HPV status in patients with head and neck of carcinoma of unknown primary site: HPV, tobacco smoking, and outcome
Introduction
A diagnosis of carcinoma of unknown primary (CUP) is given when a patient presents with metastatic disease but subsequent evaluation fails to identify the primary tumor. CUP presenting as neck metastasis is rare, accounting for only 2% of head and neck cancers.1 Between 70% and 90% of patients with CUP are diagnosed with squamous cell carcinoma after pathologic examination.2
According to treatment guidelines, such as those from the National Comprehensive Cancer Network,3 patients presenting with neck metastases typically undergo diagnostic procedures including histologic analysis of fine-needle aspirates of the node, followed by tonsillectomy, and random biopsies of mucosal sites, where appropriate. In Germany, standard of care also includes resection of the base of the tongue. If these procedures fail to establish the location of the primary tumor, a diagnosis of CUP syndrome is made followed by a neck dissection of levels I to V.
Lack of information about the location of primary tumors presents the physician with challenges regarding subsequent therapy. Standard radiotherapy for CUP involves treatment of the nasopharynx, oropharynx, and neck; if malignant adenopathy is centered in level III/IV, the hypopharynx and larynx should be irradiated, but the oral cavity is not generally irradiated unless submandibular lymphadenopathy is present.4 Some institutions irradiate the neck only.3 Complications associated with extensive irradiation include acute and chronic mucositis and xerostomia; skin reaction; subcutaneous fibrosis; and lymphedema of the neck or laryngeal edema. Chemotherapy may be used with radiotherapy, in particular when extracapsular spread is evident.[4], [5] Widespread irradiation can, however, result in excessive long-term toxicities.6
A link has been established between human papillomavirus (HPV) infection and various cancers, in particular cervical and oropharyngeal cancers, where 70% and 38%, respectively, of cases are estimated to be linked to HPV infection.[7], [8] Studies suggest that the presence of HPV in cervical lymph nodes is strongly associated with tumors originating in the oropharynx, although none of these studies have been conducted in a true CUP population. Begum et al. analyzed 77 aspirates from neck metastases of patients with squamous cell carcinoma of the head and neck (SCCHN), the primary site of which was known in 67 cases.9 HPV16 was detected in 13 aspirates including aspirates from 10 of 19 oropharyngeal metastases and 3 of 10 cases where the primary site was never diagnosed. HPV was not observed in any metastases from non-oropharyngeal sites. El-Mofty et al. demonstrated the reliability of using HPV status to predict the primary site in patients with cervical lymph node metastases, although this was known in the majority of patients.10 In contrast, however, Desai et al. reported a broad distribution of primary locations for HPV DNA-positive metastases including the oral cavity, skin, oropharynx, and tonsils, among others, in their study of 43 patient samples.11 Although the site of the primary tumor was known for the majority of the samples, the researchers were blinded to this information.
This retrospective analysis was initiated to assess the incidence of HPV involvement and survival outcomes in a large population of patients presenting with neck metastases with true CUP syndrome. The HPV DNA status of a lymph node metastasis is likely to be representative of the tumor, as demonstrated by Hoffmann et al.,12 therefore establishing whether a metastasis is HPV DNA-positive or -negative provides useful information regarding the primary tumor site, even if the latter cannot be identified.
Section snippets
Patients and methods
A search of the multidisciplinary cancer center registry at the Department of Otorhinolaryngology, Head and Neck Surgery, at the University Medical Center Hamburg-Eppendorf (UKE), Germany, and the Department of Otorhinolaryngology, Head and Neck Surgery of the Christian-Albrechts-University of Kiel, Germany, identified patients who presented with squamous cell carcinoma metastases and CUP syndrome between 2002 and 2011. All patients underwent diagnostic procedures starting with examination
Patients
Sixty-three patients fulfilled the study inclusion criteria: 28 were treated at the UKE and 35 at the University of Kiel. The median follow-up was 23.0 months for all patients, 15 months (range 1–105 months) for UKE patients and 32.0 months (range 1–103 months) for those recruited in Kiel. Patient characteristics are summarized in Table 1. Men outnumbered women by a factor of 3:1, which is similar to the 3.5:1 ratio observed for patients with oropharyngeal cancer in Germany.23 The majority of
Discussion
Treatment for patients with CUP of the head and neck is an unaddressed challenge for physicians. A primary squamous cell carcinoma in the head and neck was identified subsequently in only 6% of patients in this study. Therefore with the inability to identify the primary tumor, and in the absence of guidelines for radiotherapy planning on the basis of nodal metastases, treatment usually targets all mucosal sites from the nasopharynx to the larynx and therefore many patients are overtreated and
Conflict of interest statement
None declared.
