Introduction
High-risk human papillomavirus (hr-HPV) has been associated with a subset of Barrett’s dysplasia (BD) and oesophageal adenocarcinoma (OAC).1,2,3,4 The L1 major capsid protein has been closely linked to disease regression and is a prognostic factor in HPV driven cancers of the cervix and anus.5,6 The progression of cervical intraepithelial neoplasia to invasive cancer is accompanied by a loss of viral L1 capsid protein expression.
Aims & Methods
Thus, in a retrospective, cross-sectional study, we investigated L1 protein expression in HPV-positive patients representing the oesophageal squamous (controls) [Group1]-Barrett’s metaplasia [Group 2]-low-grade dysplasia [Group 3]-high-grade dysplasia [Group 4]-adenocarcinoma [Group 5] sequence. L1 protein immuno-histochemical staining was correlated with p16 overexpression and E6/E7 mRNA in-situ hybridization. The association between the 5 patient groupings and L1 expression was analysed using the Chi-square test. Multivariable logistic regression was undertaken to investigate the above association with adjustment of potential confounders (age, gender, BMI, ever smoked and excess alcohol). Adjusted odds ratio (95% CI) was calculated.
Results
Of 116 HPV DNA-positive patients [(age range: 19-90, mean (SD), 63.2 (13.5)], 88 males and 28 females), 73 (62.9%) were genotype 16, 37 (31.9%) genotype 18 and 6 (5.2%) were genotype 6. L1 nuclear staining was observed in 64 individuals. L1 expression was detected in 84.9% (28/33) of controls; 94.1% (16/17) of BO patients; 50% (7/14) of LGD subjects; 38.1% (8/21) of HGD individuals and 16.1% (5/31) of OAC patients; [adjusted P < 0.0001]. Conversely, p16 was present in 9.1% (3/33) of controls, 17.7% of BO (3/17), 57.1% (8/14) in LGD individuals, 61.9% (13/21) of HGD patients and 64.5% (20/31) of OAC subjects [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.
Conclusion
HPV L1 capsid expression is incrementally lost with increasing oesophageal disease severity as in viral driven anal and cervical lesions. Utility of L1 alone or in combination with p16/E6/E7 mRNA in stratifying HPV-positive oesophageal lesions for treatment should be further explored.
References
1. Rajendra S, Wang B, Snow ET, et al. Transcriptionally active human papillomavirus is strongly associated with Barrett’s dysplasia and esophageal adenocarcinoma. Am J Gastroenterol 2013;108:1082–1093.
2. Rajendra S, Yang T, Xuan W, et al. Active human papillomavirus involvement in Barrett's dysplasia and oesophageal adenocarcinoma is characterized by wild-type p53 and aberrations of the retinoblastoma protein pathway. Int J Cancer. 2017;141(10):2037-2049.
3. Li X, Gao C, Yang Y, et al. Systematic review with meta-analysis: the association between human papillomavirus infection and oesophageal cancer. Aliment Pharmacol Ther. 2014;39(3):270-281.
4. Rajendra, S., W. Xuan, N. Merrett, et al. Survival Rates for Patients With Barrett High-grade Dysplasia and Esophageal Adenocarcinoma With or Without Human Papillomavirus Infection. JAMA Netw Open. 2018; 1: e181054.
5. Choi YS, Kang WD, Kim SM, et al. Human papillomavirus L1 capsid protein and human papillomavirus type 16 as prognostic markers in cervical intraepithelial neoplasia 1. Int J Gynecol Cancer 2010;20(2):288-293.
6. Hernandez J, Elahi A, Siegel E, Coppola D, Riggs B, Shibata D. HPV L1 capsid protein detection and progression of anal squamous neoplasia Am J Clin Pathol 2011; 135: 436-41.
Disclosure
None