Abstract
Few data are available concerning human papillomavirus (HPV) in early esophageal squamous cell carcinoma (ESCC) in Western population. Our study intended to determine the prevalence of HPV infection and the histological characteristics in such early tumors. A monocentric and retrospective study was conducted including 86 patients with early ESCC treated by endoscopic resection or esophagectomy, from 2012 to 2018. Histopathological prognostic criteria were evaluated. Immunohistochemistry for p16 and p53 and an HPV mRNA in situ hybridization were performed. The tumors were composed of 25 (29%) in situ carcinomas, 21 (24%) intramucosal carcinomas, and 40 (47%) submucosal carcinomas, of which 34 had a deep infiltration (> 200 μm). Emboli, present in 12 cases, were associated with deep infiltration. P16-positive ESCC accounted for 21% of the patients. It was not correlated with active HPV infection as no cases were found to be positive in RISH analysis for RNA detection of this virus. However, there was a correlation between p16 expression and alcohol or tobacco consumption. The only histopathological criterion correlated with p16 positivity was marked inflammatory infiltrate. Local or distant neoplastic recurrence occurred in 25% of patients. Overall survival was 95.8% and local or metastatic recurrence-free survival was 75%. There was a correlation between positive resection margins and tumor recurrence. In contrast to oropharynx carcinoma, our study showed that ESCC were not associated with an active HPV infection, highlighting the negligible role of this virus in early ESCC carcinogenesis in the Western world.
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00428-020-02860-2/MediaObjects/428_2020_2860_Fig1_HTML.jpg)
![](http://media.springernature.com/m312/springer-static/image/art%3A10.1007%2Fs00428-020-02860-2/MediaObjects/428_2020_2860_Fig2_HTML.jpg)
Similar content being viewed by others
Abbreviations
- HPV:
-
Human papillomavirus
- ESCC:
-
Esophageal squamous cell carcinoma
- HNSCC:
-
Head and neck squamous cell carcinoma
- RISH:
-
HPV mRNA in situ hybridization
References
Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D (2011) Global cancer statistics. CA Cancer J Clin 61:69–90. https://doi.org/10.3322/caac.20107
Abnet CC, Arnold M, Wei W-Q (2018) Epidemiology of esophageal squamous cell carcinoma. Gastroenterology 154:360–373. https://doi.org/10.1053/j.gastro.2017.08.023
Napier KJ, Scheerer M, Misra S (2014) Esophageal cancer: a review of epidemiology, pathogenesis, staging workup and treatment modalities. World J Gastrointest Oncol 6:112–120. https://doi.org/10.4251/wjgo.v6.i5.112
Syrjänen K, Syrjänen S (2013) Detection of human papillomavirus in sinonasal carcinoma: systematic review and meta-analysis. Hum Pathol 44:983–991. https://doi.org/10.1016/j.humpath.2012.08.017
Sitas F, Egger S, Urban MI, Taylor PR, Abnet CC, Boffetta P, O'Connell DL, Whiteman DC, Brennan P, Malekzadeh R, Pawlita M, Dawsey SM, Waterboer T, on behalf of the InterSCOPE Collaboration (2012) InterSCOPE study: associations between esophageal squamous cell carcinoma and human papillomavirus serological markers. J Natl Cancer Inst 104:147–158. https://doi.org/10.1093/jnci/djr499
Wang J, Zhao L, Yan H, Che J, Huihui L, Jun W, Liu B, Cao B (2016) A meta-analysis and systematic review on the association between human papillomavirus (types 16 and 18) infection and esophageal Cancer worldwide. PLoS One 11:e0159140. https://doi.org/10.1371/journal.pone.0159140
Gillison ML, Shah KV (2001) Human papillomavirus-associated head and neck squamous cell carcinoma: mounting evidence for an etiologic role for human papillomavirus in a subset of head and neck cancers. Curr Opin Oncol 13:183–188
