The goals of treatment are to optimise survival and locoregional disease control, and prevent spread to distant areas of the body (
metastasis), while minimising short- and long-term
morbidity. There is no high quality
Level I evidence from prospective clinical trials in HPV+OPC, therefore treatment guidelines must rely on data from treatment of OPC in general and from some retrospective unplanned
subsetting of those studies, together with data for head and neck cancer in general. Treatment for OPC has traditionally relied on
radiotherapy,
chemotherapy, and/or other systemic treatments, and surgical resection. Depending on the stage and other factors, treatment may include a combination of
modalities. The mainstay has been radiotherapy in most cases. a pooled analysis of published studies suggested comparable disease control between radiation and surgery, but higher complication rates for surgery +/− radiation. Ideally a single modality approach is preferred since triple modality is associated with much more toxicity and a multidisciplinary team in a large centre with high patient volumes is recommended. Differences in response to treatment between HPV-OPC and HPV+OPC may include differences in the extent and manner in which cellular growth-regulatory pathways are altered in the two forms of OPC. For instance, in HPV+OPC, the HPV E6 and E7 oncogenes merely render the p53 and pRb pathways dormant, leaving open the possibility of reactivation of these pathways by
down-regulating (reducing) expression of the oncogenes. This is in contrast to the mutant form of p53 found in HPV-OPC, which is associated with treatment resistance. Furthermore, it is suggested that the effects of E6 and E7 on these pathways render the tumour more radiosensitive, possibly by interference with mechanisms such as
DNA repair, repopulation signalling, and cell-cycle redistribution. The microenvironment is also important, with radiation increasing host
immune response to viral
antigens expressed on the tumour. Also, there is an association between an increase in
tumour-infiltrating lymphocytes and in circulating
white blood cells in HPV+OPC patients and better prognosis. This implies a role for an
adaptive immune system in suppressing
tumour progression.
Surgery Historically, surgery provided a single approach to head and neck cancer. Surgical management of OPC carries significant morbidity with a transcervical (through the neck) approach, often involving mandibulotomy, in which the jawbone (
mandible) is split. This is referred to as an open surgical technique. Consequently, surgical approaches declined in favour of radiation. In the United States, the use of surgery declined from 41% of cases in 1998 to 30% by 2009, the year that the
Food and Drug Administration approved the use of the newer techniques. These improvements in surgical techniques have allowed many tumours to be
resected (removed) by transoral (through the mouth) surgical approaches (TOS), using transoral
endoscopic head and neck surgery (HNS). Consequently, surgery became used more, increasing to 35% of cases by 2012. This approach has proven safety, efficacy and tolerability, and includes two main
minimally invasive techniques,
transoral robotic surgery (TORS) and
transoral laser microsurgery (TLM). No direct comparisons of these two techniques have been conducted, and clinical trials in head and neck cancer such as ECOG 3311 allow either. They are associated with substantial postoperative morbidity, depending on the extent of resection but compared to older techniques have a shorter hospital stay, faster recovery, less pain, and less need for
gastrostomy or
tracheostomy, and less long-term effects, which are minimal in the absence of postoperative radiation (RT), or chemoradiation (CRT). TORS has the practical advantage that angled telescopes and rotating robotic surgical arms provide better line of sight. Outcomes of minimally invasive procedures also compare favourably with more invasive ones. In early-stage disease, including involvement of neck nodes, TORS produces a 2-year survival of 80–90%. TLM is similarly reported to have a five-year survival of 78% and local control rates of 85–97%. In addition to early disease, minimally invasive surgery has been used in advanced cases, with up to 90% local control and disease-specific survival. Postoperative swallowing was excellent in 87%, but long-term dysphagia was associated with larger (T4) cancers, especially if involving the base of the tongue. The details of the surgical approach depend on the location and size of the primary tumour and its N stage.
Neck dissection to examine the draining lymph nodes may be carried out simultaneously or as a second staging procedure. For tumours of the tonsil and lateral pharyngeal wall, and clinically node-negative (N0) disease, dissection of the neck typically involves levels 2–4 (
see diagram in Dubner 2017)
ipsilaterally. Where nodes are involved clinically, dissection will depend on the location and size of the node or nodes. In the case of tongue base primaries, close to the
midline, bilateral dissection is recommended.
