Oral Cavity and Oropharyngeal Cancer: Etiology, Diagnosis and Staging

Robert S. Julian, DDS, MD; Brian M. Woo, DDS, MD; and Eric C. Rabey, DDS

ABSTRACT

Background: The objective of this review is to examine the etiology, screening, diagnosis and staging for oral cavity and oropharyngeal cancer.

Types of studies reviewed: Textbooks, review articles and large institution databases and guidelines were used in this review as appropriate. Case studies and smaller retrospective studies applied in specific and more controversial areas. Current phase 3 clinical trials and their reports were used in reviewing very recent developments.

Results: Smoking, alcohol, viruses and genetic predisposition are the main etiologic factors responsible for oral cavity and oropharyngeal cancer. Screening by dental health care professionals can save lives through early detection, and biopsy remains the mainstay of establishing a diagnosis. Oral cavity cancer staging includes depth of invasion and even a small tumor with doi > 5mm is considered T2. Oropharyngeal cancers are staged separately from cancer of the oral cavity and separated into (HPV) p16 positive and p16 negative given the drastically improved survival for the p16 positive group (70% five years versus 50% five years for p16 negative).

Practical implications: Dental health care professionals should routinely perform oral cancer screening exams. Early detection is paramount but even advanced p16 positive oropharyngeal tumors of the soft palate or tonsillar pillar may be quite treatable given favorable responses to radiation and chemotherapy. Survival is greatly improved when oral cavity cancers are treated before cervical lymph node involvement.

Key words: Oral cavity, oropharyngeal, carcinoma, NCCN, p16, depth of invasion, cervical lymphadenopathy

AUTHORS

Robert S. Julian, DDS, MD, is the chairman and program director of the department of oral and maxillofacial surgery at Community Medical Centers/UCSF-Fresno.

Brian M. Woo, DDS, MD, is the program director of the head and neck and microvascular surgery fellowship at Community Medical Centers/ UCSF-Fresno.

Eric C. Rabey, DDS, is a third-year resident in the department of oral and maxillofacial surgery at UCSF-Fresno.

Conflict of Interest Disclosure for all authors: None reported.

Cancer is caused by alterations in the genetic code and gene expression via carcinogens, viruses and inherited genetic predisposition. It is the second leading cause of death in the U.S. overall after heart disease for ages 60–70. Oral cavity (OC) and oropharyngeal (OP) cancers affect nearly 500,000 individuals worldwide. It is imperative that dental health care professionals understand the etiology, diagnosis and treatment of oral cavity and oropharyngeal cancer. The overall five-year survival rate is improving and is now at 65% compared to 50% 30 years ago. This improved survival relates mainly to surgical factors including microvascular reconstruction, clearer surgical indications for elective neck dissection, and more liberal treatment of the contralateral neck. Combined chemoradiation, more effective radiation therapy with intensity modulated radiation therapy, targeted therapy and, more recently, immunotherapy have all contributed to this improvement as well. Tumor behavior for all head and neck squamous cell carcinomas includes local invasion, lymphatic spread and late distant metastasis (lungs, bone). Recently, the depth of invasion (DOI) has been found to have a major impact on prognosis in oral cavity cancer where, for example, a T1 tumor (< 2 cm) with DOI > 5 mm is now considered T2 = Stage II, thus mandating combined therapy for best outcomes. Most oropharyngeal cancers are HPV p16+ and imbue a better prognosis based on very favorable responses to radiation therapy. This fact makes screening by dentists and dental hygienists even more important than ever given early detection of a soft palate or tonsillar-based carcinoma can lead to very favorable outcomes. In this article, we review the etiology, diagnosis and staging of oral cavity and oropharyngeal cancer. The following article reviews treatment including surgery, radiation and systemic therapy. Systemic therapy includes cytotoxic chemotherapy, targeted therapy (cetuximab) as of 2006, and immunotherapy (anti PD-1 nivolumab) for recurrent/metastatic disease after failed chemotherapy as of 2016 and primary systemic therapy (anti PD-1 pembrolizumab) as of 2019. Both targeted therapy and immunotherapy are rapidly evolving treatment modalities that may well dramatically change our overall approach to treatment in the near future.

Anatomic Site: Oral Cavity vs. Oropharynx

The National Comprehensive Cancer Network (NCCN) further delineates head and neck cancer sites based on analysis of the Surveillance, Epidemiology and End Results (SEER) program of the National Cancer Institute division of the National Institutes of Health (NIH) based data through application of meaningful site differential outcome measurements from clinical trials and high-level oncologic publications. Accordingly, head and neck cancer conditions and/or sites can be independently staged and treated ( FIGURE 1).