Begum S, Cao D, Gillison M, Zahurak M, Westra WH (2005) Tissue distribution of human papillomavirus 16 DNA integration in patients with tonsillar carcinoma. Clin Cancer Res Off J Am Assoc Cancer Res 11:5694–5699. https://doi.org/10.1158/1078-0432.CCR-05-0587
Hoffmann M, Ihloff AS, Görögh T, Weise JB, Fazel A, Krams M, Rittgen W, Schwarz E, Kahn T (2010) p16(INK4a) overexpression predicts translational active human papillomavirus infection in tonsillar cancer. Int J Cancer 127:1595–1602. https://doi.org/10.1002/ijc.25174
Lewis JS (2012) p16 immunohistochemistry as a standalone test for risk stratification in oropharyngeal squamous cell carcinoma. Head Neck Pathol 6(Suppl 1):S75–S82. https://doi.org/10.1007/s12105-012-0369-0
Jordan RC, Lingen MW, Perez-Ordonez B, He X, Pickard R, Koluder M, Jiang B, Wakely P, **ao W, Gillison ML (2012) Validation of methods for oropharyngeal cancer HPV status determination in US cooperative group trials. Am J Surg Pathol 36:945–954. https://doi.org/10.1097/PAS.0b013e318253a2d1
Affonso VR, de Moura Campos Montoro JR, de Freitas LCC et al (2015) Peritumoral infiltrate in the prognosis of epidermoid carcinoma of the oral cavity. Braz J Otorhinolaryngol 81:416–421. https://doi.org/10.1016/j.bjorl.2014.09.010
Pimentel-Nunes P, Dinis-Ribeiro M, Ponchon T, Repici A, Vieth M, de Ceglie A, Amato A, Berr F, Bhandari P, Bialek A, Conio M, Haringsma J, Langner C, Meisner S, Messmann H, Morino M, Neuhaus H, Piessevaux H, Rugge M, Saunders B, Robaszkiewicz M, Seewald S, Kashin S, Dumonceau JM, Hassan C, Deprez P (2015) Endoscopic submucosal dissection: European Society of Gastrointestinal Endoscopy (ESGE) guideline. Endoscopy 47:829–854. https://doi.org/10.1055/s-0034-1392882
Kerr DA, Arora KS, Mahadevan KK, Hornick JL, Krane JF, Rivera MN, Ting DT, Deshpande V, Faquin WC (2015) Performance of a branch chain RNA in situ hybridization assay for the detection of high-risk human papillomavirus in head and neck squamous cell carcinoma. Am J Surg Pathol 39:1643–1652. https://doi.org/10.1097/PAS.0000000000000516
Kreimer AR, Alberg AJ, Daniel R, Gravitt PE, Viscidi R, Garrett ES, Shah KV, Gillison ML (2004) Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis 189:686–698. https://doi.org/10.1086/381504
Gillison ML, D’Souza G, Westra W et al (2008) Distinct risk factor profiles for human papillomavirus type 16-positive and human papillomavirus type 16-negative head and neck cancers. J Natl Cancer Inst 100:407–420. https://doi.org/10.1093/jnci/djn025
Wilczynski SP, Lin BT, **e Y, Paz IB (1998) Detection of human papillomavirus DNA and oncoprotein overexpression are associated with distinct morphological patterns of tonsillar squamous cell carcinoma. Am J Pathol 152:145–156
Gillison ML, Koch WM, Capone RB et al (2000) Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst 92:709–720
El-Mofty SK, Lu DW (2003) Prevalence of human papillomavirus type 16 DNA in squamous cell carcinoma of the palatine tonsil, and not the oral cavity, in young patients: a distinct clinicopathologic and molecular disease entity. Am J Surg Pathol 27:1463–1470
Augustin J, Outh-Gauer S, Mandavit M, Gasne C, Grard O, Denize T, Nervo M, Mirghani H, Laccourreye O, Bonfils P, Bruneval P, Veyer D, Péré H, Tartour E, Badoual C (2018) Evaluation of the efficacy of the 4 tests (p16 immunochemistry, polymerase chain reaction, DNA, and RNA in situ hybridization) to evaluate a human papillomavirus infection in head and neck cancers: a cohort of 348 French squamous cell carcinomas. Hum Pathol 78:63–71. https://doi.org/10.1016/j.humpath.2018.04.006
