Oropharyngeal Squamous Cell Carcinoma

Etiology

The etiology of oropharyngeal carcinoma is broadly categorized into HPV-associated and non-HPV-associated carcinomas. 

HPV-associated oropharyngeal squamous cell carcinoma occurs in patients who have been infected with the human papillomavirus. Among the many types of human papillomavirus, HPV16 is the most common type found in oropharyngeal cancers [2]. 

Oral sex and open-mouthed kissing are the most common reasons for oral HPV infection [3].

On the other hand, smoking tobacco and alcohol consumption have been widely identified as the major risk factors for non-HPV-associated oropharyngeal carcinomas [4]. Other less common risk factors include a diet low in vegetables and fruits, betel quid chewing, poor nutrition, marijuana smoking, asbestos exposure, and certain genetic mutations such as P53 mutation and CDKN2A (p16) mutations [5][6][7].

Epidemiology

Oropharyngeal cancer is the sixth most common cancer worldwide [8]. HPV 16 is responsible for almost 90% of HPV-positive oropharyngeal cancers, and the prevalence is higher in males than females [9][10]. The presence of HPV-associated OPSCC is much higher in the tonsils and base of the tongue. HPV-associated OPSCC tends to occur in a younger population that smokes and drinks less; a higher percentage are males and report more oral sex partners [11].

Pathophysiology

In the case of HPV-associated OPSCC, the oral mucosa is exposed to the HPV infection, which persists and is not cleared. This persistence can lead to a precancerous lesion that may regress or not. If it does not, it will eventually progress to invasive OPSCC. Persistent HPV infections may progress to invasive cancer within ten years. However, the majority of these infections are cleared in one to two years [11].

Histopathology

In patients affected by oropharyngeal squamous cell carcinoma, the accumulation of genetic changes results in progression from mild and moderate dysplasia to severe dysplasia/carcinoma in situ. However, in most HPV-positive oropharyngeal cancers, the tumor originates deep inside the tonsillar crypt epithelium. This is why these cancers are neither visible on inspection nor noticeable by superficial brush biopsy [12].

History and Physical

Patients with oropharyngeal cancer can present with a variety of symptoms depending on the location of the tumor. The most common presentations include persistent sore throat, dysphagia, odynophagia, dysarthria, presence of a lump in the neck, and otalgia. In addition, the patients may also complain of voice changes (hoarseness), unexplained weight loss, and hematemesis.

Physical examination of the oropharynx may reveal either an ulcer or a red or white patch on the base or posterior one-third of the tongue, posterior and lateral pharyngeal walls, soft palate, or tonsils.

Evaluation

A comprehensive protocol of investigations should be employed if there is a clinical suspicion of oropharyngeal cancer. These include:

Radiography

Plain radiography is done for dental assessment and bony invasion, but it is of limited value.

Ultrasonography

It is recommended to perform ultrasound with or without needle biopsy in all the patients reporting a neck lump because of its excellent accuracy of staging the nodal disease if employed by an experienced operator [13].

Magnetic Resonance Imaging (MRI)

MRI provides excellent visualization of the tumor infiltrating the soft tissue, is not distorted by the metallic dental restorations, and is considered optimal for the staging of the primary tumor [13].

Computed Tomography (CT)

A CT scan can not only be utilized to estimate the size of the tumor but also assist in deciding on surgical removal of the tumor and its spread to the lymph nodes in the neck or lower mandible.

Positron Emission Tomography (PET)

PET combined with CT-scan should be employed in cases where conventional cross-sectional imaging fails to identify primary tumors [13]. PET scan is also employed for the assessment and detection of the recurrence of the primary tumors [13].

Endoscopy and Laryngoscopy

Endoscopy and laryngoscopy are performed after using an anesthetic spray or general anesthesia to visualize and examine the suspicious sites in detail and take the biopsy sample.

Biopsy

A biopsy of the suspicious area is performed to make a definitive diagnosis. The type of biopsy i.e., a fine-needle aspiration biopsy using a fine needle to collect a sample or oral brush biopsy, which is a newer, simpler, and more convenient method employing a small brush to collect the sample during routine dental examinations, depends upon the location of the cancer.

Human Papillomavirus Testing (HPV testing)

The American Society of Clinical Oncology recommends that HPV testing should be done on all newly diagnosed oropharyngeal cancers. This is done by polymerase chain reaction, which detects the HPV DNA.

Treatment / Management

Surgery and radiotherapy are the two principle modalities used in the treatment of patients suffering from oropharyngeal cancers. Surgery or radiotherapy can be used primarily if the tumor is small and has not advanced. However, if the disease has advanced or the tumor is larger, then a combination of surgery and radiotherapy is used. Implementing minimally invasive procedures, such as transoral laser microsurgery (TLM), as a first-line treatment modality for oropharyngeal carcinomas have been found safe and efficacious [14].

Other resection methods include transoral robotic surgery, transoral video laryngoscopic surgery, transoral ultrasound surgery, and endoscopic laryngopharyngeal surgery [15].

