Autoridades Reguladoras Internacionales

short term.

On top of the costs of screening, each case of cervical cancer costs the health system $23,116 and other HPV related cancers likely bear similar costs. Investment in vaccination represents the most cost effective strategy long term for the prevention of all HPV associated cancers.

6.5 Possibilities for the early detection of HPV positive oropharyngeal cancer

Although vaccination will likely lead to dramatic reductions in OPC in the future, this will take decades as those who are vaccinated must be in in at least their forties before effects are seen.

Once we had established the burden of HPV positive OPC in New Zealand, we began to explore what might be possible in terms of early detection. The first step was to establish if a minimally invasive pap-test equivalent taken from conscious individuals was capable of detecting HPV (Chapter 5). To date many studies have used anaesthetised patients [123,125] or ex vivo brushings [126,127] which are useful for

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the simple detection of virus, but limits test practicalities. Furthermore, we sought to investigate any precancerous lesions that may occur adjacent to the tumour using cytology. Precancerous lesions for OPC are yet to be described, but adjacent dysplasia is described in the literature [81], and in 33% of pathology reports from Chapter two research. p16 staining in the adjacent epithelium of cases from Chapter two was also recorded.

Both the PAP2 and SPLIT studies aimed to detect precancerous lesions for HPV positive OPC in healthy individuals, and failed to find any such lesions [123,126]. As discussed in Chapter five, the study population for PAP2 was not optimally designed for OPC, and similar concerns can be raised with the SPLIT population. The SPLIT study population consisted of 200 patients aged over 15 years with a mean age of 30.3 years, of which 137 participants had undergone tonsillectomy for infectious reasons [127]. By comparison, our study was of known oropharyngeal cancer patients. From my work in cervical screening I was used to seeing the continuum of cytological changes present in cervical cancer samples and thought the same continuum may be seen in HPV positive OPC. The use of oropharyngeal cancer patients to explore lesions adjacent to known HPV positive tumours is a useful approach when so little is known about the natural history and progression of this disease. It is uncertain how long before the development of cancer such lesions will be present, and based on the study population demographics of the PAP and SPLIT studies they have assumed there will be a long lag time of 10-20 years as seen in cervical cancer.

The cytological abnormalities we have identified are comparable to cervical precancerous lesions. Cellular changes reported in Chapter five were coded using the

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Bethesda reporting system, and applied cervical criteria for low / high grade and malignant changes. The applicability of this system highlights similarities in the appearance between these changes and cervical lesions. Interestingly the continuum of low / high grade to malignant changes seen within samples was only present in p16 positive cases. Based on cytology alone these observed changes cannot be classified as precancerous lesions for OPC. Histological confirmation of the location of these cells in relation to the tumour, and molecular studies of the presence of transcriptionally active HPV within these cells is required. HPV behaves similarly in all anogenital cancers with precancerous lesions for cervical, anal, penile, vaginal and vulvar cancers being well described [14]. The changes observed in this study suggest similar behaviour of HPV in OPC.

Because of the low incidence of OPC, difficulties in sampling the tonsillar crypts, and the current lack of any defined precancerous lesions, population based screening as is used for cervical cancer is not a feasible option [128,165]. However, the pursuit of early detection of smaller tumours, ideally without regional metastases, remains a worthy one. Currently, the majority of OPC are detected when there is involvement of regional lymph nodes [46]. In theory, the detection of smaller localised tumours would result in reduced need for chemo- or radio- therapy and permit more surgical therapy being used. One such approach is trans oral robotic surgery (TORS). This is a new technique allowing tumour resection through the open mouth instead of by open surgery [53]. Early data on the use of TORS shows improved functional and oncologic outcomes for OPC patients [188].

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Chapter five reported that brushings taken from conscious patients can reliably detect HPV 16 DNA when there is an oropharyngeal abnormality. These recorded brushing site abnormalities ranged from slightly enlarged or irregular, to visible tumours and occurred in 50% of participants with recorded site appearances. The use of brushings from conscious individuals is important as it could in the future possibly translate to a point of care test that may provide referrals from primary care to Ear Nose and Throat (ENT) services. Currently, ENT referrals are at the GPs discretion and may vary between GPs and practices. From my first hand collection of samples, the brushing procedure was well tolerated by patients with only minimal discomfort. Only one participant I sampled refused to have an adjacent site sample once the first brushing was taken and this was not due to the procedure, but instead the pain associated with holding his jaw open due to the location of the tumour.

Aside from a mass in the neck the symptoms of OPC can be vague. Consistent with other published data [189], Chapter four reported that many patients experienced a sore throat, pain when swallowing, earache, a feeling of something being stuck in the throat, and hoarseness of the voice in the six months before their diagnosis. These symptoms are often associated with more benign conditions, and taking brushings from every patient with a sore throat would not be a feasible early detection approach for HPV positive OPC. The development of a set of criteria, or a simple questionnaire to determine risk and thus prioritize who has brushings taken should be considered. Based on finding from this thesis, criteria could include: appearance of the tonsils, the presence and progression of symptoms, and a brief questionnaire on sexual behaviours and exposures to hazardous substances.

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Part of this further research on the use of brushings for early detection would need to carefully consider what would happen after the detection of HPV 16 in a sample. The simple detection of virus may not be associated with the presence of cancer, however, study participants in this research have reported neck masses have appeared over a matter of days, and others that the neck masses over doubled in size in two months. It has been suggested HPV infection in the oropharynx is more likelythan HPV infection in the cervix to progress to cancer [166], and OPC is also more likely to metastasize regionally than cervical cancer [190]. The aggressive behaviour of these tumours suggests that any follow up after the detection of HPV 16 may need to be rapid. Hypothetically, performing a tonsillectomy on all those with HPV 16 positive brushings would likely help in the description of any precancerous lesions, and could in itself be a curative treatment. However, tonsillectomy is not without its own risks and involves considerable use of finite healthcare resources. Other approaches could include the use of narrow band imaging technology which has in limited case reports been used in the detection of very small OPC [172,173].

The thematic analysis of free text comments also revealed four reports of a delay between presentation of symptoms to primary health care and final diagnosis. These comments fell below the required number (six) to be identified as a theme but nevertheless represent an important issue in OPC. These participants’ accounts mirror a recently published case study [191]. In the case study, a woman presented to her primary care physician with left ear pain and received antibiotics and increasing doses of pain medication over the next 23 months, until she had speech difficulties and was referred for an MRI. This confirmed a large mass which was an HPV positive OPC [191]. In the primary care setting, there needs to be awareness of OPC as a potential

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diagnosis, particularly in younger, otherwise healthy patients. Recently, Whanganui District Health Board organised an inter-professional education evening raising awareness on HPV positive OPC targeted at those working in primary healthcare. Approaches such as this are important as it is possible an earlier referral to ENT services could lead to earlier diagnosis.