HPV-positive oropharyngeal cancer
|HPV-positive oropharyngeal cancer|
|Microscopic image of tumour showing HPV positivity by in situ hybridization|
|Classification and external resources|
Human papillomavirus (HPV)-positive oropharyngeal cancer (OPC) also known as HPV16+ oropharyngeal cancer or HPV+OPC is a recognized subtype of oropharyngeal squamous cell carcinomas (OSCC), associated with the HPV type 16 virus (HPV16). Historically cancer of the oropharynx (throat) was associated with the use of alcohol and tobacco, but the majority of cases are now associated with the HPV virus. HPV+OPC differs in a number of respects to OPC not associated with HPV (HPV-OPC), as is considered a separate disease. HPV has long been associated with cancers in the anogenital region, but in 2007 was also recognised as a cause of oropharyngeal cancer. HPV is common among healthy adults and is largely transmitted through sexual contact, but tobacco use increases the risk of cancer. 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 tumour), N stage (extent of involvement of regional lymph nodes) and M stage (whether there is spread of the disease (metastasis) outside the region or not), and combined into an overall stage from I–IV. In 2016, for the first time a separate staging system was developed for HPV+OPC distinct from HPV-OPC.
The historical treatment of OPC was surgical, with an approach through the neck (transcervical) and splitting of the jaw bone (mandible), with considerable morbidity. Later, radiotherapy with or without the addition of chemotherapy provided a less invasive alternative, and the results in terms of treating the cancer, were considered comparable. Newer minimally invasive surgical techniques through the mouth (transoral) have reduced morbidity, and surgery is often followed by radiation and or chemotherapy in high risk cases. In the absence of high quality evidence through clinical trials, patient management decisions are often based on technical factor, likely functional loss and patient preferences. Some HPV+OPC may first appear in lymph nodes in the neck (cervical nodes), without an obvious source (cancer of unknown primary origin) but removal of tonsil tissue from the oropharynx will often show hidden disease there. 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. While most head and neck cancer has been declining with reduced smoking rates, HPV+OPC has been increasing. Compared to HPV-OPC patients, HPV+OPC 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+OPC increasing faster than the decline in HPV-OPC. The increase is seen particularly in young men in developed countries, and HPV+OPC now accounts for the majority of all OPC cases.
Attempts are being made to reduce the incidence of HPV+OPC by introducing vaccination that includes HPV types 16 and 18, found in 95% of these cancers, prior to exposure to the virus. Early data suggest a reduction in infection rates.
- 1 Anatomy
- 2 Causation
- 3 Diagnosis
- 4 Treatment
- 5 Prognosis
- 6 Epidemiology
- 7 Prevention
- 8 See also
- 9 Notes
- 10 References
- 11 Bibliography
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. 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) oesophagus (gullet), below, where the larynx is situated in front of the oesophagus.
The oropharynx lies between the mouth (oral cavity) to 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 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. 
The external pharyngeal walls consisting of the four constrictor muscles form part of the mechanism of swallowing. The microscopic anatomy is composed of four layers, being from the lumen outwards, the mucosa, submucosa, muscles and the fibrosa, or fibrous layer. The mucosa consists of stratified squamous epithelium, that is generally non-keratinised, except when exposed to chronic irritants such as tobacco smoke. The submucosa contains aggregates of lymphoid tissue.
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 papilloma virus (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 increase 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 largely through sexual contact. Although less data is available, 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 increase 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. Human herpesvirus-8 infection can potentiate the effects of HPV-16.
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.