References (48)
- et al.
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) - et al.
ESMO Guidelines Working Group. Cancers of unknown primary site: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010) - et al.
Efficacy and toxicity of chemoradiotherapy using intensity-modulated radiotherapy for unknown primary of head and neck
Int J Radiat Oncol Biol Phys
(2011) - et al.
HPV in oral squamous cell carcinoma vs head and neck squamous cell carcinoma biopsies: a meta-analysis (1988–2007)
Ann Oncol
(2008) - 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) - et al.
Detection of primary sites in unknown primary tumors using FDG-PET or FDG-PET/CT
BMC Res Notes
(2011) - et al.
PCR detection of human papillomavirus of the mucosa: comparison between MY09/11 and GP5+/6+ primer sets
J Clin Virol
(2004) - et al.
HPV DNA, E6(∗)I-mRNA expression and p16(INK4A) immunohistochemistry in head and neck cancer − how valid is p16(INK4A) as surrogate marker?
Cancer Lett
(2012) - et al.
Postoperative radiotherapy in head and neck carcinoma with extracapsular lymph node extension and/or positive resection margins: a comparative study
Int J Radiat Oncol Biol Phys
(1992) - et al.
HPV-associated head and neck cancer: a virus-related cancer epidemic
Lancet Oncol
(2010)
Diagnosis of nasopharyngeal carcinoma by DNA amplification of tissue obtained by fine-needle aspiration
N Engl J Med
Management of the neck and unknown primary of the head and neck
Human papillomavirus type distribution in invasive cervical cancer and high-grade cervical lesions: a meta-analysis update
Int J Cancer
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
Histologic identification of human papillomavirus (HPV)-related squamous cell carcinoma in cervical lymph nodes: a reliable predictor of the site of an occult head and neck primary carcinoma
Head Neck Pathol
HPV16 DNA in histologically confirmed tumour-free neck lymph nodes of head and neck cancers
Anticancer Res
Prospective study of 18FDG-PET in the detection and management of patients with lymph node metastases to the neck from an unknown primary tumor. Results from the DAHANCA-13 study
Head Neck
Clinical applications of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in carcinoma of unknown primary
Chin Med J (Engl)
Clinical utility of PET/CT in the evaluation of head and neck squamous cell carcinoma with an unknown primary: a prospective clinical trial
Head Neck
Lymph node metastasis of squamous cell carcinoma from an unknown primary in the upper and middle neck: impact of 18F-fluorodeoxyglucose positron emission tomography/computed tomography
Cancer Biother Rad
Enzymatic amplification of beta-globin genomic sequences and restriction site analysis for the diagnosis of sickle cell anemia
Science
Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: report of the BIOMED-2 Concerted Action BMH4-CT98-3936
Leukemia
Cited by (67)
HPV and Oropharyngeal Cancer in the Eighth Edition of the TNM Classification: Pitfalls in Practice
2019, Translational OncologyCitation Excerpt :Based on differences between woman and men concerning HPV infection latencies, infection rates, HPV uptake according to lifetime sexual partners, and others, it might be assumed that there is a major difference in immunocompetence between women and men (detailed information on HPV infection in men is given in references 29 to 31): HPV infection of the cervix is cleared without any treatment by about 75% of women, and only 25% develop a permanent infection. These phenomena have not been described in the mucosa of the aerodigestive tract where it has been repeatedly shown that, in the head and neck, there is no detectable HPV in the mucosa without a lesion (29,30) and vice versa, and that the presence of HPV in mucosa of the head and neck region is detected only when lesions are present (2,8–11,30,31). Due to the latter, studies observing the course of latent infections in mucosae of the head and neck are not feasible.
Cystic masses of the lateral neck – Proposition of an algorithm for increased treatment efficiency
2018, Journal of Cranio-Maxillofacial SurgeryA comparison between p16-positive head and neck cancer of unknown primary (HPV-HNCUP) and oropharyngeal squamous cell carcinoma (HPV-OPSCC): are they the same disease?
2023, European Archives of Oto-Rhino-Laryngology