Terence M. Jones

Evaluation of Human Papilloma Virus Diagnostic Testing in Oropharyngeal Squamous Cell Carcinoma: Sensitivity, Specificity, and Prognostic Discrimination

Purpose: Human papillomavirus-16 (HPV16) is the causative agent in a biologically distinct subset of oropharyngeal squamous cell carcinoma (OPSCC) with highly favorable prognosis. In clinical trials, HPV16 status is an essential inclusion or stratification parameter, highlighting the importance of accurate testing. Experimental Design: Fixed and fresh-frozen tissue from 108 OPSCC cases were subject to eight possible assay/assay combinations: p16 immunohistochemistry (p16 IHC); in situ hybridization for high-risk HPV (HR HPV ISH); quantitative PCR (qPCR) for both viral E6 RNA (RNA qPCR) and DNA (DNA qPCR); and combinations of the above. Results: HPV16-positive OPSCC presented in younger patients (mean 7.5 years younger, P = 0.003) who smoked less than HPV-negative patients (P = 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P = 0.001) between 1988 and 2009. A combination of p16 IHC/DNA qPCR showed acceptable sensitivity (97%) and specificity (94%) compared with the RNA qPCR “gold standard”, as well as being the best discriminator of favorable outcome (overall survival P = 0.002). p16 IHC/HR HPV ISH also had acceptable specificity (90%) but the substantial reduction in its sensitivity (88%) impacted upon its prognostic value (P = 0.02). p16 IHC, HR HPV ISH, or DNA qPCR was not sufficiently specific to recommend in clinical trials when used in isolation. Conclusions: Caution must be exercised in applying HPV16 diagnostic tests because of significant disparities in accuracy and prognostic value in previously published techniques. Clin Cancer Res; 17(19); 6262–71. ©2011 AACR.

Oropharyngeal carcinoma related to human papillomavirus

Incidence is increasing rapidly, with implications for prognosis and policy

A Systematic Review of p53 as a Prognostic Factor of Survival in Squamous Cell Carcinoma of the Four Main Anatomical Subsites of the Head and Neck

Objectives: To summarize existing evidence about whether the presence of mutant or upregulated p53 is a prognostic factor for patients presenting with squamous cell carcinoma arising from the larynx, oropharynx, hypopharynx, or oral cavity. Method: Relevant articles were identified using strict criteria for systematic searches. Associations between mutant or upregulated p53 versus wild-type or low/undetectable p53 in relation to overall survival and DFS were summarized by extracting or deriving hazard ratio (HR) estimates. Random-effects meta-analyses were used to account for between-study heterogeneity and to summarize the effect of p53 across studies. Results: The meta-analyses gave a statistically significant pooled HR for overall survival in oral cavity [pooled HR, 1.48; 95% confidence interval, (95% CI), 1.03-2.11], and for disease-free survival in oral cavity (pooled HR, 1.47; 95% CI, 1.12-1.93) and in oropharynx (pooled HR, 0.45; 95% CI, 0.27-0.73). Despite attempts to limit it, between-study heterogeneity was large in the majority of meta-analyses and the prognostic value of p53 was generally inconsistent and inconclusive across studies. Conclusion: The meta-analysis results highlight that current evidence about the prognostic value of p53 in patients with squamous cell carcinaoma of the head and neck is inconclusive. Large heterogeneity exists across studies in study-level and patient-level characteristics, making it difficult to ascertain a clear picture. Future studies are required in which p53 expression is investigated in a more standardized and biologically informative manner. In particular, prospectively planned individual patient data meta-analyses are needed to establish the prognostic importance of p53 for specific subgroups of patients undergoing specific treatments. Cancer Epidemiol Biomarkers Prev; 19(2); 574–87

Localized amyloidosis of the parotid gland: A case report and review of the localized amyloidosis of the head and neck

Localized amyloidosis in the head and neck is a rare and benign process.

Waiting times during the management of head and neck tumours.

The waiting times incurred during the management of 75 consecutive head and neck oncology patients attending for post-treatment follow-up were reviewed. Data were gleaned from general practitioner (GP) referral letters, patient case-notes as well as radiology and histology reports. The mean time for GP referral to ENT was 5.1 weeks. From ENT to endoscopy was 3.1 weeks, to histology 3.5 weeks, to computed tomography (CT) scan 5.6 weeks, to magnetic resonance scan (MR) 4.1 weeks, to primary radiotherapy 10.3 weeks and to surgery 5.5 weeks. The mean symptom duration prior to referral was 4.9 months. Our results compare unfavourably with the standards recommended by the BAO-HNS. Local modifiations may improve matters, but significant increases in funding, manpower and equipment are required to achieve the stipulated standards. Moreover, criteria for referral have to be re-emphasized and patient education has to be addressed as these appear to contribute the longest delay in the diagnosis of head and neck tumours.

Outcomes following pharyngolaryngectomy reconstruction with the anterolateral thigh (ALT) free flap.

