HPV-positive oropharyngeal cancer

Pathology

HPV-positive oropharyngeal cancer starts in the hidden folds of the tonsils and the base of the tongue, where the lining of the throat dips into the immune tissue. Doctors classify these tumors by how much they resemble normal squamous cells and how much keratin they produce, giving grades of well, moderate, or poorly differentiated. Key features also include how deeply the tumor invades, whether it spreads along nerves, and its distance from the surgical edge.

A high-grade variant called basaloid squamous carcinoma can occur, but most cases are non-keratinising. Unlike HPV-negative forms, HPV-positive tumors appear as a single spot rather than multiple sites and do not arise from pre-cancerous dysplasia. This means patients with HPV-positive disease face a lower chance of developing other head and neck cancers, whether at the same time or later. The virus seems to cause damage only in a confined area, not across a broad field of tissue.

Staging

Staging generally uses the UICC/AJCC TNM system, based on clinical examination, diagnostic imaging, and pathology. On imaging, involved lymph nodes may appear cystic, a characteristic of HPV-positive OPC. Standard AJCC TNM staging, such as the seventh edition, had no prognostic value for HPV-positive OPC, so the eighth edition (2016) incorporated a distinct staging system for this disease. Tumour stage: T0 (no primary identified), T1 (≤2 cm), T2 (2–4 cm), T3 (>4 cm or extension to lingual surface of epiglottis), T4 (moderately advanced local disease invading larynx, extrinsic tongue muscle, medial pterygoid, hard palate, mandible, or beyond).

Nodal stage: Nx (cannot be assessed), N0 (none involved), N1 (one or more ipsilateral nodes <6 cm), N2 (contralateral or bilateral nodes <6 cm), N3 (nodes >6 cm). Clinical stage: Stage I (T0N1, T1–2N0–1), Stage II (T0N2, T1–3N2, T3N0–2), Stage III (T0–3N3, T4N0–3), Stage IV (any metastases).

Treatment

Treatment goals are to optimise survival and locoregional disease control while preventing metastasis and minimising short- and long-term morbidity. No high-quality Level I evidence from prospective clinical trials exists specifically for HPV-positive OPC, so guidelines rely on data from OPC treatment in general and from retrospective unplanned subset analyses. Traditional treatment includes radiotherapy, chemotherapy, other systemic treatments, and surgical resection, with radiotherapy being the mainstay in most cases.

A pooled analysis suggested comparable disease control between radiation and surgery but higher complication rates with surgery plus or minus radiation. Ideally a single modality is preferred, as triple modality is associated with much more toxicity. Differences in response between HPV-positive and HPV-negative OPC may relate to how cellular growth-regulatory pathways are altered: in HPV-positive OPC, the E6 and E7 oncogenes render p53 and pRb pathways dormant, leaving potential for reactivation, whereas the mutant p53 in HPV-negative OPC is associated with treatment resistance. The tumour microenvironment also plays a role, with radiation increasing host immune response to viral antigens.

Prognosis

Since the 1990s, doctors have known that HPV inside a tumor is a key predictor of survival. HPV-positive oropharyngeal cancer responds much better to treatment and leads to longer survival than HPV-negative cancer, no matter what therapy is used or how advanced the stage is. Only about ten percent of this survival gap comes from favorable patient traits. Over 80% of HPV-positive patients respond to treatment, and three-year progression-free survival ranges from 75 to 82%, compared to 45 to 57% for HPV-negative cases, with results improving over time.

HPV-positive cancer seems inherently less aggressive, since patients treated with surgery alone do better after adjusting for stage. HPV is detected through the biomarker p16, which rises when HPV is present. Some patients have discordant results—p16-positive but HPV-negative, or vice versa. Five-year survival is 81% for those positive for both, 53 to 55% for discordant cases, and 40% for those negative for both.

In one major trial, HPV status was the strongest factor determining survival, followed by smoking and stage. Among HPV-positive patients, 82% were alive at three years versus 57% of HPV-negative patients, a 58% lower risk of death. Locoregional failure was also much lower: 14% versus 35%.

Did You Know?

• HPV-positive OPC may present as an asymptomatic abnormality in the mouth found by the patient or a health professional such as a dentist.
• Patients may note discolorations such as leukoplakia, erythroplakia, or erythroleukoplakia that may represent precancerous lesions.
• The association between HPV and various squamous cell cancers, including OPC, was first described in 1983.