Article | Published:

HPV-negative tumors of the uterine cervix

Abstract

Human papillomaviruses (HPV) are the causative agents of virtually all cervical carcinomas. Nevertheless, a small proportion of cervical cancer are negative for HPV, although the significance of this finding remains unclear. We aimed to provide insight into the differential clinico-pathological characteristics of this unusual subset of HPV-negative cervical cancer. We performed HPV-DNA detection using a highly sensitive PCR test (SPF10) and p16 immunostaining in 214 cervical carcinomas specimens from women treated at the Gynecological Oncology Unit of the Hospital Clinic (Barcelona, Spain) from 2012 to 2015. The clinical and pathological characteristics, including disease-free survival and overall survival, of HPV-negative and -positive cervical carcinomas were compared. Twenty-one out of 214 tumors (10%) were negative for HPV DNA. HPV-negative tumors were more frequently of the non-squamous type (9/21, 43% vs. 37/193, 19%; p < 0.01) and showed negative p16 staining (9/21; 43% vs. 7/193; 4%; p < 0.01). HPV-negative tumors were more frequently diagnosed at advanced FIGO stage (19/21, 91% vs. 110/193, 57%; p < 0.01) and more frequently had lymph node metastases (14/21, 67% vs. 69/193, 36%; p < 0.01). Patients with HPV-negative cervical cancer had a significantly worse disease-free survival (59.8 months, 95% confidence interval 32.0–87.6 vs. 132.2 months, 95% confidence interval 118.6–145.8; p < 0.01) and overall survival (77.0 months, 95% confidence interval 47.2–106.8 vs. 153.8 months, 95% confidence interval 142.0–165.6; p = 0.01) than women with HPV-positive tumors. However, only advanced FIGO stage and lymph node metastases remained associated with a poor disease-free survival and overall survival on multivariate analysis. In conclusion, our results suggest that a low percentage of cervical cancer arise via an HPV-independent pathway. These HPV-negative tumors are diagnosed at advanced stages, show higher prevalence of lymph nodes metastases and have an impaired prognosis.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Senior authorship: Marta del Pino, Jaume Ordi.

References

  1. 1.

    Ferlay J, Soerjomataram I, Ervik M, Dikshit R, Eser S, Mathers C, et al. GLOBOCAN 2012 v1.0, Cancer Incidence and Mortality Worldwide: IARC CancerBase No. 11. Lyon, France: International Agency for Research on Cancer; 2013.

  2. 2.

    de Sanjose S, Quint WG, Alemany L, Geraets DT, Klaustermeier JE, Lloveras B, et al. Human papilomavirus genotype attribution in invasive cervical cancer: a retrospective cross-sectional worldwide study. Lancet Oncol. 2010;11:1048–56.

  3. 3.

    Bosch FX, Burchell AN, Schiffman M, Giuliano AR, de Sanjose S, Bruni L, et al. Epidemiology and natural history of human papilomavirus infections and type-specific implications in cervical neoplasia. Vaccine. 2008;26:1–16.

  4. 4.

    El-Mofty SK, Lu DW. Prevalence of high-risk human papillomavirus DNA in nonkeratinizing (cylindrical cell) carcinoma of the sinonasal tract: a distinct clinicophatololic and molecular disease entity. Am J Surg Pathol. 2005;29:1367–72.

  5. 5.

    Bishop JA, Guo TW, Smith DF, Wang H, Ogawa T, Pai SI, et al. Human Papillomavirus-related carcinomas of the sinonasal tract. Am J SurgPathol. 2013;37:185–92.

  6. 6.

    Alemany L, Pérez C, Tous S, Llombart-Bosch A, Lloveras B, Lerma E, et al. Human papillomavirus genotype distribution in cervical cancer cases in Spain. Implication for prevention. GynecolOncol. 2012;124:512–7.

  7. 7.

    Clifford GM, Smith JS, Plummer M, Muñoz N, Franceschi S. Human papillomavirus types in invasive cervical cancer worldwide: a meta-analysis. Br J Cancer. 2003;88:63–73.

  8. 8.

    Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9.

  9. 9.

    Arbyn M, Haelens A, Desomer A, Verdoodt F, Thiry N, Francart J, et al. Cervical cancer screening program and Human Papillomavirus (HPV) testing, part II: Update on HPV primary screening. KCE Reports 238. Health Technology Assessment (HTA). Brussels: Belgian Health Care Knowledge Centre (KCE); 2015.

  10. 10.

    Heideman DAM, Hesselink AT, Berkhof J, van Kemenade F, Melchers WJ, Daalmeijer NF, et al. Clinical validation of the cobas 4800 HPV test for cervical screening purposes. J ClinMicrobiol. 2011;49:3983–5.

  11. 11.

