Molecular etiology of second primary tumors in contralateral tonsils of human papillomavirus-associated index tonsillar carcinomas

Abstract

Objectives For patients with tobacco-related head and neck squamous cell carcinoma (HNSCC), the occurrence of a second primary tumor (SPT) is an ominous development that is attributed to a field cancerization effect and portends a poor clinical outcome. The goal of this study was to determine whether patients with human papillomavirus (HPV)-related index tonsillar carcinomas can also develop SPTs in the contralateral tonsil, and to discern the molecular etiology of HPV-related tumor multifocality. Materials and Methods The surgical pathology archives of The Johns Hopkins Hospital were searched for all patients with primary HPV-related tonsillar squamous cell carcinoma who developed a synchronous or metachronous carcinoma in the contralateral tonsil. The HPV-16 E6 exon was sequenced from each independent cancer site to determine whether the tumor pairs harbored the same or a different HPV-16 variant. Results Four patients with bilateral HPV-related tonsillar carcinomas were identified. In every case, the HPV DNA sequences derived from the index tumor and corresponding SPT were 100% concordant, indicating that the index and SPTs were caused by the same HPV-16 variant. Conclusion For the small subset of patients with tonsillar carcinomas who develop SPTs in the contralateral tonsil, the index case and the SPT consistently harbored the same HPV variant. This finding suggests that HPV-related tumor multi-focality can be attributed either to independent inoculation events by the same virus, or by migration of HPV-infected cells from a single inoculation site to other regions of Waldeyer’s ring.

Human Papillomavirus-associated oropharyngeal cancer: an observational study of diagnosis, prevalence and prognosis in a UK population

“…The occurrence of second HPV16-positive primaries, both in the tongue base and nasopharynx (EBV-negative) in this study is intriguing. Second HPV-associated cancers in the tonsils and nasopharynx and HPV-positive/EBV-negative nasopharyngeal carcinomas have previously been reported [22-24] and it is possible that the lymphoid tissue throughout Waldeyer’s ring is particularly susceptible to HPV-induced transformation. Second primaries occurring in patients with a history of HPV-positive OPC should be tested for HPV and further studies to investigate the frequency and timing of HPV-positive second H&N primaries are required to inform future follow-up protocols.…”

Synchronous HPV-Positive Squamous Cell Carcinoma of the Bilateral Base of the Tongue

“…Several reports have described patients diagnosed with HPV-HNSCCs who subsequently developed SPTs of the head and neck; however, the SPTs in these reports developed in the tonsils or nasopharynx [7][8][9]. Our review of the literature suggests that this is the first report of synchronous HPV-positive SCCs of the bilateral BOT.…”

“…The incidence of second primary HPV-associated carcinoma is currently unknown. Joseph et al [8] reported an incidence of 4% for SPTs in the contralateral tonsil of patients presenting with an index HPV-associated tonsillar carcinoma.…”

“…Joseph et al [8] reported that in four patients with bilateral HPV-related tonsillar carcinomas, the HPV DNA sequences derived from the index tumor and corresponding SPT were 100% identical. They also speculated that HPV-related tumor multi-focality can be attributed either to independent inoculation events by the same virus, or by migration of HPV-related cells from a single inoculation site to other regions of Waldeyer's ring.…”

“…Although there have been a number of recent reports of synchronous HPV-associated tonsillar carcinomas, there have been no reports of synchronous HPV-associated BOT carcinoma. Here we report the case of a 59-year-old man with synchronous HPV-positive SCCs of the bilateral BOT [7][8][9].…”