An increased risk of HPV+OPC is observed more than 15 years after HPV exposure, pointing to a slow development of the disease, similar to that seen in cervical cancer. HPV associated cancers are caused by high-risk strains of HPV, mainly HPV-16 and HPV-18. HPV- and HPV+OPC are distinguishable at the molecular level. HPV+OPC express the two main viral oncoproteins of the high risk HPV types, E6 and E7.[a] These interfere with a variety of predominantly antiproliferative cellular regulatory mechanisms. They bind to and inactivate the best known of these mechanisms, the tumor suppressor proteins p53 and retinoblastoma protein (pRB or pRb) leading to malignant transformation of HPV infected cells. The gene encoding p53 is inactivated by E6 at the protein level and is found as the wild type in HPV+OPC but mutated in HPV-OPC. The pRb protein is inactivated by E7 in HPV+OPC, but in HPV-OPC it is the p16 tumour suppressor part of the pRb tumour suppressor network that is inactivated. Although HPV E6 and E7 reduce tumour suppressor activity, they do so less than genetic and epigenetic processes do in HPV-OPC. Like most HPV+ cancers, HPV+OPC express p16 but the latter does not function as a tumour-suppressor, because the mechanism by which this is achieved, pRb, has been inactivated by E7.
In HPV+OPC p53 protein undergoes accelerated degradation by E6, drastically reducing its levels, instead of by genetic mutation in HPV-OPC, which may result in synthesis of an abnormal p53 protein, that may not only be inactive as a tumour suppressor, but can also bind and inactivate any non-mutated wild type p53, with an increase in oncogenic activity. Also the pRb pathway is inactivated by E7 instead of Cyclin D1 amplification and the tumor suppressor protein p16 (cyclin-dependent kinase inhibitor 2A) is upregulated (over-expression of p16 instead of inactivation due to reduced negative feedback from pRB). The tonsillar epithelia (palatine and lingual) share similar nonkeratinization characteristics with the cervix, where HPV infection plays the major role in cases of cervical cancer. Also E6 and E7 may make HPV+OPC more immunogenic than HPV-OPC, since anti-E6 and E7 antibodies may be detected in these patients. This in turn could restrict the malignant behaviour of HPV+OPC and the presence of antibodies has been associated with a better prognosis, while treatment may enhance the immunogenicity of the tumour, and hence improve response, although to what extent is not clear.
HPV+OPC is usually diagnosed at a more advanced stage than HPV-OPC. Genetic signatures of HPV+ and HPV- OPC are different. HPV+OPC is associated with expression level of the E6/E7 mRNAs and of p16. Nonkeratinizing squamous cell carcinoma strongly predicts HPV-association. HPV16 E6/E7-positive cases are histopathologically characterized by their verrucous or papillary (nipple like) structure and koilocytosis of the adjacent mucosa. Approximately 15% of HNSCCs are caused by HPV16 infection and the subsequent constitutive expression of E6 and E7, and some HPV-initiated tumors may lose their original characteristics during tumor progression. High-risk HPV types may be associated with oral carcinoma, by cell-cycle control dysregulation, contributing to oral carcinogenesis and the overexpression of mdm2, p27 and cathepsin B.
HPV+OPC is not merely characterized by the presence of HPV-16. Only the expression of viral oncogenes within the tumor cells plus the serum presence of E6 or E7 antibodies is unambiguously conclusive. There is not a standard HPV testing method in head and neck cancers, both in situ hybridization (ISH) and polymerase chain reaction (PCR) are commonly used. Both methods have comparable performance for HPV detection, however it is important to use appropriate sensitivity controls. Immunohistochemistry (IHC) staining of the tissue for p16 is frequently used as a cost effective surrogate for HPV in OPC, compared to ISH or PCR but there is a small incidence of HPV-negative p16-positive disease accounting for about 5% of HPV-OPC.
Staging is generally by the UICC/AJCC TNM (Tumour, Nodes, Metastases) system. HPV+OPC has been treated similarly to stage-matched and site-matched HPV unrelated OPC, but its unique features, which contrast smoking-related HPV-OPC head and neck cancers, for which patients' demographics, comorbidities, risk factors, and carcinogenesis differ markedly, suggest that a distinct staging system be developed to more appropriately represent the severity of the disease and its prognosis. Standard AJCC TNM staging, such as the seventh edition (2009) while predictive for HPV-OPC has no prognostic value in HPV+OPC. The 8th edition of the AJCC TNM Staging Manual (2016) incorporates this specific staging for HPV+OPC. Current treatment guidelines do not account for the different outcomes observed in HPV+OPC. Consequently, less intensive (de-intensification) use of radiotherapy or chemotherapy, as well as specific therapy, is under investigation, enrolling HPV+OPC in clinical trials to preserve disease control and minimise morbidity in selected groups based on modified TNM staging and smoking status.
