Human papillomavirus-positive oropharyngeal cancer (HPV-positive OPC or HPV+OPC), is a cancer (squamous cell carcinoma) of the throat caused by the human papillomavirus type 16 virus (HPV16). In the past, cancer of the oropharynx (throat) was associated with the use of alcohol or tobacco or both, but the majority of cases are now associated with the HPV virus, acquired by having oral contact with the genitals (oral-genital sex) of a person who has a genital HPV infection. Risk factors include having a large number of sexual partners, a history of oral-genital sex or anal–oral sex, having a female partner with a history of either an abnormal Pap smear or cervical dysplasia, having chronic periodontitis, and, among men, younger age at first intercourse and a history of genital warts. HPV-positive OPC is considered a separate disease from HPV-negative oropharyngeal cancer (also called HPV negative-OPC and HPV-OPC).

HPV-positive OPC presents in one of four ways: as an asymptomatic abnormality in the mouth found by the patient or a health professional such as a dentist; with local symptoms such as pain or infection at the site of the tumor; with difficulties of speech, swallowing, and/or breathing; or as a swelling in the neck if the cancer has spread to local lymph nodes. Detection of a tumour suppressor protein, known as p16, is commonly used to diagnose an HPV-associated OPC. The extent of disease is described in the standard cancer staging system, using the AJCC TNM system, based on the T stage (size and extent of tumor), N stage (extent of involvement of regional lymph nodes) and M stage (whether there is spread of the disease outside the region or not), and combined into an overall stage from I–IV. In 2016, a separate staging system was developed for HPV+OPC, distinct from HPV-OPC.

Whereas most head and neck cancers have been declining as smoking rates have declined, HPV-positive OPC has been increasing. Compared to HPV-OPC patients, HPV-positive patients tend to be younger, have a higher socioeconomic status and are less likely to smoke. In addition, they tend to have smaller tumours, but are more likely to have involvement of the cervical lymph nodes. In the United States and other countries, the number of cases of oropharyngeal cancer has been increasing steadily, with the incidence of HPV-positive OPC increasing faster than the decline in HPV-negative OPC. The increase is seen particularly in young men in developed countries, and HPV-positive OPC now accounts for the majority of all OPC cases. Efforts are being made to reduce the incidence of HPV-positive OPC by introducing vaccination that includes HPV types 16 and 18, found in 95% of these cancers, before exposure to the virus. Early data suggest a reduction in infection rates.

In the past, the treatment of OPC was radical surgery, with an approach through the neck and splitting of the jaw bone, which resulted in morbidity and poor survival rates. Later, radiotherapy with or without the addition of chemotherapy, provided a less disfiguring alternative, but with comparable poor outcomes. Now, newer minimally invasive surgical techniques through the mouth have improved outcomes; in high-risk cases, this surgery is often followed by radiation and/or chemotherapy. In the absence of high-quality evidence regarding which treatment provides the best outcomes, management decisions are often based on one or more of the following: technical factors, likely functional loss, and patient preference. The presence of HPV in the tumour is associated with a better response to treatment and a better outcome, independent of the treatment methods used, and a nearly 60% reduced risk of dying from the cancer. Most recurrence occurs locally and within the first year after treatment. The use of tobacco decreases the chances of survival.

Signs and symptoms HPV+OPC may presents in one of four ways:

As an asymptomatic abnormality in the mouth found by the patient or a health professional such as a dentist. This may include painless masses, discolorations or patches along the tongue, jaw or throat, Local symptoms such as pain or infection at the site of the tumor, persistent sore throat, dull aches in the ear (this is from referred pain from a primary tumor), asymmetric tonsil swelling, spitting up blood. Difficulties of speech, swallowing, and/or breathing. This can include persistent coughing, hoarseness of the voice, difficulty with opening the mouth, or difficulty with moving the tongue. Swelling in the neck (if the cancer has spread to lymph nodes). These may be accompanied by more general symptoms such as loss of appetite, weight loss, and weakness.

Patients may also note discolorations of the mouth such as leukoplakia (white or gray areas that remain unchanged when scraped), erythroplakia (raised red areas that bleed if scraped), or erythroleukoplakia (white and red patches) that may represent precancerous lesions and should be assessed.

Cause

Most mucosal squamous cell head and neck cancers, including oropharyngeal cancer (OPC), have historically been attributed to tobacco and alcohol use. However, this pattern has changed considerably since the 1980s. It was realised that some cancers occur in the absence of these risk factors, and an association between human papillomavirus (HPV) and various squamous cell cancers, including OPC, was first described in 1983. Since then, both molecular and epidemiological evidence has been accumulating, with the International Agency for Research on Cancer (IARC) stating that high-risk HPV types 16 and 18 are carcinogenic in humans in 1995, and in 2007 that HPV was a cause for oral cancers. Human papillomavirus (HPV)-positive cancer (HPV+OPC) incidence has been increasing while HPV-negative (HPV-OPC) cancer incidence is declining, a trend that is estimated to rise further in coming years. Since there are marked differences in clinical presentation and treatment relative to HPV status, HPV+OPC is now viewed as a distinct biologic and clinical condition.