Etiology

Cancer is a genetic malady in which a cell or clonal group of cells have lost their normal control on cell division caused by alterations in functional genetic code and gene expression via carcinogens, viruses and genetic predisposition. OC/OP squamous cell carcinoma (SCCA) is a multifactorial disease in which environmental, genetic and/or epigenetic (changes in the expression of genes and not actual changes in the genetic code) factors are involved in its etiology (TABLE 1). Cancer forms when proto-oncogenes (e.g., Ras) that function to regulate cellular division (mitosis) and/or tumor suppressor genes (e.g., p53) that function to regulate programmed cell death (apoptosis) become dysregulated or nonfunctional. In looking at populations with a high prevalence of OC/OP SCCA, etiologic inferences beyond just risk factors can be made. Genetic predisposition is an important determinant of nearly any cancer and the risk for OC/OP cancer is clearly increased with some rare inheritable conditions such as Fanconi anemia, dyskeratosis congenita and Bloom syndrome. [8] Oral cavity (OC) cancer occurrence has a high prevalence in developing countries and is the most common cancer in India and Pakistan. Certain populations in Pakistan demonstrate a high incidence of oral cavity cancer and have been found to have specific genetic alterations. It has been generally well established that external carcinogenic factors (tobacco, HPV) cause cancer by inducing DNA damage that leads to activation of proto-oncogenes like Ras or inactivating tumor suppressor genes such as p53 ( FIGURE 2). These environmental factors interact with the genetic code expression pathways and lead to cancer in patients with genetic predisposition and also in less susceptible genes when the carcinogenic effect is profound enough. 9 Genomically speaking, p53 mutations are found in most cancers as specific tumor suppressor gene mutations. For oral cavity carcinomas, mutant p53 positive rates have been found to correlate negatively with prognosis. [10–13] Epigenetic effects of carcinogens complicate the search for cause and effect when only analyzing the DNA nucleotide sequences in tumor cell populations. Epigenetic alterations refer to changes in gene expression that are not attributable to actual base changes in the DNA sequence, rather they relate to changes in chromatin complexed histone proteins, non-messenger RNA and other non-sequence related changes in DNA. Importantly, most “risk factors” likely exert their carcinogenic effects through epigenetic conditions as opposed to DNA sequence mutagenic mechanisms. Epigenetic alterations can be passed down through clonal cell line (tumor) replication and have a major role in the pathogenesis of cancer. Inherited susceptible genes have an important role in development of oral cavity and oropharyngeal cancer as well. Expression of this genetic predisposition to oral and oropharyngeal cancer requires environmental carcinogenic exposure in most cases. [14]

Therefore, carcinogenesis involves the following complex interplay of variables:

■ Somatic cell line genetic changes (mutations).

■ Epigenetic changes (altered DNA, histone protein and mediated silencing RNA complexes).

■ Inherited genetic susceptibility.

Epidemiology

Cancer is the second leading cause of death in the United States overall after heart disease and the leading cause for ages 60–79. Oral cavity (OC) and oropharyngeal (OP) squamous cell carcinoma (SCCA) combined (OC/OP SCCA) account for 2.1% of all cancer deaths and affects nearly half a million people worldwide. The American Cancer Society estimates that in the U.S. approximately 53,260 people will be diagnosed with oral cavity or oropharyngeal cancer in 2020, and an estimated 10,750 people will not survive. These cancers are more than twice as common in men, found equally in Blacks and whites and are the eighth most common cancer among men. [15–19] The average age of diagnosis is 62 and 25% of patients are younger than 55. The overall five-year survival rate for OC/OP cancer is 65%. The rate is lower — 48% — for Blacks as compared to 66% for whites. Overall, the five-year survival rate is approximately 80% for early stage (I, II), 65% for stage III and 39% for stage IV with only one-third of cases diagnosed early at stage I or II. It is now well-established that the survival rate is better for patients with p16+ OP cancer compared to HPV negative OP or OC cancer. [20] In 2017, the American Joint Committee on Cancer (AJCC) officially published a separate staging protocol for OC and OP carcinomas of the head and neck. This difference is based on notable differences in response to various treatments. Although the overall prevalence is steadily increasing in Western countries, there is improved prognosis seen in patients with p16+ HPV related oropharyngeal carcinoma. [21,22] Oral cavity cancer can also be found to be p16+ in up to 13% of cases, but this has never been shown to correlate with a more favorable prognosis. [23–25] Additionally, there is a disturbing trend of young patients with lateral tongue cancer (oral cavity) with higher possibility of a more aggressive type of squamous cell carcinoma that needs further elucidation. This condition was identified in 2008 and is considered to be of possible non-p16 HPV viral etiology. Studies have demonstrated that most patients are female and that the recurrence rate is higher compared to the oral cancer that develops in the older “high risk” smoker/ETOH-abusing patient. [14,26] On a positive note, the overall survival rate for patients with OC/OP carcinoma has improved over the last 30 years, from 50% to 65% overall. [27]

Screening

Screening is the process by which a practitioner evaluates an asymptomatic patient to determine their risk for having a precancerous or outright cancerous lesion. This includes both the clinical exam and adjunctive screening aids.

