of normal oral mucosa to premalignancy and subsequent carcinoma. Bau et al. reported on 174 patients with oral premalignant lesions in which LTL was assessed. Of the 23 who eventually progressed to oral carcinoma, the mean LTL of this subgroup was noted as shorter than the “non-progressors.” This finding was noted to be independent of tobacco and alcohol use histories.

The CCND1 gene, located at 11q13, encodes the protein cyclin D1, which is critical to the regulation of the G1 phase of the cell cycle. In a study by Ye and associates, single-nucleotide polymorphism analysis showed a CCND1 P241P polymorphism to be associated with an increased risk of developing oral premalignant lesions when expressed as a variant homozygous genotype. “Ever smokers” with a common homozygote cyclin-dependent kinase 6 (CDK6) genotype and a variant allele–carrying genotype of p27 5′UTR were noted to have the highest percentage of oral premalignant lesion cases (75%) in the study. It is the combination of CDK6/CDK4 and CCND1 that regulates the activity of the RB1 tumor suppressor gene.

OSF is most frequently encountered in individuals who chew betel nut and is associated with poor oral hygiene, advanced periodontitis, and the potential development of oral carcinoma. With betel nut use, the buccal mucosa becomes thickened and the entire cheek becomes fibrotic, which results in trismus. Resection of tumors that arise in the buccal mucosa in patients with submucosal fibrosis can be challenging, and reconstruction can be complicated by wound breakdown. Chaturvedi and colleagues reviewed 371 patients from India with oral cancer, 112 of whom had a history of prior OSF in association with habitual betel nut use. The most common oral cancer subsite was the buccal mucosa in more than 50% of cases, followed by the oral tongue. Patients with oral cancer associated with OSF were typically younger men (mean age, 45.11 years) with better histologic differentiation, lower rates of regional metastasis, and a lower likelihood of extranodal spread when compared with their counterparts who had oral carcinoma without OSF. Patients with a history of betel chewing also require long-term follow-up because of the incidence of multicentric primary tumor presentation and recurrent new primary presentations over time. In a study of 1836 patients in an endemic betel-chewing region the incidence of 2nd, 3rd, and 4th primary oral cavity cancer over a 10-year period was 34.6%, 8.6%, and 2.3%, respectively. In patients with their fourth primary lesion, surgery remained the treatment of choice and offered a 3-year OS of 57%.

Although uncommon, oral lichen planus, in particular the erosive subtype, has the potential for malignant degeneration to oral carcinoma. The etiology of lichen planus is unknown. T-cell lymphocyte infiltration is noted in this lesion, yet the development of lichen planus is not typically associated with immunologic disorders. The typical patient is a female in the fourth decade of life. Lesions demonstrate a lacy pattern of white striae; atrophic lesions are red and smooth, whereas erosive lesions have depressed margins and are covered by a layer of fibrinous exudate.

Dysplasia is the abnormal maturation and differentiation of mucosal epithelium with features of an increased nuclear/cytoplasmic ratio, loss of polarity, increased mitoses, and loss of intercellular adherence. Dysplasia is graded as mild, moderate, or severe. Techniques that have been described to assist in margin assessment at the time of surgery include the use of tissue fluorescence with indocyanine green conjugated to a chlorotoxin (known as BLZ-100). Baik et al. demonstrated that subcutaneous injection of BLZ-100 had good sensitivity (95%) and specificity (91%) in discerning between a tumor and nontumor interface and aiding the identification of high- versus low-risk dysplasia in a hamster dysplasia model.

Squamous Cell Carcinoma and Squamous Cell Carcinoma Variants

Several variants of SCC exist and may be encountered in the oral cavity. The spindle cell variant of SCC, also known as sarcomatoid SCC , is typically diagnosed in the oral cavity, oropharynx, or larynx. It demonstrates a heterogeneous appearance with spindle-shaped cells interwoven with squamous cells. The diagnosis of sarcomatoid SCC is confirmed by immunohistochemical staining for keratin markers. It has a high risk of locoregional recurrence; however, OS is similar to that of conventional SCC. Data suggest that this variant of squamous carcinoma may be more responsive to primary surgical management than to chemoradiation.

