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 highrisk 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 ¼ 0.003) who smoked less than HPV-negative patients (P ¼ 0.007). The proportion of HPV16-positive cases increased from 15% to 57% (P ¼ 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 ¼ 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 ¼ 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.

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In an era of advanced diagnostics, metastasis to cervical lymph nodes from an occult primary tumor is a rare clinical entity and accounts for approximately 3% of head and neck malignancies. Histologically, two thirds of cases are squamous cell carcinomas (SCCs), with other tissue types less common in the neck. With modern imaging and tissue examinations, a primary tumor initially undetected on physical examination is revealed in >50% of patients and the site of the index primary can be predicted with a high level of probability. In the present review, the range and limitations of diagnostic procedures are summarized and the optimal diagnostic workup is proposed. Initial preferred diagnostic procedures are a fine-needle aspiration biopsy (FNAB) and imaging. This allows directed surgical biopsy (such as tonsillectomy), based on the preliminary findings, and prevents misinterpretation of postsurgical images. When no primary lesion is suggested after imaging and panendoscopy, and for patients without a history of smoking and alcohol abuse, molecular profiling of an FNAB sample for human papillomavirus (HPV) and/or Epstein-Barr virus (EBV) is important.

Histologic assessment of tumor size and malignancy grade are useful in predicting metastasis. Vascular and perineural invasion are important predictors and should be included in multifactorial malignancy grading schemes. Application of the prognostic index to the biopsy specimen would aid in treatment planning.

Reporting of ECS is essential in accurate prognostication, and we advocate that all patients with OSCC and ECS should be grouped as pN3 on the basis of their prognosis. (c) 2009 Wiley Periodicals, Inc. Head Neck, 2010.

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