Following surgery, survival is increased in patients undergoing induction chemotherapy or concomitant chemoradiotherapy. In the case of unresectable tumors, concomitant cisplatin-based chemotherapy, along with radiotherapy, is considered the gold standard and has shown to be better in terms of improving survival as compared to radiotherapy alone [16]. However, some studies have shown a parallel prognostic profile of concomitant use of carboplatin/paclitaxel in stage III and IV non-metastatic oropharyngeal carcinomas but with fewer adverse effects [17].(A1)

Differential Diagnosis

The conditions with presentations similar to oropharyngeal squamous cell carcinoma and which need to be excluded include:

• Actinic keratosis
• Erythroplasia
• Lichen planus
• Leukoplakias
• Lichenoid lesions
• Oral candidiasis
• Tonsillitis
• Traumatic lesions

Staging

The American Joint Committee on Cancer (AJCC) has defined the staging of oropharyngeal cancer. This follows a TNM staging system where T relates to the extent of the primary tumor, N indicates the involvement of regional lymph nodes, and M specifies the distant metastasis. In their 8th edition of the staging manual, AJCC has modified the staging system being used for staging oropharyngeal cancer with the addition of depth of invasion (DOI) of the primary tumor as a modification to the T category and extranodal extension (ENE) to upstage node-positive oropharyngeal squamous cell carcinoma [18]. The new version of classification is more complex than its previous one, but it is better in terms of stratifying survival of oropharyngeal squamous cell carcinoma patients by stage [19].

Staging of Human Papillomavirus-Associated (p16-Positive) Oropharyngeal Cancer

Primary Tumor (T)

• T0-Primary tumor cannot be assessed
• T1-Tumor smaller than 2cm in greatest dimension
• T2-Tumor larger than 2cm but smaller than 4cm in greatest dimension
• T3-Tumor larger than 4cm or extension to the lingual surface of epiglottis
• T4-Moderately advanced local disease; tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond
• T4a-Moderately advanced local disease; tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
• T4b-Very advanced local disease; tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

Regional Lymph Nodes (N)

• NX-Regional lymph nodes cannot be assessed
• pN0-No regional lymph node metastasis
• pN1-Metastasis in 4 or fewer lymph nodes
• pN2-Metastasis in more than four lymph nodes

Metastasis (M)

• M0-No distant metastasis
• M1-Distant metastasis

Clinical Prognostic Groups for HPV-Mediated (p16+) Oropharyngeal Cancer (cTNM):

Stage I

• T0–T2N0M0
• T0–T2N1M0

Stage II

• T0–T2N2M0
• T3N0–N2M0

Stage III

• T0–T3N3M0
• T4N0–N3M0

Stage IV

• Any T/Any N M1

Pathological Prognostic Groups for HPV-Mediated (p16+) Oropharyngeal Cancer (pTNM):

Stage I

• T0–T2N0M0
• T0–T2N1M0

Stage II

• T0–T2N2M0
• T3–T4N0M0
• T3–T4N1M0

Stage III

• T3–T4N2M0

Stage IV

• Any T/Any N M1

Non-Human Papillomavirus-Associated (p16-Negative) Oropharyngeal Cancer

Primary tumor (T)

• Tx-Primary tumor cannot be assessed
• Tis-Carcinoma in situ
• T1-Tumor 2 cm or smaller in greatest dimension
• T2-Tumor larger than 2 cm but not larger than 4 cm in greatest dimension
• T3-Tumor larger than 4 cm in greatest dimension or extension to the lingual surface of epiglottis
• T4-Moderately advanced or very advanced local disease
• T4a-Moderately advanced local disease; tumor invades the larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible
• T4b-Very advanced local disease; tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

Regional lymph nodes (N)

• N0-No regional lymph node metastasis
• N1-Metastasis in a single ipsilateral lymph node, 3 cm or smaller in greatest dimension and ENE-negative
• N2-Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE-negative; or metastases in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE-negative; or metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE-negative
• N2a-Metastasis in a single ipsilateral lymph node larger than 3 cm but not larger than 6 cm in greatest dimension and ENE-negative
• N2b-Metastasis in multiple ipsilateral lymph nodes, none larger than 6 cm in greatest dimension and ENE-negative
• N2c-Metastasis in bilateral or contralateral lymph nodes, none larger than 6 cm in greatest dimension and ENE-negative
• N3-Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative; or metastasis in any lymph node(s) and clinically overt ENE-positive
• N3a-Metastasis in a lymph node larger than 6 cm in greatest dimension and ENE-negative
• N3b-Metastasis in any node(s) and clinically overt ENE-positive

Metastasis 

• M0-No distant metastasis
• M1-Distant metastasis

Prognostic Stage Groups for Clinical and Pathologic Non–HPV-Mediated (p16 -) Oropharyngeal Cancer

Stage 0

• TisN0M0

Stage I

• T1N0M0

Stage II

• T2N0M0

Stage III

• T3N0M0
• T1N1M0
• T2N1M0
• T3N1M0

Stage IVA

• T4aN0M0
• T4aN1M0
• T1N2M0
• T2N2M0
• T3N2M0
• T4aN2M0

Stage IVB

• AnyTN3M0
• T4bAnyNM0

Stage IVC

• AnyTAnyNM1

Prognosis

The overall five-year survival rate in oropharyngeal carcinoma is around 60%. However, the prognosis varies depending on the etiology. In comparison to HPV-negative oropharyngeal squamous cell carcinoma, HPV-positive oropharyngeal carcinoma shows a better prognosis and increased response to the treatment.[20] The higher survival with HPV-associated cancer is because of favorable tumor biology and a healthier and younger patient population.

Complications

Treatment modalities employed in oropharyngeal cancers can result in several complications, such as:

• Oral mucositis
• Tissue fibrosis
• Hyposalivation
• Infection
• Osteoradionecrosis
• Morbidity from jaw resection, disfigurement, and loss of function can further reduce quality of life.[21]