Mendez-Pena JE, Sadow PM, Nose V, Hoang MP (2017) RNA chromogenic in situ hybridization assay with clinical automated platform is a sensitive method in detecting high-risk human papillomavirus in squamous cell carcinoma. Hum Pathol 63:184–189. https://doi.org/10.1016/j.humpath.2017.02.021
Stelow EB, Dill EA, Davick JJ, McCabe MB, Shami VM (2019) High-grade squamous intraepithelial lesion of the gastroesophageal junction secondary to high-risk human papillomavirus. Am J Clin Pathol 152:359–364. https://doi.org/10.1093/ajcp/aqz039
Teng H, Li X, Liu X, Wu J, Zhang J (2014) The absence of human papillomavirus in esophageal squamous cell carcinoma in East China. Int J Clin Exp Pathol 7:4184–4193
Herbster S, Ferraro CTL, Koff NK, Rossini A, Kruel CDP, Andreollo NA, Rapozo DCM, Blanco TCM, Faria PAS, Santos PTS, Albano RM, Simão TA, Pinto LFR (2012) HPV infection in Brazilian patients with esophageal squamous cell carcinoma: interpopulational differences, lack of correlation with surrogate markers and clinicopathological parameters. Cancer Lett 326:52–58. https://doi.org/10.1016/j.canlet.2012.07.018
Salam I, Hussain S, Mir MM, Dar NA, Abdullah S, Siddiqi MA, Lone RA, Zargar SA, Sharma S, Hedau S, Basir SF, Bharti AC, Das BC (2009) Aberrant promoter methylation and reduced expression of p16 gene in esophageal squamous cell carcinoma from Kashmir valley: a high-risk area. Mol Cell Biochem 332:51–58. https://doi.org/10.1007/s11010-009-0173-7
Romagosa C, Simonetti S, López-Vicente L, Mazo A, Lleonart ME, Castellvi J, Ramon y Cajal S (2011) p16(Ink4a) overexpression in cancer: a tumor suppressor gene associated with senescence and high-grade tumors. Oncogene 30:2087–2097. https://doi.org/10.1038/onc.2010.614
Ling Y, Huang G, Fan L, Wei L, Zhu J, Liu Y, Zhu C, Zhang C (2011) CpG island methylator phenotype of cell-cycle regulators associated with TNM stage and poor prognosis in patients with oesophageal squamous cell carcinoma. J Clin Pathol 64:246–251. https://doi.org/10.1136/jcp.2010.082875
Sawada G, Niida A, Uchi R, Hirata H, Shimamura T, Suzuki Y, Shiraishi Y, Chiba K, Imoto S, Takahashi Y, Iwaya T, Sudo T, Hayashi T, Takai H, Kawasaki Y, Matsukawa T, Eguchi H, Sugimachi K, Tanaka F, Suzuki H, Yamamoto K, Ishii H, Shimizu M, Yamazaki H, Yamazaki M, Tachimori Y, Kajiyama Y, Natsugoe S, Fujita H, Mafune K, Tanaka Y, Kelsell DP, Scott CA, Tsuji S, Yachida S, Shibata T, Sugano S, Doki Y, Akiyama T, Aburatani H, Ogawa S, Miyano S, Mori M, Mimori K (2016) Genomic landscape of esophageal squamous cell carcinoma in a Japanese population. Gastroenterology 150:1171–1182. https://doi.org/10.1053/j.gastro.2016.01.035
Riethdorf S, Neffen EF, Cviko A, Löning T, Crum CP, Riethdorf L (2004) p16INK4A expression as biomarker for HPV 16-related vulvar neoplasias. Hum Pathol 35:1477–1483
Milde-Langosch K, Hagen M, Bamberger A-M, Löning T (2003) Expression and prognostic value of the cell-cycle regulatory proteins, Rb, p16MTS1, p21WAF1, p27KIP1, cyclin E, and cyclin D2, in ovarian cancer. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol 22:168–174
Mannweiler S, Sygulla S, Winter E, Regauer S (2013) Two major pathways of penile carcinogenesis: HPV-induced penile cancers overexpress p16ink4a, HPV-negative cancers associated with dermatoses express p53, but lack p16ink4a overexpression. J Am Acad Dermatol 69:73–81. https://doi.org/10.1016/j.jaad.2012.12.973
Pérez C, Castillo M, Alemany L, Tous S, Klaustermeier J, de Sanjose S, Velasco J (2014) Evaluation of p16(INK4a) overexpression in a large series of cervical carcinomas: concordance with SPF10-LiPA25 PCR. Int J Gynecol Pathol Off J Int Soc Gynecol Pathol 33:74–82. https://doi.org/10.1097/PGP.0b013e3182774546
Rayess H, Wang MB, Srivatsan ES (2012) Cellular senescence and tumor suppressor gene p16. Int J Cancer 130:1715–1725. https://doi.org/10.1002/ijc.27316