    Torné A, Del Pino M, Cuisidó M, Alameda F, Andia D, Castellsagué X, et al. Guía de cribado del cáncer de cuello de útero en España, 2014. RevEsp Patol. 2014;47:1–43.

  12. 12.

    Massad LS, Einstein MH, Huh WK,  Katki HA, Kinney WK, Schiffman M, et al. 2012 updated consensus guidelines for the management of abnormal cervical cancer screening tests and cancer precursors. J Low Genit Tract Dis. 2013;17:1–27.

  13. 13.

    Khan MJ, Castle PE, Lorincz AT, Wacholder S, Sherman M, Scott DR, et al. The elevated 10-year risk of cervical precancer and cancer in women with human papillomavirus (HPV) type 16 or 18 and the possible utility of type-specific HPV testing in clinical practice. J Natl Cancer Inst. 2005;97:1072–9.

  14. 14.

    Chong GO, Lee YH, Han HS, Lee HJ, Park JY, Hong DG, et al. Prognostic value of pre-treatment human papilloma virus DNA status in cervical cáncer. GynecolOncol. 2018;148:97–102.

  15. 15.

    Rodrıguez-Carunchio L, Soveral I, Steenbergen RDM, Torné A, Martinez S, Fusté P, et al. HPV-negative carcinoma of the uterine cervix: a distinct type of cervical cancer with poor prognosis. BJOG. 2015;122:119–27.

  16. 16.

    Park KJ, Kiyokawa T, Soslow RA, Lamb CA, Oliva E, Zivanovic O, et al. Unusual endocervical adenocarcinomas: an immunohistochemical analysis with molecular detection of human papillomavirus. Am J SurgPathol. 2011;35:633–46.

  17. 17.

    Alonso I, Felix A, Torne A, Fusté V, del Pino M, Castillo P, et al. Human papillomavirus as a favorable prognostic biomarker in squamous cell carcinomas of the vagina. GynecolOncol. 2012;125:194–9.

  18. 18.

    Nooij LS, Ter-Haar NT, Ruano D, Rakislova N, van Wezel T, Smit VTHBM, et al. Genomic characterization of vulvar (pre)cancers identifies distinct molecular subtypes with prognostic significance. Clin Cancer Res. 2017;23:6781–9.

  19. 19.

    Alos L, Moyano S, Nadal A,  Alobid I, Blanch JL, Ayala E, et al. Human papillomaviruses are identified in a subgroup of sinonasal squamous cell carcinomas with favorable outcome. Cancer. 2009;115:2701–9.

  20. 20.

    Larque AB, Hakim S, Ordi J, Nadal A, Diaz A, del Pino M, et al. High-risk human papillomavirus is transcriptionally active in a subset of sinonasal squamous cell carcinomas. Mod Pathol. 2014;27:343–51.

  21. 21.

    Rakislova N, Clavero O, Alemany L,Saco A, Quirós B, Lloveras B, et al. Histological characteristics of HPV-associated and -independent squamous cell carcinomas of the vulva: a study of 1.594 cases. Int J Cancer. 2017;141:2517–27.

  22. 22.

    Silva DC, Gonçalves AK, Cobucci RN,  Mendonça RC, Lima PH, Cavalcanti G. Immunohistochemical expression of p16, Ki-67 and p53 in cervical lesions—a systematic review. Pathol Res Pract. 2017;213:723–29.

  23. 23.

    Zhou R, Wei C, Liu J, Luo Y, Tang W. The prognostic value of p53 expression for patients with cervical cancer: a meta analysis. Eur J Obstet Gynecol Reprod Biol. 2015;195:210–13.

  24. 24.

    McCluggage WG, Soslow RA, Gilks CB. Patterns of p53 immunoreactivity in endometrial carcinomas: ‘all or nothing’ staining is of importance. Histopathology. 2011;59:786–88.

  25. 25.

    Kleter B, van Doorn LJ. Novel short-fragment PCR assay for highly sensitive broad-spectrum detection of anogenital human papillomaviruses. Am J Pathol. 1998;153:1731–39.

  26. 26.

    Kleter B, van Doorn LJ, Schrauwen L, Molijn A, Sastrowijoto S, ter Schegget J, et al. Development and clinical evaluation of a highly sensitive PCR-reverse hybridization line probe assay for detection and identification of anogenital human papillomavirus. J Clin Microbiol. 1999;37:2508–17.

  27. 27.

    Hesselink A, Berkhof J, van der Salm ML, van Splunter AP, Geelen TH, van Kemenade FJ, et al. Clinical validation of the HPV-Risk assay: a novel, real-time PCR assay for the detection of high-risk human papillomavirus DNA by targeting the E7 region. J Clin Microbiol. 2014;52:890–6.