HPV+ cancer of the oropharynx are staged as (AJCC 8th ed. 2016): Tumour stage
- T0 no primary identified
- T1 2 cm or less in greatest dimension
- T2 2–4 cm
- T3 >4 cm, or extension to lingual surface of epiglottis
- T4 moderately advanced local disease, invading larynx, extrinsic muscle of tongue, medial pterygoid, hard palate, or mandible or beyond
- Nx regional lymph nodes cannot be assessed
- N0 no regional lymph nodes involved
- N1 1 or more ipsilateral nodes involved, less than 6 cm
- N2 contralateral or bilateral lymph nodes, less than 6 cm
- N3 lymph node(s) larger than 6 cm
- Stage I: T0N1, T1–2N0–1
- Stage II: T0N2, T1–3N2, T3N0–2
- Stage III: T0–3N3, T4N0-3
- Stage IV: any metastases (M1)
However, the published literature and ongoing clinical trials use the older seventh edition that does not distinguish between HPV+OPC and HPV-OPC - see Oropharyngeal Cancer - Stages. The T stages are essentially similar between AJCC 7 and AJCC 8. with two exceptions. Tis (carcinoma in situ) has been eliminated and the division of T4 into substages (e.g. T4a) has been removed. The major changes are in the N stages, and hence the overall clinical stage. N0 remains the same, but as with the T stage, substages such as N2a have been eliminated. Invasion by the tumour beyond the capsule of the lymph node (extracapsular extension OR ECE) has been eliminated as a staging criterion. This results in a HPV+OPC tumour being given a lower stage than if it were HPV-OPC. For instance, a 5 cm tumour with one ipsilateral node involved that is 5 cm in size but has ECE would be considered T3N3bM0 Stage IVB if HPV- but T3N1M0 Stage II if HPV+.
The goals of care 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 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 that is associated with treatment resistance.
Historically, surgery provided the single approach to head and neck cancer. Surgical management of OPC carried significant morbidity with a transcervical approach (via the neck) and often involving mandibulotomy (splitting the mandible). Improvements in surgical techniques have allowed many tumours to be removed (resected) by a transoral approaches (through the mouth). This approach has proven safety, efficacy and tolerability, and include 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 extent of resection but compared to older techniques have 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 similarly, is 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) 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.
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 reduction in intensity and morbidity. In the United Kingdom, the Royal College of Pathologists (1998)[b] 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 studies on the overall population of patients with head and neck cancer, rather than specific studies of HPV+OPC. 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 is 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). 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. The addition of another modality of treatment is referred to as adjuvant (literally helping) 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 worst 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. A randomised clinical trial allocated patients to two dosage levels, but showed no difference in cancer control between the low and high dose, but a higher incidence of complications at the higher dose. 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).
Concerns over the morbidity associated with traditional 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. 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) 18% (grade 2); difficulty swallowing (dysphagia) 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). However altered fractionation schemes, such as RTOG 9003 and RTOG 0129 have not conferred additional benefit.
Radiation dose recommendations are largely based on older clinical trials with few HPV+OPC patients, making it difficult to determine the optimum dose for this group. 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.
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 deintensified radiation of 54 Gy and concurrent cisplatin based chemotherapy. A prospective trial (ECOG 1308) demonstrated similar locoregional control with 54 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.
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. In the postoperative adjuvant setting, the addition of radiation to surgery is largely based on historical or retrospective studies, rather than high quality randomized clinical trials.
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 prior to knowledge of HPV status. The main toxicity is an acneiform rash, but it has not been compared directly to cisplatin in HPV+OPC, although RTOG 1016 is addressing this question. Concurrent chemotherapy is also superior to chemotherapy alone (induction chemotherapy) followed by radiation.
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 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).[c][d] 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 benefit 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 which favour a non-surgiccal 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 treted 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 under way focussing on deintensification, often with risk stratification, e.g. Low, Intermediate and High risk (see Fundakowski and Lango, Table I).[e]
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 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.