Basaloid carcinoma has traditionally been considered a high-grade variant with a predilection for regional and distant metastasis; however, when clinical staging is matched, the 5-year DFS associated for oral basaloid carcinoma is similar to that of poorly differentiated and moderately differentiated oral carcinomas.

Radiation-induced squamous cell carcinomas (RISCCs) have reported median latency to development of 13 years. The prognosis is worse than for de novo development of squamous carcinoma yet less likely to be associated with regional metastasis. In a review of 34 cases by Tay et al. from Singapore General Hospital, the oral cavity was the most common site of presentation for RISCC in the head and neck. The 2-year DSS was 48.8% for RISCC versus 71.2% for de novo development of carcinoma.

With verrucous carcinoma, a thick zone of nonproliferation and nonkeratinizing cells distinguishes this entity histologically. The typical presentation is on the buccal mucosa (50%). It is considered a low-grade variant of SCC and is exophytic in appearance, has the capacity to invade locally, yet carries a low risk of regional spread. Traditionally, this lesion has been considered to be “radioresistant,” and surgical excision has been the treatment of choice. Verrucous hyperplasia is a histologic finding that appears similar to verrucous carcinoma yet differs from the malignant form in that it does not invade the lamina propria.

Other Pathologies

Additional pathologies to consider in the differential diagnosis of oral cavity lesions include pyogenic granuloma, pseudoepitheliomatous hyperplasia, lymphoma, minor salivary gland tumors, and sarcomas.

The most common malignant minor salivary gland tumors (MMSGTs) of the oral cavity are adenoid cystic carcinoma, mucoepidermoid carcinoma (low and high grade), polymorphous low-grade adenocarcinoma, and adenocarcinoma. All of these may present as a painless, slow-growing, submucosal mass at the junction of the hard and soft palate. Adenoid cystic carcinoma can manifest with PNI that can extend within the greater palatine nerve to the pterygopalatine ganglion and can ascend to the skull base.

Sarcomas of the oral cavity usually arise in the mandible or hard palate and include osteosarcoma ( Fig. 91.6 ), chondrosarcoma, malignant fibrous histiocytoma, rhabdomyosarcoma, and liposarcoma. Patel and colleagues demonstrated a 5-year local control rate for head and neck osteosarcoma of 78% and OS of 70%. Patients presented with osteosarcoma within the maxilla and mandible with approximately equal frequency, 45% to 41%, respectively. Surgery was performed in all patients and neoadjuvant chemotherapy was used in 68%. Positive surgical margins were found to be the only significant negative predictor with respect to DSS.

Malignant tumors of odontogenic origin, although uncommon, can present a challenge for diagnosis and treatment. Agar et al. performed a SEER database review from 1973 to 2011 and identified 308 cases. Of the three main categories of lesion, malignant ameloblastoma was the most common (59.7%), followed by malignant odontogenic tumors (35.4%) and ameloblastic fibrosarcoma (2.9%). The 5-year survival for the entire cohort of patients was 81% with patients diagnosed with malignant ameloblastoma having the best mean survival (237 months). Malignant odontogenic tumors encompassed a group of diagnoses including odontogenic carcinoma, primary intraosseous carcinoma, odontogenic sarcoma, and ameloblastic carcinoma. For all lesion types, patients with tumors that were 41 mm or greater in size experienced the lowest survival rate.

Typically presenting in children, Ewing sarcoma has a 1% to 2% incidence of presentation in the facial skeleton. The most common site of diagnosis in the mandible is at the ramus. Treatment typically entails wide surgical excision in combination with chemotherapy. If possible, radiation is avoided to minimize the impact on subsequent facial growth.

Kaposi sarcoma is the most common HIV-associated malignancy. The head and neck is the site for two-thirds of all presentations and may present as a pigmented mucosal nodule and is most commonly seen on the hard palate. Despite being considered an incurable disorder, a variety of treatment options may offer remission for limited disease. Local therapies include radiation, intralesional injection of chemotherapy, cryotherapy, laser therapy, and surgical excision. Systemic chemotherapy is reserved for advanced disease.

Desmoplastic neurotrophic melanoma is a nonpigmented lesion of the lower lip that presents as an ulceration and has a high incidence for PNI. Mucosal melanoma typically presents as a pigmented lesion of the oral cavity that may be associated with preexisting melanosis. Pigmented lesions of the oral cavity should be considered for biopsy to exclude this diagnosis.