Tonsillar crypts

Abstract: Purpose: Human papillomavirus 16 (HPV-16) has been implicated as a causative agent in a subset of head and neck squamous cell carcinomas (HNSCC). This study was undertaken to discern the distribution and timing of HPV viral integration during tumorigenesis of the upper respiratory tract. Experimental Design: A tissue array was assembled from a consecutive group of 176 patients with HNSCCs. The array was evaluated by HPV-16 in situ hybridization and p16 immunohistochemistry. Patients with HPV-positive tonsillar cancers who had undergone bilateral tonsillectomies were selected for more complete mapping of viral integration. Results: HPV-16 was detected in 38 of the 176 (22%) cases by in situ hybridization. When stratified by site of origin, HPV-16 was detected in 37 of 45 cancers arising from the oropharynx but in only 1 of 131 tumors arising from nonoropharyngeal sites (82% versus 0.8%, P P Conclusions: HPV-16 is strongly associated with carcinomas arising from the oropharynx, and integration is tightly coupled to the neoplastic process. Viral integration does not occur as a field alteration throughout normal tonsillar epithelium. P16 expression localizes to HPV-positive cancers, and is intrinsic to the specialized epithelium of the tonsillar crypts. For risk assessment, early cancer detection and disease surveillance, evidence of HPV-16 integration may represent a meaningful finding, whereas high p16 expression, by itself, may not.

Abstract: The early events during infection with an immunodeficiency virus were followed by application of pathogenic simian immunodeficiency virus atraumatically to the tonsils of macaques. Analyses by virologic assays and in situ hybridization revealed that the infection started locally in the tonsils, a mucosal-associated lymphoid organ, and quickly spread to other lymphoid tissues. At day 3, there were few infected cells, but then the number increased rapidly, reaching a high plateau between days 4 and 7. The infection was not detected in the dendritic cell–rich squamous epithelium to which the virus was applied; instead, it was primarily in CD4+ tonsillar T cells, close to the specialized antigen-transporting epithelium of the tonsillar crypts. Transport of the virus and immune-activating stimuli across this epithelium would allow mucosal lymphoid tissue to function in the atraumatic transmission of immunodeficiency viruses.

Abstract: The prevalence of human papillomavirus (HPV) infection is high in the oropharyngeal mucosal regions, of which the tonsil is the most commonly affected. There may be a link between HPV and the pathogenesis of tonsillar cancer (TC), because of common anatomical characteristics between cervical and tonsillar cancer. We aimed to clarify whether HPV directly affects the oncogenesis and biologic behavior of TC by making a comparison between infection prevalence, physical status and viral loading numbers, and clinicopathologic prognostic factors. To compare HPV-related molecules between TC and tonsillitis (CFT), p16, survivin, HIF-1alpha, skp-1, cyclin A, cyclin B1, c-myc and EGFR were investigated. We observed a significant difference in HPV prevalence between 52 TCs and 69 CFTs (73.1% vs. 11.6%), and most of the HPVs were type 16 (87.2%) and nonepisomal (94.1%). Most TCs associated with HPV arose from the tonsillar crypts, and tended to be inverted and poorly differentiated. Compared with HPV-negative TC, HPV-positive TC showed a strong association with p16 overexpression (p<0.0001), and an inverse association with EGFR amplification (p=0.0478). HPV-16 integration status was strongly associated with c-myc amplification (p=0.034) and HIF-1alpha overexpression (p=0.022). HPV-16 integration could be directly related to tonsillar carcinogenesis initially in tonsillar crypts, followed by cell cycle aberration such as p16 overexpression related to the G1-S phase.

Abstract: Human papillomavirus (HPV) is responsible for the rising incidence of oropharyngeal squamous cell cancers (OSCC) in the United States, and yet, no screening strategies have been evaluated. Secondary prevention by means of HPV detection and cervical cytology has led to a decline in cervical cancer incidence in the United States. Here, we explored an analogous strategy by evaluating associations between HPV16 infection, cytopathology, and histopathology in two populations at elevated risk for OSCCs. In the first, a cross-sectional study population (PAP1), cytology specimens were collected by means of brush biopsy from patients presenting with oropharyngeal abnormalities. In the second (PAP2), a nested case-control study, bilateral tonsillar cytology samples were collected at 12-month intervals from HIV-infected individuals. The presence of cytopathologic abnormality in HPV16-positive tonsil brush biopsies (cases) was compared with HPV16-negative samples (controls) matched on age and gender. HPV16 was detected in samples by consensus primer PCR and/or type-specific PCR. Univariate logistic regression was used to evaluate associations. In PAP1, HPV16 alone (OR: 6.1, 95% CI: 1.6-22.7) or in combination with abnormal cytology (OR: 20, 95% CI: 4.2-95.4) was associated with OSCC. In PAP2, 4.7% (72 of 1,524) of tonsillar cytology specimens from HIV-infected individuals without oropharyngeal abnormalities were HPV16 positive. Tonsillar HPV16 infection was not associated with atypical squamous cells of unknown significance (ASCUS), the only cytologic abnormality identified. Therefore, HPV16 was associated with OSCCs among individuals with accessible oropharyngeal lesions but not with cytologic evidence of dysplasia among high-risk individuals without such lesions. An oropharyngeal Pap-test equivalent may not be feasible, likely due to limitations in sampling the relevant tonsillar crypt epithelium.