Pathological staging An advantage of a primary surgical approach is the amount of
pathological information made available, including grade,
margin status, and degree of involvement of lymph nodes. This may change the staging, as up to 40% of patients may have a different postoperative pathological stage compared to their preoperative clinical stage. In one study, 24% had their stage reduced (downstaged), which may impact subsequent decision making, including a reduction in intensity and morbidity. In the United Kingdom, the
Royal College of Pathologists (1998) has standardised the reporting of surgical margins, with two categories, "mucosal" and "deep", and for each created groups based on the microscopic distance from invasive cancer to the margin, as follows: more than 5 mm (clear), 1–5 mm (close) and less than 1 mm (involved).
Adjuvant postoperative therapy Data on the use of postoperative
radiation therapy (PORT) is largely confined to historical or retrospective studies rather than high quality
randomized clinical trials and are based on the overall population of patients with head and neck cancer, rather than specific studies of HPV+OPC, which would have formed a very small proportion of the population studied. Despite surgical excision, in the more advanced cases, local and regional recurrence of the cancer, together with spread outside of the head and neck region (
metastases), are frequent. The risk of subsequent recurrent disease has been considered highest in those tumours where the pathology shows tumour at the margins of the resection (positive margins), multiple involved regional lymph nodes, and extension of the tumour outside of the capsule of the lymph node (extracapsular extension), based on historical experience with head and neck cancer. PORT was introduced in the 1950s in an attempt to reduce treatment failure from surgery alone. Although never tested in a controlled setting, PORT has been widely adopted for this purpose. In an analysis of surgical treatment failure at
Memorial Sloan-Kettering Cancer Center, patients treated with surgery alone between 1960 and 1970 had failure rates of 39 and 73% for those with negative and positive surgical margins, respectively. These were compared to those who received PORT (with or without chemotherapy) from 1975 to 1980. The latter group had lower failure rates of 2% and 11% respectively. In addition, one randomised study from the 1970s (RTOG 73–03) compared preoperative radiation to PORT, and found lower failure rates with the latter. The addition of another modality of treatment is referred to as
adjuvant (literally helping) therapy, compared to its use as the initial (primary) therapy, also referred to as radical therapy. Consequently, many of these patients have been treated with adjuvant radiation, with or without chemotherapy. In the above series of reports of minimally invasive surgery, many (30–80%) patients received adjuvant radiation. However, functional outcomes were worse if radiation was added to surgery and even worse if both radiation and chemotherapy were used. Radiation dosage has largely followed that derived for all head and neck cancers, in this setting, based on risk. Historically, only one randomised clinical trial has addressed optimal dosage, allocated patients to two dosage levels, stratified by risk, but showed no difference in cancer control between the low and high doses (63 and 68.4 Gy), and a higher incidence of complications at the higher doses. Consequently, the lower dose of 57.6
Gy was recommended. Because the authors used a fractionation scheme of 1.8 Gy per treatment, this dosage was not widely adopted, practitioners preferring a larger fraction of 2 Gy to produce a shorter treatment time, and a slightly higher dose of 60 Gy in 2 Gy fractions (30 daily treatments). Yet 57.6 Gy in 1.8 Gy fractions is equivalent (iso-effective dose) to only 56 Gy in 2 Gy fractions. 60 Gy corresponds to the 63 Gy used as the low dose in the high-risk group. 60 Gy was also the dose used in RTOG 73–03. Subsequently, there was a tendency to intensify treatment in head and neck cancer, and many centres adopted a dose of 66 Gy, at least for those patients with adverse tumour features. The effectiveness of PORT in HPV+OPC receives some support from a
cohort study (Level 2b), although the number of patients was low, and the number of events (recurrent disease or death), only 7%. Another retrospective population-level study (Level 4) of the
SEER database (1998–2011) concluded that there was an overall survival but not disease-specific survival effect of radiation in 410 patients with a single lymph node involved, but used only
univariate statistical analysis and contained no information on HPV status. A subsequent much larger study on a similar population in the National Cancer Database (2004–2013) of over 9,000 patients found a survival advantage but this was only in HPV-OPC, not in 410 HPV+OPC patients, and a subsequent study of 2,500 low and intermediate risk HPV+OPC patients showed similar overall survival whether PORT was given or not.