Anatomical considerations may also dictate 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 skull and extensive involvement of the larynx or more than half of the base of 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[f] 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, with the exception of 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.[g] 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 ectracapsular extension be given postoperative chemoradiation. Where gross neck disease is evident initially primary chemoradiation is usually given.
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. It is likely that treatment of this condition will continue to evolve in the direction of deintensification, in order 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 regardng 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 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. The lack of any such evidence of a primary tumour 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.
The presence of HPV within the tumour has been realised to be an important factor for predicting survival since the 1990s. Tumor HPV status is strongly associated with positive therapeutic response and survival compared with HPV-negative cancer, independent of the treatment modality chosen and even after adjustment for stage. While HPV+OPC patients have a number of favourable demographic features compared to HPV-OPC patients, such differences account for only about ten per cent of the survival difference seen between the two groups. Response rates of over 80% are reported in HPV+ cancer and three-year progression free survival has been reported as 75–82 % and 45–57 %, respectively, for HPV+ and HPV- cancer, and improving over increasing time. It is likely that HPV+OPC is inherently less maligant than HPV-OPC, since patients treated by surgery alone have a better survival after adjustment for stage. In one study, less than 50% of patients with HPV-OPC were still alive after five years, compared to more than 70% with HPV+OPC and an equivalent stage and disease burden.
In RTOG clinical trial 0129, in which all patients with advanced disease received radiation and chemotherapy, a retrospective analysis (recursive-partitioning analysis, or RPA) at three years identified three risk groups for survival (low, intermediate, and high) based on HPV status, smoking, T stage and N stage (see Ang et al., Fig. 2). HPV status was the major determinant of survival, followed by smoking history and stage. 64% were HPV+ and all were in the low and intermediate risk group, with all non-smoking HPV+ patients in the low risk group. 82% of the HPV+ patients were alive at three years compared to 57% of the HPV- patients, a 58% reduction in the risk of death.[h] Locoregional failure is also lower in HPV+, being 14% compared to 35% for HPV-. HPV positivity confers a 50–60 % lower risk of disease progression and death, but the use of tobacco is an independently negative prognostic factor. The majority of recurrences occur within the first year after treatment and are locoregional, but HPV+ does not reduce the rate of metastases, which are predominantly to the lungs. Even if recurrence or metastases occur, HPV positivity still confers an advantage.
By contrast tobacco usage is an independently negative prognostic factor, with decreased response to therapy, increased disease recurrence rates and decreased survival. The negative effects of smoking, increases with amount smoked, particularly if greater than 10 pack-years.
A possible explanation for the favourable impact of HPV+ is "the lower probability of occurrence of 11q13 gene amplification, which is considered to be a factor underlying faster and more frequent recurrence of the disease" Presence of TP53 mutations, a marker for HPV- OPC, is associated with worse prognosis. High grade of p16 staining is thought to be better than HPV PCR analysis in predicting radiotherapy response.
The global incidence of pharyngeal cancer in 2013 was estimated at 136,000 cases. HPV+OPC patients tend to be younger than HPV- patients. The clinical presentation is also changing from the “typical” head and neck cancer patient with advanced age and major substance usage. By contrast patients with HPV+ cancer are younger (4th–6th decades), male (ratio 8:1) with no or only a minimum history of smoking, generally caucasian, reached higher education levels, are married, and have higher income. The risk factors for HPV-OPC and HPV+OPC tend to be independent, with the exception of smoking which has an adverse effect on both. The presenting features are also different between HPV+ and HPV- OPC. HPV+ tumours have smaller primary lesions (less than 4 cm) but more advanced nodal disease resulting in higher TNM staging. This in turn may overestimate the severity of the disease status.
