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 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 the presence of hpv within the tumour has been realised to be an important factor for predicting survival since the 1990s. comparison with hpv-negative oropharyngeal cancer 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 malignant than hpv-opc, since patients treated by surgery alone have a better survival after adjustment for stage. determinants of survival 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. locoregional failure is also lower in hpv+, being 14% compared to 35% for hpv-. determinants of disease progression hpv positivity confers a 50–60% lower risk of disease progression and death, but the use of tobacco is an independently negative prognostic factor. a pooled analysis of hpv+opc and hpv-opc patients with disease progression in rtog trials 0129 and 0522 showed that although less hpv+opc experienced disease progression (23 v. 40%), the median time to disease progression following treatment was similar (8 months). the majority (65%) of recurrences in both groups occurred within the first year after treatment and were locoregional. although the rate of failure in the opposite neck following treatment of only one side, is 2.4%, the rate of an isolated recurrence in the opposite neck is 1.7%, and these were mainly where the primary tumour involved the midline. however the rate of failure in the contralateral neck is also greater for hpv+. of those that recur in this site, nearly all were successfully treated (salvaged) by further local treatment to the opposite neck. determinants of metastasis rates hpv+ did not reduce the rate of metastases (about 45% of patients experiencing progression), which are predominantly to the lungs (70%), although some studies have reported a lower rate. with 3-year distant recurrence rates of about 10% for patients treated with primary radiation or chemoradiation. 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. after chemoradiation for patients such as those treated on rtog 0129 with primary chemoradiation, detailed nomograms have been derived from that dataset combined with rtog 0522, enabling prediction of outcome based on a large number of variables. for instance, a 71 year old married non-smoking high school graduate with a performance status (ps) of 0, and no weight loss or anaemia and a t3n1 hpv+opc would expect to have a progression-free survival of 92% at 2 years and 88% at 5 years. a 60 year old unmarried nonsmoking high school graduate with a ps of 1, weight loss and anaemia and a t4n2 hpv+opc would expect to have a survival of 70% at two years and 48% at five years. after surgery less detailed information is available for those treated primarily with surgery, for whom less patients are available, as well as low rates of recurrence (7–10%), but features that have traditionally been useful in predicting prognosis in other head and neck cancers, appear to be less useful in hpv+opc. these patients are frequently stratified into three risk groups: low risk: no adverse pathological features intermediate risk: t3–t4 primary, perineural or lymphovascular invasion, n2 (ajcc 7) high risk: positive margins, ece development of other cancers hpv+opc patients are less likely to develop other cancers, compared to other head and neck cancer patients. 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. regional recurrence after surgery the risk of regional cancer recurrence after neck dissection is often estimated from a large series based on all upper aerodigestive squamous cell cancers. in this series, the overall risks at three years by pathological stage (ajcc 7) were: pn0 4.7% pn1 4.9% pn2 12.1% epidemiology in 2015, squamous cell cancer of the head and neck region was the fifth most common cancer other than skin cancer, globally, with an annual incidence of 600,000 cases and about 60,000 cases annually in the united states and europe. the global incidence of pharyngeal cancer in 2013 was estimated at 136,000 cases. for 2008 the global burden of disease for opc in 2008 is estimated at 85,000 cases, of which 22,000 were attributable to hpv, a population attributable fraction (paf) of 26%. of these, 17,000 were males and 4,400 females, 13,000 (60%) were aged between 50 and 69 years of age, and the majority of cases (15,000) were in developed regions compared to developing regions (6,400). age standardised incidence rates (asr) differ considerably by region and country (see de martel et al., 2017 fig. 2b). asrs for 2012 were highest in europe (hungary 3.0) and north america (united states 1.7) but much lower in africa (≤ 0.3), asia (≤ 0.6), latin america (≤ 0.4) and oceania (≤ 0.2) (other than australasia, australia 0.9). estimated average numbers of cases and asr for the us in the period 2008–2012 were 15,738 and 4.5 respectively. hpv+opc was much more common in males than females (12,638, 7.6 and 3,100, 1.7). the highest incidence age group was 60–69, and was higher in caucasians than in other races. hpv+opc patients tend to be younger than hpv- patients in general. 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. trends there has been a global trend in increasing opc incidence, particularly in north america and northern europe, but even in taiwan, which has a very high rate for all cancers of the head and neck region, opc rates increased more rapidly between 1995 and 2009 than any other cancer site. the global burden of hpv+opc increased from 22,000 in 2008 to 29,000 by 2012, and the paf from 26% to 31%, and is considered an epidemic. 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. 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 largest increase in incidence has occurred in patients under age 50. 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 the incidence of hpv associated opc was 1.56 cases per 100,000 males/year (2001–2005), rising from 19% (1987–90), to 47% (2001–05) and 63.5% (2006–2010). in canada the percentage of cases of opc attributable to hpv increased from 47% in 2000 to 74% in 2012.