Deintensification While fewer studies have been completed examining deintensification (de-escalation) in this setting than in primary radical radiation for this cancer (see below), it is an area of active investigation. In one single institution study, a decision was made to reduce the radiation dose in high-risk patients with HPV+OPC from 66 to 60 Gy, corresponding to the actual evidence, and follow-up has shown no decrease in cancer control. Current trials, both in North America and Europe (such as ECOG 3311 and PATHOS) use 50 Gy as the comparison arm. The comparator of 50 Gy was chosen on the grounds of (i) the exquisite sensitivity of HPV+OPC to radiation, both
in vitro and
in vivo; ECOG 1308 showing excellent disease control at 54 Gy; and data suggesting that 50 Gy in 1.43 Gy (iso-effective dose 43 Gy in 2.0 Gy) was sufficient to electively treat the neck. Other studies, such as MC1273 and DART-HPV have evaluated doses as low as 30–36 Gy. Lowering the radiation dose to 54 Gy was identified as one of the important Clinical Cancer Advances of 2018 by the
American Society of Clinical Oncology, under the general theme of "Less Is More: Preserving Quality of Life With Less Treatment". Chemotherapy has been used concurrently with radiation in this setting, as in primary treatment with radical radiation, particularly where pathological features indicated a higher risk of cancer recurrence. Several studies have suggested that this does not improve local control but adds toxicity.
Radiotherapy Concerns over the morbidity associated with traditional open surgical en-bloc resection led to exploring alternative approaches using radiation. Intensity-modulated radiation therapy (
IMRT) can provide good control of primary tumours while preserving excellent control rates, with reduced toxicity to salivary and pharyngeal structures relative to earlier technology. HPV+OPC has shown increased sensitivity to radiation with more rapid regression, compared to HPV-OPC. Generally, radiation can safely be delivered to the involved side alone (ipsilateral), due to the low rate of recurrent cancer on the opposite side (contralateral), and significantly less toxicity compared to bilateral treatment. IMRT has a two-year disease-free survival between 82 and 90%, and a two-year disease-specific survival up to 97% for stage I and II. Reported
toxicities include dry mouth (
xerostomia) from
salivary gland damage, 18% (grade 2); difficulty swallowing (
dysphagia) from damage to the constrictor muscles, larynx and oesophageal sphincter, 15% (grade 2);
subclinical aspiration up to 50% (reported incidence of aspiration pneumonia approximately 14%);
hypothyroidism 28–38% at three years (may be up to 55% depending on amount of the thyroid gland exposed to over 45
Gy radiation;
esophageal stenosis 5%;
osteonecrosis of the
mandible 2.5%; and need for a
gastrostomy tube to be placed at some point during or up to one year after treatment 4% (up to 16% with longer follow up). Concerns have been expressed regarding excessive short- and long-term toxicity, especially dysphagia, and xerostomia, and hence whether standard doses expose patients with better prognoses are being exposed to overtreatment and unnecessary side effects.
Dosimetry The probability of xerostomia at one year increases by 5% for every 1 Gy increase in dose to the
parotid gland. Doses above 25–30 Gy are associated with moderate to severe xerostomia. Similar considerations apply to the
submandibular gland. Xerostomia is less common if only one parotid gland is included in the radiated field and the contralateral submandibular gland is spared (less than 39 Gy) In the same manner, the radiation dose to the
pharyngeal constrictor muscles,
larynx, and
cricopharyngeal inlet determine the risk of dysphagia (and hence the dependence on
gastrostomy tube feeds). The threshold for this toxicity is volume-dependent at 55–60 Gy, with moderate to severe impairment of swallowing, including aspiration, stricture and feeding tube dependence above a mean dose of 47 Gy, with a recommended dose to the inferior constrictor of less than 41 Gy. Dose-toxicity relationships for the superior and middle constrictors are steep, with a 20% increase in the probability of dysphagia for each 10 Gy. For late dysphagia, threshold mean total constrictor doses, to limit rates of greater than or equal to grade 2 and 3 below 5% were 58 and 61 Gy respectively. For grade 2 dysphagia, the rate increased by 3.4% per Gy. Doses above 30 Gy to the thyroid are associated with moderate to severe hypothyroidism. Subjective, patient-reported outcomes of
quality of life also correlate with radiation dose received. Altered
fractionation schemes, such as RTOG 9003 and RTOG 0129 have not conferred additional benefit. Radiation dose recommendations were largely determined
empirically in clinical studies with few HPV+OPC patients, and have remained unchanged for half a century, making it difficult to determine the optimum dose for this subgroup. A common approach uses 70 Gy bilaterally and anteriorly, such as RTOG 9003 (1991–1997) and RTOG 0129 (2002–2005). For lateralized tonsil cancer, unilateral neck radiation is usually prescribed, but for tongue base primaries, bilateral neck radiation is more common, but unilateral radiation may be used where tongue base lesions are lateralised.