  28. 28.

    del Pino M, Rodríguez-Carunchio L, Alonso I, Torné A, Rodriguez A, Fusté P, et al. Clinical, colposcopic and pathological characteristics of cervical and vaginal high-grade lesions negative for HPV by Hybrid Capture 2. Gynecol Oncol. 2011;122:515–20.

  29. 29.

    Barreto CL, Martins DB, De Lima Filho JL, Magalhães V. Detection of Human Papillomavirus in biopsies of patients with cervical cancer, and its association with prognosis. Arch GynecolObstet. 2013;288:643–8.

  30. 30.

    Tao X, Zheng B, Yin F, Zeng Z, Li Z, Griffith CC, et al. Polymerase chain reaction Human Papillomavirus (HPV) –detection and HPV genotyping in invasive cervical cancers with prior negative HC2 test results. Am J ClinPathol. 2017;147:477–83.

  31. 31.

    Li N, Franceschi S, Howell-Jones R, Snijders PJ, Clifford GM. Human papillomavirus type distribution in 30,848 invasive cervical cancers worldwide: variation by geographical region, histological type and year of publication. Int J Cancer. 2011;128:927–35.

  32. 32.

    Guan P, Howell-Jones R, Li N, Bruni L, de Sanjosé S, Franceschi S, et al. Human papillomavirus types in 115,789 HPV-positive women: a meta-analysis from cervical infection to cancer. Int J Cancer. 2012;131:2349–59.

  33. 33.

    Igidbashian S, Schettino MT, Boveri S, Barberis M, Sandri MT, Carinelli S, et al. Tissue genotyping of 37 in situ and invasive cervical cancer with a concomitant negative HC2 HPV DNA test. J Low Genit Tract Dis. 2014;18:87–91.

  34. 34.

    Lai CH, Huang HJ, Hsueh S, Chao A, Lin CT, Huang SL, et al. Human papillomavirus genotype in cervical cancer: a population-based study. Int J Cancer. 2007;120:1999–2006.

  35. 35.

    Andersson S, Larson B, Hjerpe A, Silfverswärd C, Sällström J, Wilander E, et al. Adenocarcinoma of the uterine cervix: the presence of human papillomavirus and the method of detection. Acta Obstet Gynecol Scand. 2003;82:960–5.

  36. 36.

    Clifford G, Franceschi S. Members of the human papillomavirus type 18 family (alpha-7 species) share a common association with adenocarcinoma of the cervix. Int J Cancer. 2008;122:1684–5.

  37. 37.

    Tornesello ML, Losito S, Benincasa G,  Fulciniti F, Botti G, Greggi S, et al. Human papillomavirus (HPV) genotypes and HPV16 variants and risk of adenocarcinoma and squamous cell carcinoma of the cervix. GynecolOncol. 2011;121:32–42.

  38. 38.

    Riou G, Favre M, Jeannel D, Bourhis J, Le Doussal V, Orth G. Association between poor prognosis in early-stage invasive cervical carcinomas and non-detection of HPV DNA. Lancet. 1990;335:1171–74.

  39. 39.

    Crook T, Vousden KH. Properties of p53 mutations detected in primary and secondary cervical cancers suggest mechanusms of metastasis and involvement of environmental carcinogens. EMBO J. 1992;11:3935–40.

  40. 40.

    Zampronha R, de A, Freitas-Junior R, Murta EF, Michelin MA, Barbaresco AA, Adad SJ, et al. Human papillomavirus types 16 and 18 and the prognosis of patients with stage I cervical cancer. Clinics (Sao Paulo). 2013;68:809–14.

  41. 41.

    Pilch H, Gunzel S, Schaffer U, Tanner B, Brockerhoff P, Maeurer M, et al. The presence of HPV DNA in cervical cancer: correlation with clinic-pathologic parameters and prognostic significance: 10 years experience at the Department of Obstetrics and Gynecology of the Mainz University. J Gynecol Cancer. 2001;11:39–48.

  42. 42.

    Feng D, Xu H, Li X, Wei Y, Jiang H, Xu H, et al. An association analysis between mitocondrial DNA content, G10398A polymorphism, HPV infection, and the prognosis of cervical cáncer in the Chinese Han population. Tumour Biol. 2016;37:5599–607.

  43. 43.

    Li P, Tan Y, Zhu LX, Zhou LN, Zeng P, Liu Q, et al. Prognostic value of HPV DNA status in cervical cancer before treatment: a systematic review and meta-analysis. Oncotarget. 2017;8:66352–9.

Download references

Acknowledgements

We thank Donna Pringle for the English revision of the article.

Funding

This research was funded in part by Instituto de Salud Carlos III (ICSIII)-Fondo de Investigación Sanitaria, and ERDF “One Way to Europe” (PI17/00772).

Author information

Conflict of interest

The authors declare no conflict of interest.

Correspondence to Jaume Ordi.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark
Fig. 1