Abstract
Background
Approximately 1–9 % of all head and neck squamous cell carcinomas are neck metastases from clinically undetectable primary tumors. Human papillomavirus (HPV) and Epstein–Barr virus (EBV) are proven carcinogenic factors that are associated with oropharyngeal squamous cell carcinoma and nasopharyngeal carcinoma, respectively. In the present study, we evaluated the prevalence of these viruses in neck metastases from unknown primary squamous cell carcinoma.
Methods
We evaluated fresh samples from a consecutive series of 22 neck dissections for metastases from unknown primary squamous cell carcinoma obtained between 2010 and 2012 at a single institution. The samples were tested for the presence of HPV E6 and E7 mRNA and EBV DNA.
Results
Oncogenic viral infections were detected in 12 cases (54 % total; 2 HPV18, 5 HPV16, 2 EBV infection, and 3 EBV/HPV16 coinfections). The most frequent primarily involved neck level in our series was IIA (70 %), which had the highest prevalence of viral infection (66 %). We did not find any other significant correlations between virus detection and clinicopathologic parameters or prognosis.
Discussion
Neck metastasis from unknown primary squamous cell carcinoma could be another virus-related malignancy in the head and neck region, along with nasopharyngeal and oropharyngeal carcinoma. An evaluation of the impact of viral infection on patient prognosis and sensitivities to different treatment modalities could modify our prognostic assessments and treatment planning. Furthermore, virus detection would have a decisive impact on diagnostic/decisional algorithms, especially if detection methods are implemented on cytologic samples (e.g., thin prep).
Similar content being viewed by others
References
Lembersky BC, Thomas LC. Metastases of unknown primary site. Med Clin N Am. 1996;80:153–71.
Jereczek-Fossa BA, Jassem J, Orecchia R. Cervical lymph node metastases of squamous cell carcinoma from an unknown primary. Cancer Treat Rev. 2004;30:153–64.
Calabrese L, Jereczek-Fossa BA, Jassem J, et al. Diagnosis and management of neck metastases from an unknown primary. Acta Otorhinolaryngol Ital. 2005;25:2–12.
Pfister DG, Ang KK, Brizel DM, et al. National Comprehensive Cancer Network clinical practice guidelines in oncology. Head and neck cancers. Version 2.2013. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp.
Grau C, Johansen LV, Jakobsen J, Geertsen P, Andersen E, Jensen BB. Cervical lymph node metastases from unknown primary tumours. Results from a national survey by the Danish Society for Head and Neck Oncology. Radiother Oncol. 2000;55:121–9.
de Braud F, al Sarraf M. Diagnosis and management of squamous cell carcinoma of unknown primary tumor site of the neck. Semin Oncol. 1993;20:273–8.
Waltonen JD, Ozer E, Hall NC, Schuller DE, Agrawal A. Metastatic carcinoma of the neck of unknown primary origin: evolution and efficacy of the modern workup. Arch Otolaryngol Head Neck Surg. 2009;135:1024–9.
Bouvard V, Baan R, Straif K, et al. A review of human carcinogens—part B: biological agents. Lancet Oncol. 2009;10:321–2.
zur Hausen H, Schulte-Holthausen H, Klein G, et al. EBV DNA in biopsies of Burkitt tumours and anaplastic carcinomas of the nasopharynx. Nature. 1970;228:1056–8.
Pathmanathan R, Prasad U, Chandrika G, Sadler R, Flynn K, Raab-Traub N. Undifferentiated, nonkeratinizing, and squamous cell carcinoma of the nasopharynx. Variants of Epstein-Barr virus–infected neoplasia. Am J Pathol. 1995;146:1355–67.
Young LS, Rickinson AB. Epstein-Barr virus: 40 years on. Nat Rev Cancer. 2004;4:757–68.
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.
Macdonald MR, Freeman JL, Hui MF, et al. Role of Epstein-Barr virus in fine-needle aspirates of metastatic neck nodes in the diagnosis of nasopharyngeal carcinoma. Head Neck. 1995;17:487–93.
Nakao K, Yuge T, Mochiki M, Nibu K, Sugasawa M. Detection of Epstein-Barr virus in metastatic lymph nodes of patients with nasopharyngeal carcinoma and a primary unknown carcinoma. Arch Otolaryngol Head Neck Surg. 2003;129:338–40.
Khademi B, Mahmoudi J, Monabati A, et al. Molecular diagnosis of nasopharyngeal carcinoma using detection of Epstein-Barr virus latent membrane protein-1 gene in cervical metastatic lymph nodes. Am J Otolaryngol. 2009;30:95–100.
Mirghani H, Ferchiou M, Moreau F, et al. Oropharyngeal cancers: significance of HPV16 detection in neck lymph nodes. J Clin Virol. 2013;57:120–4.
Lee WY, Hsiao JR, Jin YT, Tsai ST. Epstein-Barr virus detection in neck metastases by in-situ hybridization in fine-needle aspiration cytologic studies: an aid for differentiating the primary site. Head Neck. 2000;22:336–40.
Feinmesser R, Miyazaki I, Cheung R, Freeman JL, Noyek AM, Dosch HM. Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration. N Engl J Med. 1992;326:17–21.
Strojan P, Ferlito A, Medina JE, et al. Contemporary management of lymph node metastases from an unknown primary to the neck: I. A review of diagnostic approaches. Head Neck. 2013;35:123–32.
