Audit of oropharyngeal cancer reporting and frequency of p16 testing at Derriford Hospital. Cost and clinical implications Miss S J Edwards ENT StR Dr. T Bracey Consultant Histopathologist Jan 2013

Introduction Human papilloma virus (HPV) is an etiologic agent in a subset of oropharyngeal squamous cell carcinomas (OPSCC) associated with better patient survival. Determination of HPV status is becoming recognized as an important consideration in the management and prognosis of OPSCC. p16 is a tumour suppressor protein that is also considered to be a surrogate marker of HPV infection in SCC of the cervix and head and neck. We looked at p16 and HPV testing performed on samples of OPSCC received in Derriford histopathology lab.

Guidelines RCPath - Dataset for histopathology reporting of mucosal malignancies of the pharynx -November 2013 (1) “To allow the stratification of the outcomes of treatment, the HPV status of all oropharyngeal carcinomas should be assessed.” “The immunocytochemical identification of over-expression of p16 protein is a useful screening method for HPV infection.” “Carcinomas showing p16 over-expression should have the presence of HPV confirmed by in situ hybridisation, if possible.” “The report should indicate the methods used to evaluate HPV status (p16 immunocytochemistry and/or in situ hybridisation).”

Background 1 The oropharynx is defined as the area from the junction of the hard and soft palate to the hyoid bone, bordered by the anterior tonsillar pillars laterally.

Background 2 OPSCC was traditionally associated with risk factors like increased alcohol consumption and smoking. The incidence of oropharyngeal carcinoma has been increasing despite declining tobacco consumption. It is now clear that the incidence of human papillomavirus (HPV)- associated oropharyngeal cancers is rising. Compared with the traditional smoking-associated head and neck squamous cell carcinoma, HPV-related oropharyngeal carcinoma has a favourable natural history and responds better to treatment. (2)

Background 3 Current "gold standard" based on RCPath dataset states HPV testing should be done on all oropharyngeal SCC Each p16 test costs department approximately £20 to perform. It is recommended that all the cases POSITIVE for p16 should be HPV-ISH tested, an additional £30 per slide.

Methods Patient population identified through clinical coding. Patient details obtained for head and neck histopathological samples received coded for carcinoma in 2011 and Histology reports viewed to establish Anatomical site of sample Differentiation p16 result

Limitations Patient samples may have been missed if incorrectly coded Samples predate new dataset guidelines Provisional 2013 data shows similar trend

Results 1 Total number of patient samples in database: 2011 – – 55 Number of OPSCC: 2011 – – 20 Other samples were not anatomically from the oropharynx or were not SCC E.g. hypopharyngeal samples and non-SCC carcinomas (bronchogenic and neuroendocrine) were tested for p16 in 2012

Results 1

Results 2 Total number of all H&N samples tested for p – Number of OPSCC samples tested for p – – 12 Number of OPSCC samples not tested for p – – 8

Results 2

Results 3 Actual cost of p16 testing each year £ £300 Potential cost of p16 testing all suspected OPSCC £ £400 Potential cost of p16 testing plus HPV-ISH 2011 – up to £ – up to £1000

Discussion Most of the OPSCC tested were p16 positive, in line with the literature, 50 – 80% usually quoted. (3) “Gold standard” of 100% p16 testing of OPSCC was not achieved, however frequency improved between 2011 and HPV and p16 have their importance as a prognostic tool, where patients with positive samples have better overall survival (2,4) Can also be used in testing lymph nodes of unknown origin.

Discussion 2 HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome. Chernock RD et al. Head and Neck Pathol (2009) 3:186–194 Aim to 1) sub-classify SCC of the oropharynx based upon histologic features into nonkeratinizing (NK) SCC, keratinizing (K) SCC, and hybrid SCC 2) determine the frequency of HPV and patient survival in each group. Patients with oropharyngeal SCC with a minimum of 2 years of clinical follow- up were identified from radiation oncology databases from 1997 to In situ hybridization (ISH) for high-risk HPV subtypes and immunohistochemistry for p16 were performed. Overall and disease-specific survival were assessed.

Discussion 3 HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome. Chernock RD et al. Head and Neck Pathol (2009) 3:186–194 Of 118 cases, 46.6% were NK SCC, 24.6% K SCC and 28.8% hybrid SCC. NK SCC occurred in younger patients, often male. Frequently presented with lymph node metastases and was surgically resected compared to K SCC. NK SCC was significantly more likely to be HPV and p16 positive than KSCC (P\0.001) and to have better overall and disease-specific survival (P = ; P = , respectively). Hybrid SCC was also more likely than K SCC to be HPV and p16 positive (P = 0.003; P = 0.002, respectively) and to have better overall survival (P = ). Sub-classification of oropharyngeal SCC by histologic type provides useful clinical information. NK SCC histology strongly predicts HPV-association and better patient survival compared to K SCC.

Discussion 4 p16 is not exclusively present in HPV +ve OPSCC, but those HPV –ve samples that are p16 +ve still appear to have better outcomes. (3) p16 has a high sensitivity, good histologic correlation, good availability. Downside is lower specificity. Decreasing treatment intensity in some HPV +ve OPSCC patients is currently being considered but no widespread agreement Cost implications have to be considered Important to have correct anatomical location of sample to prevent unnecessary testing and costs

Recommendations Distribution of new RCPath dataset Encourage p16 testing of all oropharynx SCC with HPV-ISH on positive cases after MDT review Surgical teams to specify anatomical location of biopsy on request form Encourage description of keratinisation as well as differentiation on histology reports Analysis of 2013 figures to predict trends and cost implication. Initial analysis suggests 20x£20=£400 + approximately 16x£30 (HPV-ISH)= £480

References 1) Helliwell T,Woolgar J. Dataset for histopathology reporting of mucosal malignancies of the pharynx.. Royal College of Pathologists, November /G111_PharynxMucosalDataset_Nov13.pdf /G111_PharynxMucosalDataset_Nov13.pdf 2) Ang KK, Sturgis EM. Human papillomavirus as a marker of the natural history and response to therapy of head and neck squamous cell carcinoma. Semin Radiat Oncol Apr;22(2): ) HPV and p16 Testing in Oropharyngeal Squamous Cell Carcinoma. Methodology, Interpretation, and Significance. p16/index.html p16/index.html 4) Chernock RD et al. HPV-Related Nonkeratinizing Squamous Cell Carcinoma of the Oropharynx: Utility of Microscopic Features in Predicting Patient Outcome. Head and Neck Pathol (2009) 3:186–194

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