L1 Capsid Protein Expression in HPV-Positive Barrett Metaplasia-Dysplasia-Adenocarcinoma Lesions

Human papillomavirus (HPV) has been associated with a subset of Barrett dysplasia and esophageal adenocarcinoma (EAC). The HPV L1 capsid protein has been closely linked to disease regression and is a prognostic factor in HPV-driven cancers of the cervix and anus.

Thus, we investigated L1 protein expression in HPV-positive patients representing the esophageal squamous-Barrett metaplasia-dysplasia-adenocarcinoma sequence. L1 protein immunohistochemical staining was correlated with p16 overexpression and E6/E7 mRNA in situ hybridization.

Of 116 HPV DNA-positive patients ([age range: 19-90, mean [SD], 63.2 [13.5], 88 men and 28 women), 73 (62.9%) were genotype 16, 37 (31.9%) genotype 18, and 6 (5.2%) were genotype 6. L1 staining was identified in 64 individuals: 84.9% (28/33) controls, 94.1% (16/17) Barrett's esophagus, 50% (7/14) low-grade dysplasia, (8/21) 38.1% high-grade dysplasia, and 16.1% (5/31) EAC (adjusted P < 0.0001). Conversely, p16 was present in 9.1% (3/33) of controls, 17.7% (3/17) Barrett's esophagus, 57.1% (8/14) low-grade dysplasia, 61.9% (13/21) high-grade dysplasia, and 64.5% (20/31) of EAC patients ( P < 0.0001). Corresponding figures for E6/E7 mRNA positivity was 6.1% (2/33), 23.5% (4/17), 28.6% (4/14), 38.1% (8/21), and 45.2% (14/31), respectively ( P = 0.008). Expression of HPV-L1 and p16 or L1 and E6/E7 mRNA was largely mutually exclusive.

HPV L1 capsid expression is incrementally lost with increasing esophageal disease severity as in viral-driven anal and cervical lesions. Utility of L1 alone or in combination with p16 and or E6/E7 mRNA in stratifying HPV-positive patients for treatment should be explored in a prospective longitudinal investigation.