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Oropharyngeal Squamous Cell Carcinoma

By

Bradley A. Schiff

, MD, Montefiore Medical Center, The University Hospital of Albert Einstein College of Medicine

Last full review/revision Oct 2019| Content last modified Oct 2019
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Oropharyngeal squamous cell carcinoma refers to cancer of the tonsil, base and posterior one third of the tongue, soft palate, and posterior and lateral pharyngeal walls. Squamous cell carcinoma comprises over 95% of oropharyngeal cancers. Tobacco and alcohol are major risk factors, but human papillomavirus (HPV) now causes most of these tumors. Symptoms include sore throat and painful and/or difficult swallowing. Treatment is with radiation, chemotherapy, or both, but primary surgery has begun to be used more often. Survival rate is much higher in HPV-positive patients.

In the US in 2018, there were an expected > 17,500 new cases of oropharyngeal cancer. Although the incidence of oropharyngeal cancer is increasing, its cure rates are also improving. The male:female ratio is > 2.7:1.

HPV type 16 causes 60% of oropharyngeal cancers, and patients have become younger (median age 57 years, and bimodal peaks at 30 years and 55 years) as HPV infection has emerged as an etiology. The number of sexual partners and frequency of oral sex are important risk factors. The risk of developing oropharyngeal cancer is 16 times higher in HPV-positive patients. In Europe and North America, HPV infection accounts for about 70 to 80% of oropharyngeal cancers.

As with most head and neck cancers, non-HPV related oropharyngeal cancer is more common among older men, with a median age of 61. Tobacco and alcohol remain important risk factors for oropharyngeal cancer. Patients who smoke more than 1.5 packs/day have about a 3-fold increased risk of cancer, and patients who drink 4 or more drinks/day have about a 7-fold increased risk. People who both drink and smoke heavily have 30 times the risk of developing oropharyngeal cancer.

Symptoms and Signs

Oropharyngeal cancer symptoms vary slightly depending on the subsite but typically patients present with sore throat, dysphagia, odynophagia, dysarthria, and otalgia. A neck mass, often cystic, is a common presenting symptom of patients with oropharyngeal cancer. Because the symptoms of oropharyngeal cancer mimic those of common upper respiratory infections, it often takes many months before patients are referred to a specialist.

Diagnosis

  • Laryngoscopy

  • Operative endoscopy and biopsy

  • Imaging tests for staging

All patients should undergo a direct laryngoscopy and biopsy before starting treatment to evaluate the primary lesion and to look for second primary lesions. Patients with confirmed carcinoma typically have neck CT with contrast, and most clinicians also do PET of the neck and chest.

HPV DNA positivity, determined by polymerase chain reaction, is diagnostic of HPV. Immunohistochemical staining for p16 (an intracellular protein present in most HPV-positive cancers but also in few HPV-negative cancers) is a commonly used surrogate to determine HPV association.

The staging criteria of HPV-associated oropharyngeal cancer correspond to the frequent lymph node involvement and better prognosis of these tumors versus HPV-negative tumors. (See tables Pathologic Staging of HPV-Associated Oropharyngeal Cancer and Pathologic Staging of Non-HPV-Associated Oropharyngeal Cancer.)

Table
icon

Pathologic Staging of HPV-Associated Oropharyngeal Cancer*

Stage

Tumor (Maximum Penetration)†

Regional Lymph Node Metastasis‡

Distant Metastasis§

I

T0-2

pN0-1

M0

II

T0-2

pN2

M0

T3-4

pN0-1

M0

III

T0-4

pN2

M0

IV

Any T

Any pN

M1

* HPV association as indicated by p16 positivity

† TNM classification: T0 = no primary tumor identified; T1 = tumor 2 cm in greatest dimension; T2 = tumor > 2 cm but ≤ 4 cm; T3 = tumor > 4 cm or invading the lingual surface of the epiglottis; T4 = tumor invading the larynx, extrinsic tongue muscles, medial pterygoid, the hard palate, mandible, or beyond

‡ pN0 = none; pN1 = metastasis in ≤ 4 lymph nodes; pN2 = metastasis to > 4 lymph nodes

§ M0 = none; M1 = present

Data from  Amin MB, Edge S, Greene F, Byrd DR, et al: American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition. New York, Springer, 2017; AJCC Cancer Staging Form Supplement, 2018.

Table
icon

Pathologic Staging of Non-HPV–Associated Oropharyngeal Cancer*

Stage

Tumor (Maximum Penetration)†

Regional Lymph Node Metastasis‡

Distant Metastasis§

I

T1

pN0

M0

II

T2

pN0

M0

III

T3

pN0

M0

T1-3

pN1

M0

IVA

T4a

pN0-1

M0

T1-4a

pN2

M0

IVB

T4b

Any pN

M0

Any T

pN3

M0

IVC

Any T

Any pN

M1

* HPV association as indicated by p16 positivity.