Human HPV has long been implicated in the pathogenesis of several anogenital cancers including those of the anus, vulva, vagina, cervix, and penis. In 2007, it was also implicated by both molecular and epidemiological evidence in cancers arising outside of the anogenital tract, namely oral cancers. HPV infection is common among healthy individuals and is acquired through oral sex. Although less data is available, the prevalence of HPV infection is at least as common among men as among women, with 2004 estimates of about 27% among US women aged 14–59.

HPV oral infection precedes the development of HPV+OPC. Slight injuries in the mucous membrane serve as an entry gate for HPV, which thus works into the basal layer of the epithelium. People testing positive for HPV type 16 virus (HPV16) oral infection have a 14 times increased risk of developing HPV+OPC. Immunosuppression seems to be an increased risk factor for HPV+OPC. Individuals with TGF-β1 genetic variations, specially T869C, are more likely to have HPV16+OPC. TGF-β1 plays an important role in controlling the immune system. In 1993 it was noted that patients with human papillomavirus (HPV)-associated anogenital cancers had a 4-fold increased risk of tonsillar squamous-cell carcinoma. Although evidence suggests that HPV16 is the main cause of OPC in humans not exposed to smoking and alcohol, the degree to which tobacco and/or alcohol use may contribute to increasing the risk of HPV+OPC has not always been clear but it appears that both smoking and HPV infection are independent and additive risk factors for developing OPC. The connection between HPV-infection and oropharyngeal cancer is stronger in regions of lymphoepithelial tissue (base of tongue and palatine tonsils) than in regions of stratified squamous epithelium (soft palate and uvula). Human herpesvirus-8 infection can potentiate the effects of HPV-16.

Risk factors Risk factors include a high number of sexual partners (25% increase >= 6 partners), a history of oral-genital sex (125% >= 4 partners), or anal–oral sex, a female partner with a history of either an abnormal Pap smear or cervical dysplasia, chronic periodontitis, and, among men, decreasing age at first intercourse and history of genital warts.

Pathology

Cancers of the oropharynx primarily arise in lingual and palatine tonsil lymphoid tissue that is lined by respiratory squamous mucosal epithelium, which may be invaginated within the lymphoid tissue. Therefore, the tumour first arises in hidden crypts. OPC is graded based on the degree of squamous and keratin differentiation into well, moderate, or poorly (high) differentiated grades. Other pathological features include the presence of finger-like invasion, perineural invasion, depth of invasion, and distance of the tumour from resection margins. Phenotypic variants include basaloid squamous carcinoma, a high-grade form (see Chung Fig. 35-3(C) and illustration here). They are most commonly non-keratinising. HPV+OPC also differs from HPV-OPC in being focal rather than multifocal and not being associated with pre-malignant dysplasia. HPV+OPC patients are therefore at less risk of developing other malignancies in the head and neck region, unlike other head and neck primary tumours that may have associated second neoplasms, that may occur at the same time (synchronous) or a distant time (metachronous), both within the head and neck region or more distantly. This suggests that the oncogenic alterations produced by the virus are spatially limited rather than related to a field defect.

Anatomy

The oropharynx, at the back of the mouth, forms a circle and includes the base of the tongue (posterior third) below, the tonsils on each side, and the soft palate above, together with the walls of the pharynx, including the anterior epiglottis, epiglottic valleculae and branchial cleft at its base. The oropharynx is one of three divisions of the interior of the pharynx based on their relation to adjacent structures (nasal pharynx (nasopharynx), oral pharynx (oropharynx) and laryngeal pharynx (laryngopharynx – also referred to as the hypopharynx), from top to bottom). The pharynx is a semicircular fibromuscular tube joining the nasal cavities above to the larynx (voice box) and oesophagus (gullet), below, where the larynx is situated in front of the oesophagus.

The oropharynx lies between the mouth (oral cavity) in the front and the laryngopharynx below, which separates it from the larynx. The upper limit of the oropharynx is marked by the soft palate and its lower limit by the epiglottis and root of the tongue. The oropharynx communicates with the mouth, in front through what is known as the oropharyngeal isthmus, or isthmus of the fauces. The isthmus (i.e., connection) is formed above by the soft palate, below by the posterior third of the tongue, and at the sides by the palatoglossal arches. The posterior third of the tongue or tongue base contains numerous follicles of lymphatic tissue that form the lingual tonsils. Adjacent to the tongue base, the lingual surface of the epiglottis, which curves forward, is attached to the tongue by median and lateral glossoepiglottic folds. The folds form small troughs known as the epiglottic valleculae. The lateral walls are marked by two vertical pillars on each side, the pillars of the fauces, or palatoglossal arches. More properly they are separately named the palatoglossal arch anteriorly and the palatopharyngeal arch posteriorly. The anterior arch is named from the palatoglossal muscle within, running from the soft palate to the tongue (glossus), while the posterior arch similarly contains the palatopharyngeal muscle running from the soft palate to the lateral pharynx. Between the arches lies a triangular space, the tonsillar fossa in which lies the palatine tonsil, another lymphoid organ.