Deintensification Concerns have been expressed regarding excessive short- and long-term toxicity, especially dysphagia and xerostomia, and hence whether standard doses expose patients with better prognoses to overtreatment and unnecessary side effects. Current toxicities have been described as "not tolerable", and hence an intense interest in de-escalation. While comparison with historical controls has limited value compared to randomised clinical trials (
phase III),
phase II studies using reduced doses of radiation compared to the historical standard of 70 Gy have been carried out. A study using 54–60 Gy (a 15–20% reduction, stratified by response to initial induction chemotherapy) demonstrated comparable levels of disease control with much lower complication rates, when compared to similar studies, using 70 Gy, such as ECOG 2399. The percentage of patients alive after 2 years was 95% at the higher dose and 98% at the lower dose. Similarly, for the percentage free of disease (86% and 92%). Toxicities were greatly reduced from an incidence of grade 3 or greater dysphagia and mucositis of 54% and 53%, respectively, to 9%. A lower incidence and severity of dysphagia also means that fewer patients require gastrostomy feeding. A similar comparison can be made with the pooled data from two RTOG studies, which utilized 70 Gy (0129 and 0522). No new guidelines dealing specifically with HPV+OPC have yet been developed, outside of clinical trials. Indirect data suggests the efficacy of less intense treatment. A retrospective analysis of advanced (N+) HPV+OPC suggested 96% 5-year local control with de-intensified radiation of 54 Gy and concurrent
cisplatin based chemotherapy. The conclusions of the above pair of similar phase II trials have been supported by several other phase II trials. A prospective trial (
ECOG 1308) demonstrated similar locoregional control with 54 Gy, and another study, a high pathological complete response rate at 60 Gy. The Quarterback trial showed comparable outcomes between 56 and 70 Gy. and was followed by Quarterback 2, comparing 50 to 56 Gy. Similarly, the Optima trial showed good disease control with doses between 45 and 50 Gy. Ongoing studies, following the experience of the
Mayo Clinic trial (MC1273), such as that the
Memorial Sloan Kettering Cancer Center are exploring doses as low as 30Gy. These studies all used well below the previous standard dose of 70 Gy. Since long-term toxicity is associated with radiation dose, determining the efficacy of lower and hence less morbid doses of radiation is a priority, since many HPV+ patients can be expected to have long-term survival. Recent commentary has highlighted investigational strategies that use tumor-intrinsic genomic measures of radiosensitivity, in particular the
Genomic Adjusted Radiation Dose (GARD) framework to help identify patients with HPV-positive oropharyngeal cancer who may be suitable for radiation de-escalation. Radiation is commonly utilised in combination with chemotherapy but also may be used as a single modality, especially in earlier stages, e.g. T1-T2, N0-1, and its use in later stages is being explored in clinical trials such as RTOG 1333 which compares radiation alone to radiation with reduced chemotherapy, in non or light smokers.
