Head and Neck Pathology

, Volume 4, Issue 2, pp 97–105

Head and Neck Squamous Cell Carcinomas in HIV-Positive Patients: A Preliminary Investigation of Viral Associations

  • Michael S. McLemore
  • Missak HaigentzJr.
  • Richard V. Smith
  • Gerard J. Nuovo
  • Llucia Alos
  • Antonio Cardesa
  • Margaret Brandwein-Gensler
Original Paper


Oncogenic human papillomaviruses (HPVs) are associated with oropharyngeal squamous cell carcinoma (SCC). Infection with human immunodeficiency virus (HIV) increases susceptibility to opportunistic infections and viral-promoted cancers. The prevalences of HPV, herpes simplex virus (HSV), Epstein-Barr virus (EBV), and human herpesvirus-8 (HHV-8) have not been established for head and neck squamous cell carcinoma in HIV-positive patients (HIV+ HNSCC). We have observed that HIV+ HNSCC tend to contain numerous multinucleated tumor giant cells, this finding has not been described previously. The goal of this study is to test for these oncogenic viruses in a small cohort of retrospectively identified patients with HIV infection, and to compare histologically these cancers to a control group of HNSCC patients. Tumors were reviewed histologically and compared to a control group of 102 patients with HNSCC (serologically untyped or HIV negative). Polymerase chain reaction (PCR) was performed on formalin-fixed, paraffin-embedded HIV+ HNSCC samples from combined 25 patients in two institutions. In situ hybridization was performed to identify EBV (EBER) and immunohistochemistry was performed to detect HSV-1, HSV-2, HHV-8, and HIV-related proteins (Nef, p24). The study sample consisted of 34 HIV+ patients with HNSCC from Montefiore Medical Center, and six HIV+ HNSCC patients from Hospital Clinic, University of Barcelona; 24 (60%) men and 16 (40%) women. The larynx was most commonly involved (65%, n = 26); followed by the oropharynx (22.5%, n = 9). Four carcinomas arose from the oral cavity (10%) and one from the nasal cavity (2.5%). Histologically, multinucleated tumor giant cells were more common in the HIV+ group (39/40, 97.5%) than the control group (27/102, 26%, p 0.001, chi-square). HPV was detected in 6 of 25 (24%) HNSCC tumors by PCR, five were typed as HPV 16 and one as HPV 26/69; five of these tumors (83%) were located in the oropharynx. EBV, HSV-1, HSV-2, and HHV-8 were detected only infrequently in tumor cells. Nef protein was detected in tumor cells in 7 of 21 (33.3%) cases; p24 was not detectable in 6 tumors studied. There were no significant associations between HPV positive tumors and co-infections with other viruses. This study is consistent with other reports that suggest an increased incidence of laryngeal carcinoma for HIV+ patients. HPV was detected in 24% of HIV+ HNSCC, however, the number of tumors with amplifiable DNA (n = 25) is too small to allow for conclusions. EBV, HSV-1, HSV-2, and HHV-8 are uncommon in HIV+ HNSCC; it is unlikely that these viruses have a promoting effect. MNTCG are significantly common in HIV+ HNSCC, but there is overlap in MNTCG counts with the control group and therefore this finding cannot be used as a biomarker of HIV infection.