In the United States the estimated number of cases was 12,410 in 2008, 13,930 in 2013 and 17,000 for 2017. Of these cases, HPV+ cancer has been increasing compared to HPV- cancer, but the increase in HPV+OPC exceeds the decline in HPV-OPC resulting an overall increase in OPC. The rise in pharyngeal cancer incidence contrasts with a marginal decline in other head and neck cancers. As a result the commonest head and neck cancer has shifted from larynx to oropharynx. A survey of 23 countries between 1983 and 2002 showed an increase in oropharyngeal squamous cell carcinoma that was particularly noticeable in young men in economically developed countries. In the United Kingdom the incidence of oral and oropharyngeal cancer in men rose 51%, from 7/100,000 to 11/100,000 between 1989 and 2006. Currently in the US there is a growing incidence of HPV associated oropharyngeal cancers, In the early 1980s HPV+ accounted for only 7.5% of cases in the US but by 2016 this was 70%, perhaps as a result of changing sexual behaviors, decreased popularity of tonsillectomies, improved radiologic and pathologic evaluation, and changes in classification. Tonsil and oropharyngeal cancers increased in male predominance between 1975 and 2004, despite reductions in smoking. HPV-OPC decreased with decreasing smoking rates from 1988 to 2004, while HPV+OPC increased by almost 7.5% per year from about 16% of all cases of OPC in the early 1980s to almost 70% in 2004. The decline in smoking may be linked to the decreasing proportion of HPV negative cancers, while changes in sexual activity may be reflected in increasing proportion of HPV positive cancers. Recently, in the US, HPV associated OPC represent about 60% of OPC cases compared with 40% in the previous decade. By 2007, in the US, incidence of general OPC, including non-HPV associated, is 3.2 cases per 100,000 males/year and 1.9 per 100,000 all-sexes/year. This makes HPV+OPC one of only five cancers that have increased in incidence in the US since 1975.
The increase in incidence of HPV associated OPC is also seen in other countries, like Sweden, with a 2007 incidence of over 80% for cancer in the tonsils, Finland and the Czech Republic. Partners of patients with HPV positive oropharyngeal cancer do not seem to have elevated oral HPV infection compared with the general population. In Australia incidence of HPV associated OPC is 1.56 cases per 100,000 males/year.
Prevention of HPV+OPC involves avoiding or reducing exposure to risk factors where possible. About 90% of HPV+OPC carry HPV 16, and another 5% type 18. These two types are both targets of available vaccines. HPV vaccines given prior to exposure can prevent persistent genital infection and the consequent precancerous state. Therefore, they have a theoretical potential to prevent oral HPV infection. A 2010 review study has found that HPV16 oral infection was rare (1.3%) among the 3,977 healthy subjects analyzed.
- The designation E, as in E6, indicates expression early in the HPV life-cycle
- Revised 3rd edition, 2013
- RTOG 9501 randomized 459 patients with head and neck cancer and any or all of the following high risk features identified on the basis of previous trials: histologic evidence of invasion of two or more regional lymph nodes, extracapsular extension of nodal disease, and microscopically involved mucosal resection margins, between radiation and chemoradiation with cisplatin postoperatively. At five years, locoregional control was improved with chemotherapy but adverse events were greater. Distant metastases were not affected. Longer follow up to ten years showed that these differences were only seen in two high risk subgroups, those with positive margins and those with extracapsular extension
- :EORC 22931, also published in 2004, used a similar design but differing definition of high risk. It showed a similar early advantage for combined therapy
- For instance ECOG 3311 stratifies HPV+OPC with AJCC 7 Stages III and IV 1-2, N1-2b into three risk groups postoperatively. Low risk is T1-T2 N0-N1 with negative margins. Intermediate risk is clear or close margins with the presence of adverse features on pathology such as perineural invasion or lymphovascular invasion, <1 mm ECE or 2–4 nodes involved. High risk is positive margins or greater than 1 mm ECE or at least 5 nodes involved.
- Early stage disease is considered as AJCC 7 as T1–22 N0–1 M0, approximately equivalent to T1–2 N0–2 M0 by AJCC 8
- Clinical trials, such as PARADIGM and DeCIDE
- In RTOG 0129 the three prognostic groups were;
- Low risk: HPV-, and had either less than 10 pack years of smoking, or more than 10 pack years but low nodal status (confined to a single node, >3 cm but ≤6 cm in greatest dimension)
- Intermediate risk: HPV+ with >10 pack year smoking and more advanced nodal status, or HPV-, <10 pack years and tumour stage T2–T3
- High risk: All others (including remainder of HPV-, <10 pack years with T4 tumours, and all with >10 pack years)
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