Baldassarri R, Aronberg R, Levi AW, Yarbrough WG, Kowalski D, Chhieng D. Detection and genotype of high-risk human papillomavirus in fine-needle aspirates of patients with metastatic squamous cell carcinoma is helpful in determining tumor origin. Am J Clin Pathol. 2015;143:694–700.
Hakima L, Adler E, Prystowsky M, et al. Hybrid Capture 2 human papillomavirus testing of fine needle aspiration cytology of head and neck squamous cell carcinomas. Diagn Cytopathol. 2015;43:683–7.
Jiong L, Berrino F, Coebergh JW, EUROCARE Working Group. Variation in survival for adults with nasopharyngeal cancer in Europe, 1978–1989. Eur J Cancer. 1998;34:2162–6.
Sanguineti G, Geara FB, Garden AS, et al. Carcinoma of the nasopharynx treated by radiotherapy alone: determinants of local and regional control. Int J Radiat Oncol Biol Phys. 1997;37:985–96.
Ang KK, Harris J, Wheeler R, et al. Human papillomavirus and survival of patients with oropharyngeal cancer. N Engl J Med. 2010;363:24–35.
Bussu F, Sali M, Gallus R, et al. Human papillomavirus (HPV) infection in squamous cell carcinomas arising from the oropharynx: detection of HPV DNA and p16 immunohistochemistry as diagnostic and prognostic indicators—a pilot study. Int J Radiat Oncol Biol Phys. 2014;89:1115–20.
Bussu F, Sali M, Gallus R, et al. HPV infection in squamous cell carcinomas arising from different mucosal sites of the head and neck region. Is p16 immunohistochemistry a reliable surrogate marker? Br J Cancer. 2013;108:1157–62.
El-Naggar AK, Westra WH. p16 expression as a surrogate marker for HPV-related oropharyngeal carcinoma: a guide for interpretative relevance and consistency. Head Neck. 2012;34:459–61.
Smeets SJ, Hesselink AT, Speel EJ, et al. A novel algorithm for reliable detection of human papillomavirus in paraffin embedded head and neck cancer specimen. Int J Cancer. 2007;121:2465–72.
Compton AM, Moore-Medlin T, Herman-Ferdinandez L, et al. Human papillomavirus in metastatic lymph nodes from unknown primary head and neck squamous cell carcinoma. Otolaryngol Head Neck Surg. 2011;145:51–57.
Tribius S, Hoffmann AS, Bastrop S, et al. HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome. Oral Oncol. 2012;48:1178–84.
Desai PC, Jaglal MV, Gopal P, et al. Human papillomavirus in metastatic squamous carcinoma from unknown primaries in the head and neck: a retrospective 7 year study. Exp Mol Pathol. 2009;87:94–8.
Hoffmann M, Gottschlich S, Gorogh T, et al. Human papillomaviruses in lymph node neck metastases of head and neck cancers. Acta Otolaryngol. 2005;125:415–21.
Armas GL, Su CY, Huang CC, Fang FM, Chen CM, Chien CY. The impact of virus in N3 node dissection for head and neck cancer. Eur Arch Otorhinolaryngol. 2008;265:1379–84.
Barwad A, Sood S, Gupta N, Rajwanshi A, Panda N, Srinivasan R. Human papilloma virus associated head and neck cancer: a PCR based study. Diagn Cytopathol. 2012;40:893–7.
Robbins KT, Clayman G, Levine PA, et al. Neck dissection classification update: revisions proposed by the American Head and Neck Society and the American Academy of Otolaryngology-Head and Neck Surgery. Arch Otolaryngol Head Neck Surg. 2002;128:751–8.
Robbins KT, Shaha AR, Medina JE, et al. Consensus statement on the classification and terminology of neck dissection. Arch Otolaryngol Head Neck Surg. 2008;134:536–8.
Gregoire V, Levendag P, Ang KK, et al. CT-based delineation of lymph node levels and related CTVs in the node-negative neck: DAHANCA, EORTC, GORTEC, NCIC,RTOG consensus guidelines. Radiother Oncol. 2003;69:227–36.
Stransky N, Egloff AM, Tward AD, et al. The mutational landscape of head and neck squamous cell carcinoma. Science. 2011;333:1157–60.
Jensen DH, Hedback N, Specht L, et al. Human papillomavirus in head and neck squamous cell carcinoma of unknown primary is a common event and a strong predictor of survival. PLoS One. 2014;9:e110456.
Begum S, Gillison ML, Nicol TL, Westra WH. Detection of human papillomavirus-16 in fine-needle aspirates to determine tumor origin in patients with metastatic squamous cell carcinoma of the head and neck. Clin Cancer Res. 2007;13:1186–91.
Thorley-Lawson DA, Gross A. Persistence of the Epstein-Barr virus and the origins of associated lymphomas. N Engl J Med. 2004;350:1328–37.
Fukayama M, Hino R, Uozaki H. Epstein-Barr virus and gastric carcinoma: virus–host interactions leading to carcinoma. Cancer Sci. 2008;99:1726–33.
Disclosure
The authors declare no conflict of interest.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Bussu, F., Sali, M., Gallus, R. et al. HPV and EBV Infections in Neck Metastases from Occult Primary Squamous Cell Carcinoma: Another Virus-Related Neoplastic Disease in the Head and Neck Region. Ann Surg Oncol 22 (Suppl 3), 979–984 (2015). https://doi.org/10.1245/s10434-015-4808-5
Received:
Published:
Issue Date:
DOI: https://doi.org/10.1245/s10434-015-4808-5