Human papillomavirus (HPV)-associated cancers of the anus, cervix, oropharynx, penis, vagina, and vulva constitute 5% of all cancers worldwide. In the United States, human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV+OPSCC) has been rapidly increasing in incidence, surpassing cervical cancer as the most common HPV-associated malignancy, with an estimated annual increase of 5% in White men aged 55 to 64 years from 1992 to 2015.1 By the year 2030, HPV+OPSCC will account for more than 30,000 new cancer diagnoses per year. Clinical practice guidelines from the College of American Pathologists currently recommend p 16 im-munohistochemistry as the diagnostic of choice for HPV+OPSCC because of its widespread availability, reproducibility of interpretation, low cost, and high correlation with high-risk human papillomavirus (HR-HPV) infection. Although p16 overexpression is a safe, effective, and widely used surrogate marker for HR-HPV in oropharyngeal squamous cell carcinoma (OPSCC), it suffers from a number of limitations. First, HPV+OPSCC classically presents with large cystic nodal metastases and small primary tumors; thus, the most common diagnostic approach is fine-needle aspiration (FNA) of a neck lymph node. FNA has intrinsic failure rates due to inadequate cellular material for evaluation in the range of 20% to 30% for the diagnosis of HPV+OPSCC. " Even at high-volume institutions with dedicated head and neck radiologists and surgeons performing ultrasound-guided FNA and experienced head and neck cytopathologists, repeat biopsy is necessary in — 15% of cases (unpublished institutional data). Furthermore, the interpretation of p16 on FNA specimens lacks consensus guidelines and is more variable than tissue interpretation, and this has resulted in a lack of standardization and decreased sensitivity. " Repeat FNA or subsequent tissue biopsy is often required to confirm a diagnosis of HPV+OPSCC, and this leads to increased costs, delays in diagnosis, patients being subjected to multiple invasive procedures, and increased diagnostic uncertainty. Second, although p16 is a relatively sensitive and specific surrogate marker for HR-HPV when used on tissue biopsies from oropharynx tumors in the United States, its performance and utility in other clinical settings are less clear. The most widely cited performance metrics for p 16 are based on US studies examining staining patterns in comparison with direct HPV testing (DNA polymerase chain reaction (PCR) or RNA in situ hybridization/reverse transcription-PCR in OPSCC, where HPV infection rates range from 60% to 80%. However, HPV is significantly less prevalent in other parts of the world. When the HPV-associated fraction of OPSCC drops, p16 specificity decreases as well, and this limits the utility of p16 for much of the world. Similarly, HPV is known to be an oncogenic driver in additional subsites of the head and neck. For example, a subset of nasopharyngeal carcinomas are HPV-associated, as are up to approximately one-quarter of sinonasal squamous cell carcinomas. The utility of p16 as a surrogate marker for HPV at these sites appears to be much less reliable, likely for similar reasons.
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