Braakhuis BJM, Snijders PJF, Keune W-JH, Meijer CJLM, Ruijter-Schippers HJ, Leemans CR, Brakenhoff RH (2004) Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst 96:998–1006
Smeets SJ, Braakhuis BJM, Abbas S, Snijders PJF, Ylstra B, van de Wiel MA, Meijer GA, Leemans CR, Brakenhoff RH (2006) Genome-wide DNA copy number alterations in head and neck squamous cell carcinomas with or without oncogene-expressing human papillomavirus. Oncogene 25:2558–2564. https://doi.org/10.1038/sj.onc.1209275
Friesland S, Mellin H, Munck-Wikland E, Nilsson A, Lindholm J, Dalianis T, Lewensohn R (2001) Human papilloma virus (HPV) and p53 immunostaining in advanced tonsillar carcinoma--relation to radiotherapy response and survival. Anticancer Res 21:529–534
Sisk EA, Soltys SG, Zhu S, Fisher SG, Carey TE, Bradford CR (2002) Human papillomavirus and p53 mutational status as prognostic factors in head and neck carcinoma. Head Neck 24:841–849. https://doi.org/10.1002/hed.10146
Li W, Thompson CH, O’Brien CJ et al (2003) Human papillomavirus positivity predicts favourable outcome for squamous carcinoma of the tonsil. Int J Cancer 106:553–558. https://doi.org/10.1002/ijc.11261
Ritchie JM, Smith EM, Summersgill KF, Hoffman HT, Wang D, Klussmann JP, Turek LP, Haugen TH (2003) Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer 104:336–344. https://doi.org/10.1002/ijc.10960
Licitra L, Perrone F, Bossi P, Suardi S, Mariani L, Artusi R, Oggionni M, Rossini C, Cantù G, Squadrelli M, Quattrone P, Locati LD, Bergamini C, Olmi P, Pierotti MA, Pilotti S (2006) High-risk human papillomavirus affects prognosis in patients with surgically treated oropharyngeal squamous cell carcinoma. J Clin Oncol Off J Am Soc Clin Oncol 24:5630–5636. https://doi.org/10.1200/JCO.2005.04.6136
Weinberger PM, Yu Z, Haffty BG, Kowalski D, Harigopal M, Brandsma J, Sasaki C, Joe J, Camp RL, Rimm DL, Psyrri A (2006) Molecular classification identifies a subset of human papillomavirus--associated oropharyngeal cancers with favorable prognosis. J Clin Oncol Off J Am Soc Clin Oncol 24:736–747. https://doi.org/10.1200/JCO.2004.00.3335
Kumar B, Cordell KG, Lee JS, Prince ME, Tran HH, Wolf GT, Urba SG, Worden FP, Chepeha DB, Teknos TN, Eisbruch A, Tsien CI, Taylor JMG, D'Silva NJ, Yang K, Kurnit DM, Bradford CR, Carey TE (2007) Response to therapy and outcomes in oropharyngeal cancer are associated with biomarkers including human papillomavirus, epidermal growth factor receptor, gender, and smoking. Int J Radiat Oncol Biol Phys 69:S109–S111. https://doi.org/10.1016/j.ijrobp.2007.05.072
Author information
Authors and Affiliations
Contributions
Conception and design of the study, or acquisition of data, or analysis and interpretation of data: Christina Kanaan, Diane Lorenzo, Maximilien Barret, Anne Audebourg, Sarah Leblanc, Stanislas Chaussade, Frédéric Prat, Benoît Terris.
Drafting the article or revising it critically for important intellectual content: Christina Kanaan, Diane Lorenzo, Maximilien Barret, Anne Audebourg, Sarah Leblanc, Stanislas Chaussade, Frédéric Prat, Benoît Terris.
Final approval of the version to be submitted: Christina Kanaan, Diane Lorenzo, Maximilien Barret, Anne Audebourg, Sarah Leblanc, Stanislas Chaussade, Frédéric Prat, Benoît Terris.
Corresponding author
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Additional information
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Rights and permissions
About this article
Cite this article
Kanaan, C., Lorenzo, D., Barret, M. et al. Early esophageal squamous cell carcinoma in a western series is not associated with active HPV infection. Virchows Arch 477, 697–704 (2020). https://doi.org/10.1007/s00428-020-02860-2
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00428-020-02860-2