Clinical signs of invasive cancer include induration, persistent ulceration, tissue proliferation or destruction, red and white color variegation, tissue fixation, progressive lesion growth, unexplained pain, dysesthesia, paresthesia or loss of function and cervical lymph node enlargement. [28] TABLE 2 details the exam process.

Diagnosis

Once the diagnosis of oral cavity or oropharyngeal carcinoma is determined from biopsy, [41,42] further workup completed using NCCN guidelines including imaging, lab work, clinical exam and a team-based approach to determine clinical staging (AJCC staging system) is performed (TABLE 3).

Staging

TNM Staging for Head and Neck Squamous Cell Carcinoma

OC/OP SCCA cancers are staged with the TNM classification where the clinical stage is based on information gained from physical exam, biopsy and imaging. Pathological staging adds the histopathological findings from the surgical specimen(s) to the clinical findings to further refine the stage and thus improves the prognostic predictive value. The discrepancy between cTNM and definitive pTNM staging may vary about 20% to 30%, leading to “stage migration.” Importantly, staging also can allow for proper assignment of patients to clinical trials, which essentially leads to direct improvements in outcomes through scientific method. Generally, for oral cavity SCCA, we use classic clinical staging at the beginning of treatment and then add pathological staging once surgery is performed and the histomorphologic, histochemical, molecular and genomic features are evaluated. The 8th edition AJCC Staging Manual was published in 2017 and integrated into NCCN guidelines in 2018. Both p16 (HPV) status and DOI were added to assist in more accurate staging of oropharyngeal and oral cavity cancers, respectively. In general, both OC and OP p16 negative cancers are stage I for lesions less than 2 cm, stage II for lesions 2 cm to 4 cm and stage III for lesions larger than 4 cm; any neck involvement no matter the tumor size is at least stage III. The staging guidelines for oral cavity SCCA have been further refined as they relate to T staging based on specific DOI. It is important to mention that DOI is not the same as tumor thickness. [43] Pathologists measure DOI by dropping a “plumb line” to the deepest point of the invasive tumor from the level of the basement membrane of the normal mucosa closest to the invasive tumor ( FIGURE 3). [44] Any DOI greater than 5 mm makes the tumor at least stage II. DOI over 10 mm indicates stage III or worse. DOI has been shown to be a more reliable prognostic indicator in the tongue, gingival, palate and floor of mouth cancers and less so with buccal mucosal and retromolar trigone subsites. [45]

P16+ OP cancers enjoy a clearly better prognosis compared with p16– and, in most cases, do not require surgical treatment beyond diagnosis and staging procedures. Therefore, separate staging systems have been established for HPV p16 positive and HPV p16 negative oropharyngeal carcinomas. The TNM system for HPV positive disease uses p16 positivity as a marker for HPV and, generally, advanced stage disease (III, IV) is defined only in cases of large primary tumors, extensive neck involvement and/or metastatic disease. [46]

Extranodal extension (ENE) of disease has also proven to be a meaningful negative prognostic indicator and has been added to the N staging of oral cavity and p16– (p16 negative) oropharyngeal cancers. Extranodal extension of disease, designated ENE (+), is generally identified during pathological N staging and similarly increases the stage of the nodal disease. Prognosis is also adversely affected by adverse features including close or positive margins as defined as a tumor within < 2 mm of the surgical margin, the presence of perineural and/or angiolymphatic invasion and/ or poorly differentiated tumor cells. These adverse features are indications for postoperative adjuvant treatment with radiation or chemoradiation therapy. Some clinicians would add continued tobacco and/or alcohol usage, rapid clinical growth, significant weight loss, low functional performance status, low hematologic lab values and lack of immunoantigen PD-L1 to the list of adverse features that do not officially change the stage. [47]

The use of PET/CT scans with 18- FDG radioisotope has proved to be useful in staging and surveillance of patients with head and neck tumors, providing accuracy rates of 80%. PET/CT is a very useful tool for detecting metastatic disease and few would contest its value over chest X-ray and random CT imaging in more advanced-stage settings. [48] The future holds the high likelihood that persistent, occult cervical nodal and/or metastatic disease can be detected through hematogenous circulating neoplastic cells and/or genomic markers. [49] Similarly, blood-based biologic assays are being developed that can detect the presence of circulating HPV-related DNA that could help diagnose recurrent or metastatic disease. The ramifications here for staging, prognosis and treatment for patients with HPV-related oropharyngeal cancer cannot be overstated. [50]

Staging leads to better outcomes through evidence-based treatment algorithms. In the next article, treatment will be reviewed and the importance of NCCN guidelines in determining the type and sequence of such treatment will be emphasized.

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THE CORRESPONDING AUTHOR, Robert S. Julian, DDS, MD, can be reached at rjulianiii@gmail.com.