Chemotherapy As with the radiotherapy data, most of the available knowledge on the efficacy of chemotherapy derives from the treatment of advanced head and neck cancer rather than specific studies of HPV+OPC. Since 1976, many clinical studies have compared CRT to RT alone in the primary management of locally advanced head and neck cancers and have demonstrated an advantage to CRT in both survival and locoregional control. Cisplatin is considered the standard agent, and a survival advantage was seen for those patients who received radiation with concurrent cisplatin. Despite this no trials directly comparing cisplatin with other agents in this context have been conducted. The other agent that is widely used is
Cetuximab, a
monoclonal antibody directed at the
epidermal growth factor receptor (EGFR). A 10% survival advantage at three years was noted when cetuximab was given concurrently with radiation (bioradiation). Cetuximab trials were completed before knowledge of HPV status. Laboratory and clinical studies on the utility of cetuximab in this context are conflicting. The main toxicity is an
acneiform rash. It had not been compared directly to cisplatin in HPV+OPC until RTOG 1016 (
see Talk) addressed this question. Analysis of the results three years after the trial was completed demonstrates that cetuximab is inferior to cisplatin. Concurrent chemotherapy is also superior to chemotherapy alone (
induction chemotherapy) followed by radiation. Cetuximab shows no advantage when added to cisplatin in combination with radiation. Although chemoradiation became a treatment standard based on clinical trials and in particular,
meta-analyses, a subsequent
population-based study of patients with OPC, indicated no advantage to the addition of chemotherapy to radiation in either HPV+OPC or HPV-OPC, and significant concerns about added toxicity. Chemotherapy also has a role, combined with radiation, in the postoperative setting (adjuvant therapy). Generally, it is used where the
pathology of the resected specimen indicates features associated with a high risk of locoregional recurrence (e.g., extracapsular extension through involved lymph nodes or very close margins). It has shown improved disease-free survival and locoregional control in two very similar clinical trials in such high-risk patients,
EORTC 22931 (1994–2000) and RTOG 9501 (1995–2000). However, for HPV+OPC patients, such extracapsular spread does not appear to be an adverse factor and the addition of chemotherapy to radiation in this group provided no further advantage. Since the
sample size to detect a survival advantage is large, given the small number of events in this group, these studies may have been
underpowered and the question of the utility of adding chemotherapy is being addressed in a randomized clinical trial (ADEPT) with two-year locoregional control and disease-free survival as the endpoint. The addition of chemotherapy to radiation increases acute and late toxicity. In the GORTEC trial, chemotherapy with
docetaxel provided improved survival and locoregional control in locally advanced OPC but was associated with increased mucositis and need for feeding by gastrostomy. Chemotherapy and radiation are associated with a risk of death of 3–4% in this context. It is unclear whether the added toxicity of adding chemotherapy to radiation is offset by significant clinical benefits in disease control and survival. It is thought that HPV+OPC patients benefit better from radiotherapy and concurrent
cetuximab treatment than HPV-OPC patients receiving the same treatment, and that radiation and cisplatin induce an immune response against an
antigenic tumour which enhances their effect on the cancer cells. Although the incidence of HPV positivity is low (10–20%), an advantage for HPV+OPC was seen in trials of both cetuximab and
panitumumab, a similar anti-EGFR agent, but not a consistent interaction with treatment, although HPV+OPC appears not to benefit to the same extent as HPV-OPC to second line anti-EGFR therapy, possibly due to lower EGFR expression in HPV+OPC.
Choice of treatment approach In the absence of high-quality evidence comparing a primary surgical approach to other modalities, decisions are based on consideration of factors such as adequate surgical exposure and anatomically favourable features for adequate resection, post-treatment function, and
quality of life. Such patient selection may enable them to avoid the morbidity of additional adjuvant treatment. In the absence of favourable surgical features, the primary treatment of choice remains radiation with or without chemotherapy. Tumor characteristics that favour a non-surgical approach include invasion of the base of the tongue to the extent of requiring resection of 50% or more of the tongue, pterygoid muscle involvement, extension into the
parapharyngeal fat abutting the
carotid, involvement of the mandible or
maxilla or invasion of the
prevertebral space. The adequacy of surgical
resection is a major factor in determining the role of postoperative adjuvant therapy. In the presence of a
positive margin on pathological examination, most radiation oncologists recommend radiation to the primary site and concurrent chemotherapy. A negative margin is more likely to be treated with lower doses and a smaller treatment volume. Also, the removal of a bulky tumour may allow reduced dosage to adjacent uninvolved pharyngeal structures and hence less effect on normal
swallowing. The cancer outcomes (local control, regional control, and survival) for transoral resection followed by adjuvant therapy are comparable to primary chemoradiation, so that treatment decisions depend more on treatment-related morbidity, functional outcome, and quality of life. Patient factors also need to be taken into account, including general baseline functionality, smoking history, anesthesia risk, oropharyngeal function, swallowing and airway protection, and potential for rehabilitation. Patient preference is equally important. Many clinical trials are underway, focusing on deintensification, often with risk
