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Cancer of an unknown primary (CUP), or an occult primary, is the existence of metastatic tumors confirmed by histological examination when there is no detectable site of the primary cancer by conventional methods1. Unfortunately, CUP of head and neck is one of the most common malignant neoplasms in the world. Suboptimal treatment planning might be result from not detecting occult primary, thus negatively affecting patient prognosis1. 18F-FDG PET/CT, a non-invasive molecular imaging procedure, has proven to be a valuable imaging technique in the detection of CUP. In addition, the association between Human papillomavirus (HPV) and primary tumors has been established. The purpose of this research is to explore the role of PET/CT in the assessment of occult primary of the head and neck cancers analyzed by HPV status.
Keywords: PET/CT, occult primary, HPV.

PET/CT In Diagnosis of Occult Primary Of Head And Neck Cancers Analyzed by HPV status
Head and neck cancers are a major cause of morbidity and mortality around the world.2 In 2008, more than 500,000 patients were diagnosed of head and neck cancers, with around 6,000 cases from the United Kingdom, making them the most fifth prevalent carcinomas.3 In addition, cancer of unknown primary (CUP) of the head and neck often metastasizes to the lymph nodes, representing 3-5% of all head and neck malignant tumors.4 Schmalbach and Miller4 pointed out that identifying the sites of occult primary cancer is essential for allowing site-specific therapy and for minimizing the side effects of radiation from treatment. Thus, various methods have been utilized for the detection of primary lesions. These methods include physical assessment and endoscopic examination of the head, neck, and upper aerodigestive tract in addition to cross-sectional imaging with Computed Tomography (CT) and Magnetic Resonance Imaging (MRI). Although the majority of primary tumors are successfully detected by these investigations, 2-9% of the origins of primary tumors remain undiscovered.5
With advances in medical imaging technology,18F-fluorodeoxy-D-glucose positron emission tomography-computed tomography (18F-FDG PET/CT) has been widely utilized for staging, restaging, and post-therapy follow-up in several head and neck cancers. According to Cammaroto et al.,2 PET/CT has been proven superior at identifying cancer of unknown primary, cervical lymph nodes adenopathy, and distal metastatic disease. It also has advantages over CTs and MRIs in the detection of recurrent and second primary lesions.2 In a study of 78 patients who presented with neck nodal metastases with no primary cancer identified by CT/MRI, the authors found that PET/CT detected primary malignancies in 30 patients, with a recorded sensitivity and specificity of 100% and 66.7%, respectively, thus improving detection of occult primaries by 40%. 6 However, it remains unclear how often PET/CT is currently performed in routine clinical practice for occult primary.
Another imperative question is weather PET/CT should be performed as a first step in identifying occult primary or as a second procedure after CT/MRI imaging. In 2016, the National Institute for Health and Care Excellence (NICE)? recommended performing PET/CT as the first procedure to identify the primary site in patients presenting with metastatic nodal squamous cell carcinoma of unknown origin that is thought to arise from the upper aerodigestive tract.7 Nonetheless, a limited number of studies have evaluated the utility of a baseline PET/CT in the detection of occult primary of head and neck cancers.
Despite the advantages of PET/CT, Park et al.5 emphasized that small lesions might not be easily identified by 18F-FDG PET/CT, which may cause false-negative and false-positive scans.4 As a result, extensive research has been conducted to examine the association between various biomarkers, such as Human papillomavirus (HPV) and SCCUP, in order to identify the effects of positive or negative HPV status on the management of head and neck cancers. For instance, in a matched-pairs analysis conducted on 136 patients diagnosed of CUP, the results revealed a significant connection between HPV positive status and discovery of unknown lesions, which improved overall survival, cause-specific survival, and disease-free survival.8 In a retrospective study of 61 patients diagnosed with oropharyngeal squamous cell carcinoma (OSCC), the authors found that overall recurrence rates in positive and negative HPV patients were 24% and 55%, respectively. The results suggested that a negative first PET/CT post-therapy is associated with an improve in the prognostic value and less recurrence, particularly in patients affected by positive HPV infection.9 However, more research should be carried out to assess the effectiveness of PET/CT in identifying second primary/metastatic rates of head and neck carcinomas in patients affected by HPV.
Therefore, in this research, I will conduct a systematic review to assess the value of PET/CT scanning for the detection occult primary of head and neck cancers analyzed by HPV status. Then, I will undertake a survey to determine how many patients undergo PET/CT at a baseline, for what indications, how many PET/CTs are conducted for an occult primary, and at what point in the pathway. Furthermore, I will assess the utility of PET/CT scanning for identifying the occult primary in a series of around 120 patients from UHB and Mount Vernon Hospital. I will also identify the second primary/metastases rates on PET/CTs done for primary HNSCC by HPV status. Finally, I will describe the factors that affect SUVs and provide recommendations for acquiring SUV information.
Methodology:
A systemic search will be performed using PubMed, Google Scholar, and ScienceDirect to identify relevant studies published from 2005 to the present within scientific journals such as Clinical Oncology Journal, Journal of Otolaryngology – Head and Neck Surgery, and International Journal of Oncology. In addition, a survey will be generated and distributed (via email) to clinicians. Furthermore, a retrospective study of the medical records of around 120 patients who underwent PET/CT for occult primary will be analyzed to assess the utility of PET/CT in detection of unknown primary cancers, second primary, and metastatic rates in patients with head and neck carcinomas.