AIDS HIV HNSCC Squamous carcinoma HPV 


  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin. 2005;55:74–108.CrossRefPubMedGoogle Scholar
  2. 2.
    Argiris A, Karamouzis MV, Ferris RL. Head and neck cancer. Lancet. 2008;371:1695–709.CrossRefPubMedGoogle Scholar
  3. 3.
    Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2009. CA Cancer J Clin. 2009;59:225–49.CrossRefPubMedGoogle Scholar
  4. 4.
    Forastiere A, Koch W, Trotti A, Sidransky D. Head and neck cancer. N Engl J Med. 2001;345:1890–900.CrossRefPubMedGoogle Scholar
  5. 5.
    Castellsague X, Quintana MJ, Martinez MC, et al. The role of type of tobacco and type of alcoholic beverage in oral carcinogenesis. Int J Cancer. 2004;108:741–9.CrossRefPubMedGoogle Scholar
  6. 6.
    Gillison ML, Koch WM, Capone RB, et al. Evidence for a causal association between human papillomavirus and a subset of head and neck cancers. J Natl Cancer Inst. 2000;92:709–20.CrossRefPubMedGoogle Scholar
  7. 7.
    Van Houten VMM, Snijders PJF, van den Brekel MWM, et al. Biological evidence that human papillomaviruses are etiologically involved in a subgroup of head and neck squamous cell carcinomas. Int J Cancer. 2001;93:232–5.CrossRefPubMedGoogle Scholar
  8. 8.
    Gillison ML, Shah KV. 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. 2001;13:183–8.CrossRefPubMedGoogle Scholar
  9. 9.
    Frisch M, Biggar RJ, Engels EA, Goedert JJ. Association of cancer with AIDS-related immunosuppression in adults. JAMA. 2001;285:1736–45.CrossRefPubMedGoogle Scholar
  10. 10.
    Haigentz M Jr. Aerodigestive cancers in HIV infection. Curr Opin Oncol. 2005;17:474–8.CrossRefPubMedGoogle Scholar
  11. 11.
    Klussman JP, Weissenborn SJ, Wieland U, et al. Prevalence, distribution, and viral load of human papillomavirus 16 DNA in tonsillar carcinomas. Cancer. 2001;92:2875–84.CrossRefGoogle Scholar
  12. 12.
    Herrero R, Castellsague X, Pawlita M, et al. Human papillomavirus and oral cancer: the international agency for research on cancer multicenter study. J Natl Cancer Inst. 2003;95:1772–83.PubMedGoogle Scholar
  13. 13.
    Smith EM, Ritchie JM, Summersgill KF, et al. Human papillomavirus in oral exfoliated cells and risk of head and neck cancer. J Natl Cancer Inst. 2004;96:449–55.PubMedGoogle Scholar
  14. 14.
    Ernster JA, Sciotto CG, O’Brien MM, et al. Rising incidence of oropharyngeal cancer and the role of oncogenic human papilloma virus. Laryngoscope. 2007;117:2115–28.CrossRefPubMedGoogle Scholar
  15. 15.
    Hobbs CGL, Sterne JAC, Bailey M, et al. Human papillomavirus and head and neck cancer: a systematic review and meta-analysis. Clin Otolaryngol. 2006;310:259–66.CrossRefGoogle Scholar
  16. 16.
    D’Souza G, Kreimer AR, Viscidi R, et al. Case-control study of human papillomavirus and oropharyngeal cancer. N Engl J Med. 2007;356:1944–56.CrossRefPubMedGoogle Scholar
  17. 17.
    Ritchie JM, Smith EM, Summersgill KF, et al. Human papillomavirus infection as a prognostic factor in carcinomas of the oral cavity and oropharynx. Int J Cancer. 2003;104:336–44.CrossRefPubMedGoogle Scholar
  18. 18.
    El-Mofty SK, Lu DW. 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. 2003;27:1463–70.CrossRefPubMedGoogle Scholar
  19. 19.
    Kreimer AR, Clifford GM, Boyle P, Franceschi S. Human papillomavirus types in head and neck squamous cell carcinomas worldwide: a systematic review. Cancer Epidemiol Biomarkers Prev. 2005;14:467–75.CrossRefPubMedGoogle Scholar
  20. 20.
    zur Hausen H. Viruses in human cancers. Science. 1991;254:1167–73.CrossRefPubMedGoogle Scholar
  21. 21.