stratification, e.g., Low, Intermediate, and High Risk (
see Fundakowski and Lango, Table I). Clinical decisions also take into account morbidities, particularly if cancer outcomes are comparable, for instance, surgery is associated with a risk of bleeding between 5–10%, and a 0.3% risk of fatal postoperative haemorrhage. Surgery may also be complicated by
dysphagia, and while most patients can tolerate a diet on the first postoperative day, long-term use of a feeding tube has been reported as high as 10%. Patients with larger tumours, involvement of base of the tongue and requiring postoperative adjuvant therapy are more likely to require a long-term feeding tube. Overall, function and quality of life appear relatively similar between surgery with postoperative radiation and primary chemoradiation, but HPV+OPC patients tend to have a better quality of life at diagnosis than HPV-OPC but may sustain greater loss following treatment. Anatomical considerations may also dictate a preference for surgical or non-surgical approaches. For instance,
trismus, a bulky tongue, limited extension of the neck, prominent teeth,
torus mandibularis (a bony growth on the mandible), or limited width of the mandible would all be relative contraindications to surgery. Tumour-related considerations include invasion of the mandible,
base of the skull, and extensive involvement of the larynx or more than half of the base of the tongue. Technical considerations in offering surgery as a primary modality include the presumed ability to achieve adequate margins in the resected specimen and the degree of resulting defect, since close or positive margins are likely to result in subsequent adjuvant therapy to achieve disease control, with resultant increased morbidity. Costs are difficult to estimate but one US study, based on estimates of 25% of all OPC patients receiving surgery alone and 75% surgery followed by adjuvant therapy, using the criteria of the
NCCN, found that this approach was less expensive than primary chemoradiation. Early stage disease is associated with a relatively favourable outcome, for which single modality therapy is recommended, the choice depending on tumour location and accessibility. For instance, unilateral tonsil or tongue base tumours will generally be treated with transoral resection and selective ipsilateral neck dissection. On the other hand, a large midline tongue lesion would require bilateral neck dissection, but in the absence of what are considered adverse pathology (positive margins, extracapsular extension) will likely be treated by surgery alone or radiation including ipsilateral or bilateral neck radiation fields, with surgery for those instances where the likelihood of adjuvant therapy is low. But many HPV+OPC present with involvement of the lymph nodes in the neck, and hence a higher stage of disease, generally referred to as locally advanced disease. This group is mostly treated with multimodality therapy, except one of the more favourable subgroups with small primary tumours and lymph node involvement confined to a single node no larger than 3 cm in size, which, as noted, are considered early-stage disease. The three main options for locally advanced but operable disease are resection, neck dissection, and adjuvant therapy; chemoradiation (with possible
salvage surgery); induction chemotherapy followed by radiation or chemoradiation. However, the last option has not been supported in clinical trials that tested it.{{efn|Clinical trials, such as PARADIGM and DeCIDE}. The primary consideration of surgery for locally advanced disease is to obtain adequate negative margins and spare the patient postoperative chemoradiation. But this must be balanced against the morbidity and functional loss from extensive resection, particularly where the tongue base is involved. To avoid such morbidity, primary chemoradiation is preferred. The management of disease within the cervical lymph nodes has to be taken into account in treating locally advanced disease. Guidelines for all OPC dictate that extracapsular extension be given postoperative chemoradiation. Where gross neck disease is evident initially, primary chemoradiation is usually given.
Patient preferences Current guidelines are based on data for OPC as a whole, so that patients are generally being treated regardless of HPV status, yet many clinicians and researchers are considering deintensification. Treatment of this condition will likely continue to evolve in the direction of deintensification, to minimize loss of function but maintain disease control. In the absence of specific clinical trials and guidelines, patient preferences need to be taken into consideration to minimise short- and long-term toxicity and functional loss and optimize quality of life, given the prolonged survival frequently seen. This may involve exploring patients' values regarding
trade-offs of disease control against adverse effects of treatment. Patients who have received CRT as primary treatment for OPC place a high value on survival, and although agreeing that deintensification is desirable, were reluctant to trade off much survival advantage for lower toxicity, though they would be more likely to forgo chemotherapy than accept reduced radiation.
Carcinoma of unknown primary In some situations, HPV+OPC may present with cervical lymph nodes but no evident disease of a primary tumour (T0 N1–3) and is therefore classed as
Squamous Cell Carcinoma of Unknown Primary Origin. This occurs in 2–4% of patients presenting with metastatic cancer in the cervical nodes. The incidence of HPV positivity is increasing at a similar rate to that seen in OPC. In such situations, resection of the lingual and palatine tonsils together with neck dissection may be diagnostic and constitute sufficient intervention, since recurrence rates are low. ==Prognosis==