A provisional timetable for the project
Time Period Anticipated Activities
Year One • In-depth reading around the topics in areas such as:
PET/CT in occult primary, HPV status
• Preparation and drafting of Literature Review
• Preparing a structured survey
Year Two • Data collection
• Initial attempts of Data Analysis begin
Year Three • Data Analysis continues
• Begin planning write up
Year Four • Completion of Final Write up

References

1. Kwee TC1, Kwee RM. Combined FDG-PET/CT for the detection of unknown primary tumors: systematic review and meta-analysis. Eur Radiol Internet. 2009 Mar cited 2018 Jul 16 ;19(3):731-44. Available from: https://www.ncbi.nlm.nih.gov/pubmed/18925401 DOI: 10.1007/s00330-008-1194-4
2. Cammaroto G, Quartuccio N, Sindoni A, Di Mauro F, Caobelli F. The role of PET/CT in the management of patients affected by head and neck tumors: a review of the literature. Eur Arch Otorhinolaryngol Internet. 2016 Aug cited 2018 Jul 13;273(8):1961-1973. Available from: https://link.springer.com/article/10.1007%2Fs00405-015-3651-4 DOI: 10.1007/s00405-015-3651-4
3. Mccarthy CE, Field JK, Rajlawat BP, Field AE. Marcus MW. Trends and regional variation in the incidence of head and neck cancers in England. ?Int J Oncol ?Internet. 2015 Mar cited 2018 Jul 13;47(1):204-210. Available from: https://www.spandidos-publications.com/ijo/47/1/204 DOI: 10.3892/ijo.2015.2990??????????
4. Schmalbach CE, Miller FR. Occult primary head and neck carcinoma. Curr Oncol Rep?Internet. 2007 Mar cited 2018 Jul 14;9(2):139-46. Available from: https://www.ncbi.nlm.nih.gov/pubmed/17288881
5. Park GC, Roh JL, Cho KJ, Seung Kim J, Hyeon Jin M, Choi S, et al. 18F-FDG PET/CT vs. human papillomavirus, p16 and Epstein–Barr virus detection in cervical metastatic lymph nodes for identifying primary tumors. Int J Cancer Internet. 2016 Dec cited 2018 Jul 14;140: 1405-12. Available from: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ijc.30550 DOI:10.1002/ijc.30550
6. Wong WL, Sonoda LI, Gharpurhy A, Gollub F, Wellsted D, Goodchild K, et al. 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the assessment of occult primary head and neck cancers — an audit and review of published studies. J CLIN ONCOL Internet. 2012 Apr cited 2018 Jul 14;24(3):190-95. Available from: https://doi.org/10.1016/j.clon.2011.11.001 DOI: 10.1016/j.clon.2011.11.001
7. The National Institute for Health and Care Excellence. Cancer of the upper aerodigestive tract: assessment and management in people aged 16 and over Internet. 2016 Feb updated 2018 Jun; cited 2018 Jul 15. Available from: https://www.nice.org.uk/guidance/ng36/chapter/Recommendations
8. Davis KS, Byrd JK, Mehta V, Chiosea SI, Kim S, Ferris RL, et al. Occult primary head and neck squamous cell carcinoma: utility of discovering primary lesions. Otolaryngol Head Neck Surg Internet. 2014 Aug cited 2018 Jul 14;151(2): 272–8. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4604041/ DOI: 10.1177/0194599814533494
9. Koshkareva Y, Branstetter BF, Gaughan JP, Ferris RL. Predictive accuracy of first post?treatment PET/CT in HPV?related oropharyngeal squamous cell carcinoma. Laryngoscope Internet. 2014 Aug cited 2018 Jul 15;124(8): 1843-7. Available from: http://111081of5.y.https.onlinelibrary.wiley.com.kau.proxy.deepknowledge.io/doi/10.1002/lary.24617 DOI:10.1002/lary.24617

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