† Definition of Primary Tumor (T) in Oropharynx (p16-)

Tis

Carcinoma in situ

T1

Tumor ≤ 2 cm in greatest dimension

T2

Tumor > 2 cm but ≤ 4 cm

T3

Tumor > 4 cm OR extension to lingual surface of epiglottis

T4a

Moderately advanced local disease; tumor invades the larynx, extrinsic tongue muscles, medial pterygoid, hard palate, or mandible (Note: mucosal extension to lingual surface of epiglottis from primary tumors of the base of the tongue and vallecula does not constitute invasion of the larynx)

T4b

Very advanced local disease; tumor invades lateral pterygoid muscle, pterygoid plates, lateral nasopharynx, or skull base or encases carotid artery

† Definition of Primary Tumor (T) in Hypopharynx

Tis

Carcinoma in situ

T1

Tumor limited to one subsite of hypopharynx and/or ≤ 2 cm

T2

Tumor invades more than one subsite of hypopharynx or an adjacent site, OR is > 2 cm but ≤ 4 cm without fixation of hemilarynx

T3

Tumor > 4 cm OR with fixation of hemilarynx or extension to esophagus

T4a

Moderately advanced local disease; tumor invades thyroid/cricoid cartilage, hyoid bone, thyroid gland, or central compartment soft tissue (including prelaryngeal strap muscles and subcantaneous fat)

T4b

Very advanced local disease; tumor invades prevertebral fascia, encases carotid artery, or involves mediastinal structures

‡ Definition of Pathologic N (pN) — Oropharynx (p16-) and Hypopharynx

N0

No regional lymph node metastasis

N1

Metastasis to one ipsilateral lymph node, ≤ 3 cm, no extranodal extension

N2

Metastasis in one ipsilateral node ≤ 3 cm with extranodal extension OR > 3 cm but ≤ 6 cm and no extranodal extension; OR in multiple ipsilateral nodes, < 6 cm and no extranodal extension; OR in bilateral or contralateral lymph nodes ≤ 6 cm and no extranodal extension

N3

Metastasis in a lymph node > 6 cm and no extranodal extension; OR in one ipsilateral node > 3 cm with extranodal extension; OR in multiple ipsilateral, contralateral, or bilateral nodes, any with extranodal extension

§ Definition of Distant Metastasis (M) — Oropharynx (p16-) and Hypopharynx

M0

No distant metastasis

M1

Distant metastasis

Data from  Amin MB, Edge S, Greene F, Byrd DR, et al: American Joint Committee on Cancer (AJCC) Cancer Staging Manual, 8th edition. New York, Springer, 2017; AJCC Cancer Staging Form Supplement, 2018.

Prognosis

The overall 5-year survival rate is about 60%. However, prognosis varies with the cause. Patients who are HPV-positive have a 5-year survival of > 75% (and a 3-year survival of almost 90%), whereas HPV-negative patients have a 5-year survival of < 50%. The higher survival with HPV-positive cancer is due to a favorable tumor biology and a younger, healthier patient population. High expression of p16 appears to improve prognosis for both HPV-positive and HPV-negative oropharyngeal tumors.

Treatment

  • Surgery, increasingly, transoral laser microsurgery

  • Radiation therapy, with or without chemotherapy

Surgery is increasingly being used as primary treatment of oropharyngeal cancer. Transoral laser microsurgery (TLM) is increasingly being used to resect tumors of the tonsil and base of tongue endoscopically, avoiding the morbidity of open surgery. Transoral robotic surgery (TORS) is an increasingly popular means of treating select oropharyngeal lesions. In TORS, a surgical robot with multiple adaptable arms is controlled by a surgeon at a console. The articulating arms of the robot and an endoscopic camera are inserted through the patient's mouth (which is held open by a retractor). The robotic procedure provides better visualization of structures and causes less surgical morbidity compared to open surgery. However, the indications for using TORS are not yet well defined. When TORS is used on patients with more advanced tumors, postoperative radiation or chemoradiation is often done.

Radiation therapy, sometimes combined with chemotherapy (chemoradiation), can be used as primary therapy or postoperatively. Traditionally, radiation has been used for early-stage cancers and chemoradiation has been used for advanced cancers. Intensity-modulated radiation therapy (IMRT) has increasingly been used as a way to spare surrounding tissue and decrease long-term adverse effects.

Because the oropharynx is rich in lymphatics, cervical lymph node metastasis is common and must be considered in all patients with oropharyngeal cancer. If a cervical lymph node metastasis does not resolve after radiation or chemoradiation, post-treatment neck dissection is warranted.

Treatment of oropharyngeal carcinoma is the same regardless of the HPV status of the tumor. Deintensified treatment of HPV-associated tumors is being studied to see if less harmful treatments can achieve successful disease management.

Key Points

  • Most cases of oropharyngeal cancer are caused by human papillomavirus (HPV) infection.

  • Symptoms of oropharyngeal cancer depend on the location of the tumor; a neck mass is a common finding.

  • Diagnose oropharyngeal cancer with laryngoscopy, operative endoscopy, and imaging studies for staging.

  • Treat oropharyngeal cancer with transoral laser microsurgery or transoral robotic surgery when possible as alternatives to open surgery.

  • Use radiation therapy, sometimes combined with chemotherapy for advanced cancers, as primary treatment or postoperatively.

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