    Walboomers JMM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of invasive cervical cancer worldwide. J Pathol. 1999;189:12–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Smith JS, Lindsay L, Hoots B, et al. Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update. Int J Cancer. 2007;121:621–32.CrossRefPubMedGoogle Scholar
  23. 23.
    Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. NEJM. 2003;348:518–27.CrossRefPubMedGoogle Scholar
  24. 24.
    zur Hausen H. Immortalization of human cells and their malignant conversion by high risk human papillomavirus genotypes. Semin Cancer Biol. 1999;9:405–11.CrossRefPubMedGoogle Scholar
  25. 25.
    zur Hausen H. Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst. 2000;92:690–8.CrossRefPubMedGoogle Scholar
  26. 26.
    Hagensee ME, Cameron JE, Leigh JE, Clark RA. Human papillomavirus infection and disease in HIV-infected individuals. Am J Med Sci. 2004;328:57–63.CrossRefPubMedGoogle Scholar
  27. 27.
    Fakhry C, D’Souza G, Sugar E, et al. Relationship between prevalent oral and cervical human papillomavirus infections in human immunodeficiency virus-positive and -negative women. J Clin Microbiol. 2006;44:4479–85.CrossRefPubMedGoogle Scholar
  28. 28.
    Strickler HD, Palefsky JM, Shah KV, et al. Human papillomavirus type 16 and immune status in human immunodeficiency virus-seropositive women. J Natl Cancer Inst. 2003;95:1062–71.PubMedCrossRefGoogle Scholar
  29. 29.
    Strickler HD, Burk RD, Fazzari M, et al. Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst. 2005;97:577–86.PubMedCrossRefGoogle Scholar
  30. 30.
    Kreimer AR, Alberg AJ, Daniel R, et al. Oral human papillomavirus infection in adults is associated with sexual behavior and HIV serostatus. J Infect Dis. 2004;189:686–98.CrossRefPubMedGoogle Scholar
  31. 31.
    Naher H, Gissmann L, von Knebel Doeberitz C, et al. Detection of Epstein-Barr virus-DNA in tongue epithelium of human immunodeficiency virus-infected patients. J Invest Dermatol. 1991;97:421–4.CrossRefPubMedGoogle Scholar
  32. 32.
    Sandvej K, Krenacs L, Hamilton-Dutoit SJ, et al. Epstein-Barr virus latent and replicative gene expression in oral hairy leukoplakia. Histopathology. 1992;20:387–95.CrossRefPubMedGoogle Scholar
  33. 33.
    Martel-Renoir D, Grunewald V, Touitou R, et al. Qualitative analysis of the expression of Epstein-Barr virus lytic genes in nasopharyngeal carcinoma biopsies. J Gen Virol. 1995;76:1401–8.CrossRefPubMedGoogle Scholar
  34. 34.
    Shimakage M, Horii K, Tempaku A, et al. Association of Epstein-Barr virus with oral cancers. Hum Pathol. 2002;33:608–14.CrossRefPubMedGoogle Scholar
  35. 35.
    Wong M, Pagano JS, Schiller JT, et al. New Associations of human papillomavirus, simian virus 40, and Epstein-Barr virus with human cancer. J Natl Cancer Inst. 2002;94:1832–6.PubMedGoogle Scholar
  36. 36.
    Jiang G, Qu W, Ruan H, Burk RD. Elimination of false positive signals in enhanced chemiluminescence (ECL) detection of amplified HPV DNA from clinical samples. Biotechniques. 1995;19:566–8.PubMedGoogle Scholar
  37. 37.
    Qu W, Jiang G, Cruz Y, et al. PCR detection of human papillomavirus: comparison between MY09/MY11 and GP5+/GP6+ primer systems. J Clin Microbiol. 1997;35:1304–10.PubMedGoogle Scholar
  38. 38.
    Herrero R, Hildesheim A, Bratti C, et al. Population-based study of human papillomavirus infection and cervical neoplasia in rural Costa Rica. J Natl Cancer Inst. 2000;92:464–74.CrossRefPubMedGoogle Scholar
  39. 39.
    Castle PE, Schiffman M, Gravitt P, et al. Comparisons of HPV DNA detection by MY09/11 PCR methods. J Med Virol. 2002;68:417–23.CrossRefPubMedGoogle Scholar
  40. 40.