We retrospectively reviewed 15 cases of pharyngolaryngectomy for advanced laryngeal carcinoma reconstructed with the anterolateral thigh (ALT) free flap. Thirteen patients had primary surgery and adjuvant treatment (radiotherapy or chemoradiotherapy), and two had salvage surgery. Thirteen had stage III or IV disease, and eight had cervical nodal extracapsular spread. In this series all the flaps survived, and at median follow-up of 14.5 months (range 3.7-31.2), 12 of the 15 patients were alive. One patient developed a chronic pharyngocutaneous fistula, and five required repeat balloon dilatations for late pharyngeal strictures. Six patients enjoyed restoration of full oral intake, seven were able to take a soft diet, and two were dependent on feeding by percutaneous endoscopic gastrostomy. Four patients developed adequate tracheo-oesophageal speech, and one successfully developed oesophageal speech. In this series many of the surgical problems associated with pharyngolaryngectomy reconstruction were addressed successfully by the ALT, but late dysphagia remained troublesome in an appreciable minority. While adjuvant radiotherapy could have contributed to this, future innovations will focus on the reduction of late strictures.

Treatment of Squamous Cell Carcinoma of the Tongue Base: Irradiation, Surgery, or Palliation?

Objectives: Squamous cell carcinoma of the tongue base has a poor prognosis, and treatment is accompanied by a number of major problems. In view of this, it is important to recognize which patients will benefit from treatment with curative intent and which treatment method to use. Methods: One hundred sixty-five patients with squamous cell carcinoma of the tongue base were identified on our database. Eighty-two patients were treated by radical irradiation, and 41 by surgery. A further 42 patients were considered unsuitable for curative treatment. Results: The 5-year cause-specific survival rate was 41% for those treated by irradiation, 58% for those treated by surgery, and 9% for untreated patients. There was no difference in the efficacy of treatment methods (p = .5362), but a highly significant difference was seen in survival rate between treated and untreated patients (p = .0028). The decision regarding administration of curative treatment was based on the extent of locoregional involvement at the primary site (p = .0139; odds ratio, 0.43) and in the neck (p = .0078; odds ratio, 0.23). No factors affected the decision to treat by irradiation or surgery. When the observed survival rate was calculated, there was no significant difference in 5-year survival rate between treated and untreated patients (p = .2762). Those with early (T1-2) disease at the primary site had an improved survival rate from 0.5 to 4 years compared with those who were untreated (T3-4; p = .0081; odds ratio, 2.2). In addition, those with early (T1-2) disease had a better survival rate than those with advanced cancers (p = .0139; odds ratio, 2.09). There was, however, no difference in survival rate at 5 years. Those with early disease compared with those with advanced disease were twice as likely to be alive at 2 years; however, all survival advantages had disappeared by 5 years. Conclusions: In terms of observed survival, treating tongue base squamous cell carcinoma that is locally advanced (T3-4) at presentation offers no survival advantage over palliation alone. Treating early disease (T1-2) doubles the survival rate for up to 4 years, but by 5 years this survival advantage is lost. The present study finds radiotherapy and surgery to be equivalent at controlling this disease.

IGF-1R expression is associated with HPV-negative status and adverse survival in head and neck squamous cell cancer

Head and neck squamous cell carcinomas (HNSCC) are treated with surgery, radiotherapy and cisplatin-based chemotherapy, but survival from locally-advanced disease remains poor, particularly in patients whose tumors are negative for Human papillomavirus (HPV). Type 1 IGF receptor (IGF-1R) is known to promote tumorigenesis and resistance to cancer therapeutics. Here, we assessed IGF-1R immunohistochemistry on tissue microarrays containing 852 cores from 346 HNSCC patients with primary tumors in the oropharynx (n = 231), larynx (85), hypopharynx (28), oral cavity (2). Of these, 236 (68%) were HPV-negative, 110 (32%) positive. IGF-1R was detected in the cell membrane of 36% and cytoplasm of 92% of HNSCCs; in 64 cases with matched normal tonsillar epithelium, IGF-1R was overexpressed in the HNSCCs (P < 0.001). Overall survival (OS) and disease-specific survival (DSS) were reduced in patients whose tumors contained high membrane IGF-1R [OS: hazard ratio (HR) = 1.63, P = 0.006; DSS: HR = 1.63, P = 0.016], cytoplasmic IGF-1R (OS: HR = 1.58, P = 0.009; DSS: HR = 1.58, P = 0.024) and total IGF-1R (OS: HR = 2.02, P < 0.001; DSS: HR = 2.2, P < 0.001). High tumor IGF-1R showed significant association with high-tumor T-stage (P < 0.001) and HPV-negativity (P < 0.001), and was associated with shorter OS when considering patients with HPV-positive (P = 0.01) and negative (P = 0.006) tumors separately. IGF-1R was independently associated with survival in multivariate analysis including HPV, but not when lymphovascular invasion, perineural spread and T-stage were included. Of these factors, only IGF-1R can be manipulated; the association of IGF-1R with aggressive disease supports experimental incorporation of anti-IGF-1R agents into multimodality treatment programs for HPV-negative and high IGF-1R HPV-positive HNSCC.

Loss of MTBP expression is associated with reduced survival in a biomarker-defined subset of patients with squamous cell carcinoma of the head and neck†

Recent genetic studies have implicated p53 mutation as a significant risk factor for therapeutic failure in squamous cell carcinoma of the head and neck (SCCHN). However, in a recent meta‐analysis in the literature of p53 from major anatomical subsites (larynx, oral cavity, oropharynx/hypopharynx), associations between patient survival and p53 status were ambiguous.

How we do it: Head and neck cancer waiting times

After instigation of rapid access referrals from GPs and the Calman‐Hine 2‐week rule, the times taken from initial presentation to the GP, until the start of definitive treatment for patients with head and neck cancer managed was audited and compared with national guidelines.