    Flaitz CM, Nichols CM, Adler-Storthz K, Hicks MJ. Intraoral squamous cell carcinoma in human immunodeficiency virus infection. A clinicopathologic study. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 1995;80:55–62.CrossRefPubMedGoogle Scholar
  41. 41.
    Singh B, Balwally AN, Shaha AR, et al. Upper aerodigestive tract squamous cell carcinoma. The human immunodeficiency virus connection. Arch Otolaryngol Head Neck Surg. 1996;122:639–43.PubMedGoogle Scholar
  42. 42.
    Roland JT, Rothstein SG, Mittal KR, Persky MS. Squamous cell carcinoma in HIV-positive patients under age 45. Laryngoscope. 1993;103:509–11.PubMedGoogle Scholar
  43. 43.
    Blenke EJSM, Clement WA, Andrews JM, et al. Squamous cell carcinoma of the larynx in HIV-positive patients: difficulties in diagnosis and management. Dysphagia. 2007;22:68–72.CrossRefPubMedGoogle Scholar
  44. 44.
    Moyano S, Ordi J, Caballero M, et al. Laryngeal squamous cell carcinoma in HIV-positive patients: lack of association with human papillomavirus infection. HIV Medicine. 2009. doi:10.1111/j.1468-1293.2009.00737.x.
  45. 45.
    Gallagher B, Wang Z, Schymura MJ, et al. Cancer incidence in New York State acquired immunodeficiency syndrome. Am J Epidemiol. 2001;154:544–56.CrossRefPubMedGoogle Scholar
  46. 46.
    Demopoulos BP, Vamvaka E, Ehrlich JE, et al. Non-acquired immunodeficiency syndrome-defining malignancies in patients infected with human immunodeficiency virus. Arch Pathol Lab Med. 2003;127:589–92.PubMedGoogle Scholar
  47. 47.
    Chaturvedi AK, Madeleine MM, Biggar RJ, Engles EA. Risk of human papillomavirus-associated cancers among persons with AIDS. J Natl Cancer Inst. 2009;101:1120–30.CrossRefPubMedGoogle Scholar
  48. 48.
    Qureshi MN, Barr CE, Seshamma T, et al. Infection of oral mucosal cells by human immunodeficiency virus type 1 in seropositive patients. J Infect Dis. 1995;171:190–3.PubMedGoogle Scholar
  49. 49.
    Qureshi MN, Barr CE, Hewlitt I, et al. Detection of HIV in oral mucosal cells. Oral Dis. 1997;3(Suppl 1):S73–8.PubMedGoogle Scholar
  50. 50.
    Cox M, Maitland N, Scully C. Human herpes simplex-1 and papillomavirus type 16 homologous DNA sequences in normal, potentially malignant and malignant oral mucosa. Eur J Cancer B Oral Oncol. 1993;29B:215–9.CrossRefPubMedGoogle Scholar
  51. 51.
    Rassekh CH, Rady PL, Arany I, et al. Combined Epstein-Barr virus and human papillomavirus infection in nasopharyngeal carcinoma. Laryngoscope. 1998;108:362–7.CrossRefPubMedGoogle Scholar
  52. 52.
    Tyan YS, Liu ST, Ong WR, et al. Detection of Epstein-Barr virus and human papillomavirus in head and neck tumors. J Clin Microbiol. 1993;31:53–6.PubMedGoogle Scholar
  53. 53.
    Pou AM, Vrabec JT, Jordan J, et al. Prevalence of herpes simplex virus in malignant laryngeal lesions. Laryngoscope. 2000;110:194–7.CrossRefPubMedGoogle Scholar

Copyright information

© Humana 2010

Authors and Affiliations

  • Michael S. McLemore
    • 1
  • Missak HaigentzJr.
    • 2
  • Richard V. Smith
    • 3
  • Gerard J. Nuovo
    • 4
  • Llucia Alos
    • 5
  • Antonio Cardesa
    • 5
  • Margaret Brandwein-Gensler
    • 6
  1. 1.Department of PathologyMD AndersonHoustonUSA
  2. 2.Department of Medicine, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  3. 3.Department of Otorhinolaryngology, Head & Neck Surgery, Montefiore Medical CenterAlbert Einstein College of MedicineBronxUSA
  4. 4.Department of PathologyOhio State University College of MedicineColumbusUSA
  5. 5.Hospital ClinicUniversity of BarcelonaBarcelonaSpain
  6. 6.Department of Pathology, NP 3545University of Alabama at BirminghamBirminghamUSA

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